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CANCER

1Division of Biological Sciences, and Department of Computer Science, Department ofMathematical Sciences, University of Montana, Missoula, MT 59812, USA. 2CellSignaling Technology, Danvers, MA 01923, USA. 3Department of PharmacologicalSciences, Mount Sinai Center for Bioinformatics, BD2K-LINCS (Big Data to KnowledgeLibrary of Integrated Network-based Cellular Signatures) Data Coordination and Inte-gration Center, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA.*Corresponding author. Email: mark.grimes@mso.umt.edu

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Integration of protein phosphorylation, acetylation,and methylation data sets to outline lung cancersignaling networksMark Grimes,1* Benjamin Hall,2 Lauren Foltz,1 Tyler Levy,2 Klarisa Rikova,2 Jeremiah Gaiser,1

William Cook,1 Ekaterina Smirnova,1 Travis Wheeler,1 Neil R. Clark,3 Alexander Lachmann,3

Bin Zhang,2 Peter Hornbeck,2 Avi Ma’ayan,3 Michael Comb2

Protein posttranslational modifications (PTMs) have typically been studied independently, yet many proteins aremodified bymore than one PTM type, and cell signaling pathways somehow integrate this information.We coupledimmunoprecipitation using PTM-specific antibodies with tandem mass tag (TMT) mass spectrometry to simulta-neously examine phosphorylation, methylation, and acetylation in 45 lung cancer cell lines compared to normallung tissue and to cell lines treated with anticancer drugs. This simultaneous, large-scale, integrative analysis ofthese PTMs using a cluster-filtered network (CFN) approach revealed that cell signaling pathways were outlinedby clustering patterns in PTMs.Weused the t-distributed stochastic neighbor embedding (t-SNE)method to identifyPTM clusters and then integrated each with known protein-protein interactions (PPIs) to elucidate functional cellsignaling pathways. The CFN identified known and previously unknown cell signaling pathways in lung cancer cellsthat were not present in normal lung epithelial tissue. In various proteins modified by more than one type of PTM,the incidence of those PTMs exhibited inverse relationships, suggesting that molecular exclusive “OR” gates deter-mine a large number of signal transduction events.We also showed that the acetyltransferase EP300 appears to be ahub in the networkof pathways involvingdifferent PTMs. In addition, the data shed light on themechanismof actionof geldanamycin, an HSP90 inhibitor. Together, the findings reveal that cell signaling pathways mediated by acet-ylation, methylation, and phosphorylation regulate the cytoskeleton, membrane traffic, and RNA binding protein–mediated control of gene expression.

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INTRODUCTIONProteins covalently attachmoieties such as phosphate,methyl, and ace-tyl groups to other proteins to regulate cell signaling events crucial forall cellular physiological functions, including differentiation, prolifera-tion, cell movement, and cell death. Inmany human diseases, these cellsignaling mechanisms go awry (1). Much progress has been made inidentifying proteins that attach (writers), recognize (readers), and re-move (erasers) different posttranslational modifications (PTMs) (2),and our understanding of these mechanisms has led to the develop-ment of targeted therapeutics, such as cancer treatments that target ki-nases (3), histone deacetylases (HDACs) (4), and bromodomains,which are the associated structures of readers of acetylation (5, 6).

The canonical view of PTMs is that protein acetylation and meth-ylation are mainly involved in epigenetic chromatin modifications,whereas signal transduction pathways are mainly regulated via phos-phorylation. This view dominated the field mainly because differentmodification types have been typically studied independently.However,there is now increasing appreciation that histones are not the only classof proteins affected by acetylation andmethylation (4, 7). Thismeans thatdrugs targeting enzymes responsible for regulatingmethylation and acet-ylation of histonesmay have amuch broader effect. It is therefore impor-tant to understand in detail molecular signaling pathways that involvethese PTMs. In addition, further understanding of cell signaling path-

ways will provide new opportunities for therapeutic intervention. Forexample, multiple PTMs are involved in signaling cascades that arelinked to neurological disorders (8) and the innate immune response (9).

Here, we sought to understand molecular signaling pathways thatare active in lung tumor–derived cell lines by simultaneously examiningpatterns of protein phosphorylation, methylation, and acetylation on alarge scale. The data we collected provide a unique opportunity for anintegrated study of cell signaling networks involving these three differ-ent PTMs. Our goal is to define the relationship between kinases, phos-phatases, acetyltransferases, deacetylases, methyltransferases, anddemethylases. Our approach was to integrate two different kinds ofinformation: clustering based on statistical relationships among varioustypes of PTMs and protein-protein interaction data from public data-bases (10).

The sequencing of the human genome provided a parts list of manyof the molecular constituents that make up the human cell, but we stillhave a limited understanding about how these parts interact and areorganized into functional complexes to regulate the cell signaling path-ways that govern molecular biological processes. Protein-protein inter-action (PPI) databases attempt to catalog how proteins interact withone another and how these interactions are organized into networks(11–16). Networks are useful to model signal transduction pathways(17–22), but these models are difficult to understand and validate be-cause such models are complex, integrate information from a variety ofsources, and commonly are not specific to a particular tissue or cell typein the proper context. They also suffer from biases, such as literaturefocus biases or experimental platform biases. Here, we hypothesizedthat empirical information about PTMs may be used to constrain thecomplexity of cell signalingmodels to better understand the system un-der study (10, 23).We reasoned that clustering of PTMs under different

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conditions reveals patterns specific to the system, in this case lung can-cer cell lines. Clusters identified by statistical relationships that containproteins known to interact likely represent functional cell signalingpathways. This data-drivenmodeling approach (24) is somewhat anal-ogous to using gene coexpression data to identify cell signaling path-ways in yeast (25). However, PTMs are much closer to cell signalingevents than mRNA coexpression, which makes our approach morelikely to identify cell signaling events upstream of gene expressionchanges (10).

We used immunoprecipitation with antibodies specific for tyrosineand serine/threonine phosphorylation, lysine acetylation, and lysineand arginine methylation, coupled with mass spectrometry. This tech-nique was originally described to study only phosphorylated proteins(10, 26–28).Mass spectrometry determines the identity of peptides withmodified residues and the relative amounts of these peptides. Thismethod has a low false-positive rate, but a high false-negative rate. Thisis mainly due to stochastic sampling of peptides for detection and sub-sequent fragmentation (29–33). This limitation of mass spectrometryintroduces two challenges: (i) The resulting data have a large numberof missing values, and (ii) comparing experimental conditions is diffi-cult when peptides are stochastically detected. Tandemmass tag (TMT)experiments surmount the latter issue by labeling samples with differentisotopic mass tags and mixing them, so that when a peptide is selectedby the mass spectrometer, different tags are resolved upon subsequentfragmentation (34). This allows direct comparison of peptide amountsinmultiplexed samples and accurate calculation of treatment-to-controlratios within a TMT multiplex. When comparing two or more TMTruns, however, there is still a large fraction of missing values becauseof the stochastic nature of detection. Therefore, the TMT data are dif-ferent from the gene expression data derived from microarray or RNAsequencing experiments, and thus require special considerations fordata analysis (text S1). Building on previous work (10, 23), we evaluateddifferent methods for handling these data, which can be grouped intothree approaches: imputing missing values, pairwise-complete, and pe-nalized matrix decomposition (PMD). Statistical relationships (Spear-man correlation, Euclidean distance) were embedded into a reduceddimension representation using t-distributed stochastic neighborembedding (t-SNE), which is effective in identifying clusters in a widevariety of nonlinear real-world and biological data (10, 23, 35–38). PMDfollowed by an additional t-SNE step further resolved large clusters toproduce a coclustered correlation network (CCCN) for strongly asso-ciated modifications. This clustering method was used to decipher cellsignaling pathways by filtering PPI edges to retain only interactions be-tween proteins whose modifications coclustered, creating a cluster-filtered network (CFN). The CFN and CCCN data structures werefurther evaluated in a number of ways and then used to outline cellsignaling pathways, starting from the target proteins that are affectedby drugs. The analysis highlights molecular pathways defined by highlycorrelated clusters of PTMs and revealed antagonistic relationshipsamong PTMs that were negatively correlated. Signaling pathways thatare regulated by multiple PTMs involve heat shock, RNA binding, cy-toskeletal, andmembrane trafficking proteins that are linked to canon-ical tyrosine kinase pathways.

RESULTSClustering PTMsOur goal was to use large-scale mass spectrometry data to integrate cellsignaling pathways that involve protein phosphorylation, methylation,

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

and acetylation. We hypothesized that proteins that interact with oneanother and are posttranslationally modified in patterns identified byclose statistical relationships likely represent functional cell signalingpathways. We therefore combined PTM clustering information withPPI databases to create the CFN. The CFN only retained PPIs whosemodifications coclustered (Fig. 1A). Thus, the resulting network onlyretained interactions between proteins that are also supported by pro-tein modification data (10).

PTM data were obtained using immunoprecipitation with anti-bodies that are nonspecific to individual proteins but specific to PTMsand combined with TMT mass spectrometry (Fig. 1B). Forty-five lungcancer cell lines were compared to normal lung tissue in nine multiplexruns. In addition, selected lung cancer cell lines were treated with theanticancer drugs crizotinib, gefitinib, gleevec, and geldanamycin in sixmultiplex runs. Because each experiment represents a different state ofthe lung cancer cell line signaling system, and because combining datafrom different cell lines improves the quality of clustering (10), we com-bined comparison of cell lines to normal lung tissue (8729modifications)and drug-treated cell lines (9321 modifications) into one data matrixcontaining 13,798 unique modifications; 90 samples from 15 indepen-dent experiments (6 samples in each experiment). The combined datamatrix contained 78% missing values because there are a large numberof PTMs that were not detected across differentmultiplex runs.Missingvalues may represent either the absence of PTMs in samples or simplythe lack of data, so we developed approaches to reduce their influenceon data analysis (10, 23).

Because identification of groups of statistically related PTMs fromsparse data sets is challenging, we evaluated different methods to deriveclusters from the statistical relationships between the identified PTMs(described in detail in text S1). We found that the t-SNE method whenused with dissimilarity representations was the most effective at re-solvingmeaningful clusters based on the uniformity and density of eachcluster, and the number of prior knowledge PPIs found among theproteins within the identified clusters (figs. S1 and S2) (10, 23). To usethe PTM data to filter edges in PPI databases (Fig. 1A), we evaluatedanalytical methods that identify PTM clusters whose proteins tend tointeract (figs. S3 and S4). We found that breaking up large clusters(>80 PTMs) by applying PMD, and another round of t-SNE, workedbest for defining clusters that were most justifiable by several criteria(fig. S4).

Well-studied proteins have more interactions within PPI databases.Hence, filtering edges using PTM clustering enriched for interac-tions specific to the lung cancer cell line data and mitigated the biasin PPI databases toward well-studied proteins (figs. S5 and S6).There was a weak correlation between CFN “betweenness,” a measurethat indicates how frequently proteins are found on shortest pathsthrough the network, and the number of PTMs found on each protein(fig. S7). However, the most highly modified proteins were not theproteins that were common tomany paths, that is, had high between-ness. The number of modifications did not always correlate withserving as a hub within cell signaling pathways, although some high-ly modified proteins may act as hubs. We defined the minimumSpearman correlation to be used to delineate edges that represent cor-relations between PTMs (Fig. 1A) by examining the effect on networksize and density (figs. S8 and S9). Finally, using drug responses thataffect known kinase pathways, we determined that binning largeratio values and using log2-transformed data for clustering producedthe best results (fig. S10). This is likely because TMT ratio data con-tain extreme values, which may skew correlation analyses, and it

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can be argued that PTM ratios beyond 100-fold are not functionallydifferent.

Having established an effective method to cluster PTM data derivedfrom TMT mass spectrometry, and having then used these PTMclusters to filter PPI in a CFN that outlines cell signaling pathways inlung cancer cell lines (Fig. 1A), we then defined a threshold for Spear-man correlations between PTMs to display edges in a CCCN (Fig. 1C).

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

The CFN and CCCNnetworks are avail-able for further exploration at https://cynetworkbrowser.umt.edu/.

Pathways in CFNs based ondrug-affected PTMsWe next used these networks to examinepathways from drug targets to proteinswhose PTMs were affected by drug treat-ment, to outline cell signaling pathwaysactive in lung cancer cell lines. We beganwith drugs that directly inhibit receptortyrosine kinases (RTKs).We reasoned thatRTK inhibitors will affect kinase pathwaysand therefore phosphorylation and otherPTMsof substrates anddownstreampath-way effectors. We traced pathways byidentifying shortest paths in theCFN fromknown RTK drug targets to other proteinswhose PTMs changed at least twofoldafter drug treatment. Crizotinib, which in-hibits the RTKs MET [also called c-METor hepatocyte growth factor receptor(HGFR)] and ALK (anaplastic lymphomakinase), inhibited the modification of anumber of proteins that are involved incytoskeletal rearrangements and adhe-sion (Fig. 2A; blue indicates a decrease inPTMs), consistent with the oncogenic roleMET is playing in metastasis (39). Epi-dermal growth factor receptor (EGFR)phosphorylation was also decreased bycrizotinib (Fig. 2A), and the EGFR inhib-itor gefitinib decreased MET phospho-rylation (Fig. 2B), indicating cross-talkbetween these RTKs or possibly off-targeteffects. TheCFNconnections downstreamof MET, ALK, and EGFR linked to thetyrosine kinase LYN, the tyrosine phos-phatase PTPN11 (also known as SHP2),and the adaptor/scaffolding proteinsIRS1 (insulin receptor substrate 1) andCRK (v-crk avian sarcoma virus CT10 on-cogene homolog) (40). These connectionsindicate known interactions supported bythe statistical clustering of PTMs.

In addition to decreases in phospho-rylation of downstream targets, we notedan increase in acetylation of many pro-teins (Fig. 2B, yellow nodes). In a groupof proteins that were both phosphorylatedand acetylated, phosphorylation decreased

and acetylation increased with gefitinib treatment (Fig. 2C). The acet-yltransferase EP300 itself showed increased acetylation with gefitinibtreatment and was linked to HSP90 in the CFN (Fig. 2B). Also presentwas fatty acid synthase, whose activity and expression are controlled byEP300 (41). EP300 and HSP90 had many links in the CFN to proteinsdually modified by both phosphorylation and acetylation (Fig. 2B).Thus, examination of several PTMs in the same experiment revealed

MED1 ack K1113

CAD p S1407

DDX31 rme R828RABL6 p Y726

HIST1H1E ack K168

AGTRAP p Y133

ZNF638 ack K1477

GSTO1 ack K152

NSUN2 ack K586

VDAC1 ack K274

RNPEP ack K446

YWHAE ack K142

SETDB1 kme K1170

SEPT10 ack K104

KIAA0556 p T1164

DLG5 p T718

TUBA1A ack K352

PRKCD p T511

AIFM1 p S249

MPLKIP p T120PLEC p S21

PTRF p Y308

ERRFI1 p S326

LMO7 p S1510

PKP3 p S99

ATXN2L p Y349

MAPK9 p Y185

PPP1CA p Y306RBM27 ack K799MPLKIP rme R117

RPS19 ack K122

NT5DC1 ack K359

PROSER2 rme R414

SPATS2L p S452

PIK3R3 p Y199ARCN1 p Y310

TXNRD1 p Y281

HSPA2 rme R472

FAM83H p S9

PSMB2 rme R93

PDLIM7 rme R103

CSTF2 rme R402

GTF3C1 p S739

EIF4G2 rme R23

PPP1R3F rme R12

RALY rme R141

UBXN7 p S288

CDAN1 rme R134

CAD p S133

PHF3 rme R1915

TOP2A p S1476

KDM1A p S69

HMGN2 ack K11

TRA2B rme R228

ASPM rme R8

ZSWIM8 rme R1454

WIPF2 p S235

DDX23 rme R301

HNRNPUL2 rme R700

DSTYK rme R29CSTF2 rme R468

SCAF11 rme R308

HNRNPL ack K59

CACYBP ack K207

C1orf106 rme R578

KRT4 rme R27

YBX1 rme R239

KIF18B p S681

SRFBP1 ack K423

PKP2 rme R46

MBTD1 ack K115

LMNA p T409

EP300 ack K1583

HELZ2 p T340

WWC3 p S907

CYFIP1 ack K189

MSN ack K83

CNPY2 p S23PPP1R18 rme R23

ALB ack K499

YAP1 p T114

DDX5 ack K32

SYMPK ack K358

CTDP1 rme R865

ARPP19 ack K58; ENSA ack K63

VPS41 p S249

PRRC2C rme R255

ARID1A p S614

THG1L ack K263

SEPT10 p S432

HNRNPC rme R151

SYNCRIP rme R496

NACAP1 ack K141

NCL rme R687

SPAG9 p S254

DYRK3 p S372

PEG10 rme R598

PLEC rme R4640

ATP2B1 p Y220

TPT1 ack K102

ARID1A ack K980

ANKIB1 p S1053

MLF1 p S34PEG10 rme R611POLR1A p S1489

VRK1 kme K5

KHDRBS1 p Y435

KIRREL p Y745

TRA2B p Y235

ZNF827 p S764

FRMD8 rme R217

CIRBP rme R127

SSBP3 p S352

APC p S2290

PIK3R2 p Y460PHYH p Y111ABI1 p Y198

DNAL4 p Y13FAM129B p S601

DOCK5 p T1758

PPP1R9A p Y904

AHNAK2 rme R344 SRRM2 p T1043

MYOF p S729

RPL29 p S66CD2AP p Y361LPP p Y297

CTNND1 p Y228CTNND1 p Y193PVRL2 p S465 CBLB p Y763

KMT2A p S2796

DSC2 p Y853

SVIL p S1322

LMO7 p T818SLC20A2 p T346

PPP1R7 p S44

ACTB ack K215

ARAP3 p Y160THRAP3 rme R71

EPB41L1 p S541

RPS17 p S113

PLEKHA5 p Y398

DLG1 p Y447

CTNND1 p Y302

ATXN2L p T683

PPFIBP2 p Y855

SOS1 p Y1196

DAZAP1 p Y405

STK39 ack K312

FKBP1A ack K36

NCL kme K132

ZC3H13 p S407

GPRC5C p S398

THUMPD1 p S275

BAG4 rme R185

FUS rme R218

HNRNPD rme R282

PRKG1 p T521

ATP1A1 p S653

MAP1B p Y1904

UBR5 rme R977

PGK1 ack K323

ALYREF rme R63DOCK7 ack K1962

ECH1 ack K231KAT6A ack K415

ACTB ack K61TUFM ack K91

HNRNPD ack K243SLC25A6 kme K52

ACAT1 ack K174HIST1H4A ack K16

HIST1H4A p Y51

PRDX3 ack K91QSOX1 p S426

TPI1 ack K225

ALYREF rme R197HNRNPAB rme R322

ALYREF rme R38

FUS rme R242

DDX5 rme R502

HNRNPA1 rme R225 HNRNPA1 rme

R206 HNRNPA1 rme R194

SETDB1 p S1066

VIM p Y30

DIDO1 rme R1835

HNRNPAB ack K101

RBM3 rme R105

SRP14 p Y27

TPR ack K457

TAF15 rme R483

EIF5A ack K68

ILF3 rme R609

POM121 rme R223 EP400 ack K1553

SPR ack K230

NPM1 ack K250SMC3 ack K105

RPL23 ack K13

ATP5O ack K54

ANXA2 ack K169

HIST1H4A ack K91

PKP2 p S172

ACTR3 ack K348

PHB2 p Y248

LIMCH1 p S754

DOCK7 p S1421AKAP8 p S328VDAC3 ack K63

HSPD1 ack K250

GAPDH ack K334PHB2 ack K89

PYCR1 ack K51

LASP1 kme K75

SF1 rme R662

CEP170 p S1205

TPM3 ack K162LSM14B rme R351

DYRK2 p Y382

AKAP8 rme R277

PARP4 rme R1476

VPS37B rme R218

PYGO2 rme R105

CRIP1 rme R68ZNF768 rme R243

WIZ rme R1460

DIDO1 rme R1993

CTTN ack K124

AGR2 ack K165

VDAC1 ack K224

NCOR2 ack K2301

ESRP2 rme R677

PCF11 rme R790

CPSF7 rme R227

TET2 ack K53

HNRNPH1 rme R212

BRD2 ack K345

CLASP2 p S455RBM22 ack K416UBXN1 p S199SLC25A5 kme

K147

SCRIB rme R1623AKAP13 p S1895

FBL rme R78LMO7 rme R915

KMT2D ack K2755

CNBP rme R34PSMA7 ack K52

PPAT ack K81

OGFR p S361

C11orf68 rme R29BPTF rme R2155

FAM208A p S1103

HNRNPA2B1 rme R238

AHCY ack K408

EEF1A1 ack K392

HLTF rme R27

KANK2 rme R117

SART1 p S84

RNF34 p S169

EEF1A1 ack K386

PCM1 p S121

OTUD4 p Y1087

TJP2 p Y1035

YWHAZ p T232RBM3 rme R131

VDAC2 ack K74PPIA ack K155

FASN ack K436PSMA2 ack K92HMGB1 ack K12

NAT10 ack K426

SUPT16H rme R1029

DYRK1A p Y321

UBE2E3 ack K58

AKAP8L rme R171

PDLIM2 ack K282ULK1 p S556

KCT2 p Y263EPHB2 p Y596

DLGAP4 p T718OTUD4 rme R1061

DPF2 p Y172

EIF4H p T201

HIST1H2BK ack K21

MISP p T377

CFL1 p Y89

MYO18A p S132

HIST1H4A ack K12EIF3B p Y525

INPP5D p Y40DGCR14 rme

R415

IRS1 p Y941

IRS1 p Y989

TXNRD1 p Y163

SLC38A10 p T772

ST5 p Y537

ALK p Y1096

GLG1 p S262

ALK p Y1586

SYNJ1 p S1053

ARHGAP21 p S484

EML1 p Y186VIM p Y61

YBX1 p T271

RBM33 rme R1070MERTK p Y929

HNRNPUL2 p Y741

LIMA1 p S55PCNT p T191

NAV1 p S1000

CHMP7 p Y164

CARD6 rme R779

CTR9 p S1106

MAP1B p T1799SQSTM1 p T269

LDHB p S238

SRRM1 p S655

VPS13C ack K3626

CHAMP1 rme R398

HNRNPD rme R345

PABPC1 rme R385CSTF2T rme R396

LDHB ack K318

DHX9 rme R1160

KIN rme R36ADAR rme R91FXR2 rme R432

HNRNPUL2 rme R656

PRR3 rme R99

EZR ack K577SF3B2 rme R515

RANBP2 p S2831KHSRP rme R415

UGDH ack K329

PRRC2A rme R1164

ZNF326 rme R173

EWSR1 rme R300DHX9 rme R1174

TBC1D4 p S1207

CLTC p Y1206

CEP170 p S633SPTAN1 ack

K1784 SMC1A p S358

SGOL2 p S1144RBM10 p S22

BAZ1A ack K1396

PCF11 rme R916

NUMA1 p S1844

FAM76B p S22

CCAR1 p S1091 RANBP2 rme R945

SMARCA5 rme R1044

IRS2 p T520ATP5O p S166

RBM3 p Y127

NNT kme K430HMGA1 p S99

TAGLN p T191

HERC1 p S2706

GNPNAT1 p Y177

PI4KA p S1479

CACTIN p S135

PML rme R872

PPAT ack K372

VPS13C rme R3519

PPP1R10 rme R693

SERBP1 rme R188

SYNRG ack K744

GPSM1 rme R421

LDHA ack K126CIRBP rme R131

EIF4G2 rme R360

CD2BP2 rme R181

XRCC6 ack K544

ALYREF rme R73

SLC30A6 rme R449

TUBB4B ack K216

TP53BP1 rme R1355

FUS rme R481

ATP1A1 ack K54

LYN p Y316

NANS ack K74COL25A1 ack

K511

MUC1 p Y1191

SHMT2 ack K181

GAREM p Y453

LOC113230 rme R81

ENO1 ack K80

ATP5A1 ack K506

TBL1XR1 p S119

NAMPT ack K216

SMARCA5 ack K1036

GFPT2 ack K17FASN ack K1827

NRBP1 ack K131ZBTB4 rme R691

DDAH2 ack K51

HIST1H2AA ack K118 STAT1 ack K379

HNRNPL rme R344

PABPN1 rme R238HDAC5 p S1108

HNRNPA2B1 rme R228

ACTB p Y362

HNRNPUL2 rme R738

SFPQ ack K338

SLC25A5 p Y191

HYOU1 ack K685

TUBB ack K19

EP300 ack K1794RDH11 ack K98

PRDX2 ack K10

MDH2 ack K296

TM9SF3 ack K160

HNRNPA1 rme R336

ZNF326 ack K240

ZNF326 ack K140

ZNF326 rme R200HNRNPK rme

R286

HNRNPUL2 rme R695

RALGAPA2 kme K679

ZNF579 rme R92

EPHB4 p Y590

SFN ack K159

EPHB4 p Y906

CD164 p Y194

MUC1 p Y1212

EGFR p S1166

NANS p Y71

ERRFI1 p Y395

ST5 rme R270ODF3 rme R186

PRPF40A rme R51

EIF4G1 rme R681

SNRPA1 ack K56

MYH9 ack K1370

COPB1 ack K378

CCT5 ack K265

ADAR p S608

MYH9 ack K1052

PLEKHA5 rme R424

ATP5A1 ack K539

CCT8 p Y30

NKD2 p S299

PDCD6IP rme R745 CCT2 ack K154

YARS2 ack K355PPFIBP1 rme R527

SPTAN1 p S1041

TRAPPC1 p S128HNRNPH1 rme R44

ZNF644 kme K582C8orf33 rme R27BCLAF1 p S690ZFP91 kme K174

RTKN rme R14XRN2 ack K641

ANP32A ack K68SUV420H1 ack

K20

HSP90B1 p S64

RBMX p Y260

LMNA p S326

SPTAN1 p S2066

LIMA1 p S61

MORF4L2 rme R35RBMXL1 rme R372

KNOP1 rme R430

BCLAF1 ack K335EIF4G1 rme R110

ZNF622 p S174

BRPF1 p T56

RPL3 ack K136

SON rme R1022TRIM33 rme R440

C19orf53 kme K17 PRDM10 ack K658

CCT8 ack K318RBM3 rme R138

SON rme R1015

RCC2 ack K293

RPL14 ack K85RPL13 rme R74TPR ack K854ACLY ack K540

FUBP3 rme R337

MSI2 rme R197

IRS2 rme R429

TOMM70A rme R71

MFAP1 p S133

RCL p S123

CRTC2 rme R161ACADS ack K306

HADHA ack K60

SPTAN1 p S1226

HSPD1 ack K389

TPM3 ack K249

LMNA p S414

LARP1 rme R334

KIAA1217 p T1633

DIEXF p S10

UGDH p Y352

HNRNPU rme R702

RBMX rme R339

SCEL p T437

LMO7 p T1588

IQSEC2 p S383

NSRP1 p T275HSPB1 ack K141

ATP5A1 rme R204

NARR rme R24

EIF4G1 ack K535TOX4 rme R442EIF4G1 rme R1032

MYH9 ack K1372

BAG4 rme R53

BAG4 rme R40

HNRNPH3 rme R110

UGDH p Y199

HNRNPA3 rme R226

PKM ack K393

MYH9 ack K30

PPFIBP1 p Y336

PCF11 p S1406

CIRBP rme R145

FUS ack K510

RFX5 rme R354

CIRBP rme R154

WDR33 rme R915

TPX2 p T499

UGDH ack K355

CBARP p Y306

EHHADH p S189CDK1 ack K33

GPRC5C p Y324

SF3B1 ack K430

EIF4H rme R170

SLC25A3 ack K234 ABCF3 p S83

CNN3 kme K158VIM p S459

PHF2 p S899

ANKHD1 rme R1840

CDK2 p Y15DYNC1I2 p T95

KLC4 p S598

SNX29 p T641

LSM1 p T129

LBR ack K601RBMX rme R258

BCLAF1 p T355RACGAP1 kme

K614 CSTF2 rme R303CHD7 rme R148

PDCD5 p Y80 URI1 p S372

USP36 p S952

SF3B1 p T303

RASA1 p Y460

EIF4B p Y211

LAD1 p T19

RUVBL2 p Y215TPX2 p T147

EPB41L3 p T462

POGZ p S1013SQSTM1 p S370POP1 p S584NOP2 p S807

DHX9 rme R1219FUS rme R377

PAPOLA p S550

TXNRD1 kme K150

NDE1 p T246MISP p S395

SPTAN1 ack K871RPRD2 p S965HSD17B4 p S309MAP1B p Y1905IRX5 p S464

AFAP1 p S668

MFF p S146ATP5L ack K54

GNPAT p T16

CCT2 p T261FAM120A p S510

ERCC5 p S382

CNOT11 rme R41

ADAR p S217

KHDRBS1 rme R310

VIM rme R45

ITSN1 p S687

MCM3 p T255

LASP1 p S150

RPS8 p T45CAV2 p Y27FHL3 p T193

CDK13 p S867

PLEC p T3152DISP2 p S1175

INADL p T458

BAZ2B p T740USO1 p S799GBAS p T70

PRKCSH p S434GPBP1L1 p S49CCDC9 p T286

CCAR1 p T629

RPS10 rme R153

SYPL1 p S249ZMYM4 p S1096

PFDN6 p S92

TRIP11 p S1376

LGALS3BP p S428

ATG16L1 p S278

DDX42 p Y707

CLTC p Y1096

COX7C p T63NAA50 p S66HSP90B1 p Y677

YTHDF2 p S508

EIF4B rme R297

KIF23 p S911

SLC25A3 p T199PRKG1 p T517

URB2 p S1140CHAMP1 p S405

TPM3 p T238

WAC p S511

PYGL p T520DDB1 p S331

YWHAZ ack K120

EIF4H rme R136

SRP9 p S67

DBNL p Y224

TNS4 p T347

HNRNPUL2 rme R693

CTPS1 p Y473

ADAR rme R26

AFP p S408

EWSR1 ack K439

SRSF5 rme R73

EMD p Y161

DBNL ack K280

DUT ack K251

YBX1 rme R142

CC2D1A rme R13

PRKCD p S664

NPM1 ack K154

PLEKHA2 p S182

SGK223 p S270

KMT2B rme R217

RTF1 kme K587

GORASP2 p S441RPLP2 p S64

LMNA p T19

IRS1 p S277

NUMA1 p S1228

LASP1 p T68

PI4KA p Y1154

EPB41 p Y660

ZNF185 p S519

CTNND1 p Y280

PRKDC kme K2694

UGP2 p S13

DDX17 ack K547KRT13 rme R27

SLC12A8 p T485

AHNAK ack K2299HNRNPA2B1 p Y336

LMO7 p S1197

COG5 rme R309

FLVCR1 p T69EIF2B4 p T86

SPEN p T1140DCP1A p T531

TAGLN2 p T180ZC3HAV1 p T393FNBP4 p T479

PSEN1 p T354PPP1R18 p T199

ERCC5 p S384RANBP2 p T1396

TANK p T213

RBMX p S208

PHLDA2 p S42FZD6 p T607KANK1 p T1334

TCOF1 p T974PACS1 p T504TCOF1 p T1358

AXIN1 p T60

NPM1 p S218

ZCCHC6 p T64

ALB ack K219

EIF3C p T911MFF p Y148

NCOR2 rme R1765

SUN2 p S12HBB p T39

CAMK2D p T287

ANK1 p S1686

ALB ack K598

HBA2 ack K140PRDX2 ack K29LAT p S224

ASPN ack K137

APCS ack K162FGD5 p S744

ZRANB2 p S120

CA1 ack K157

ALB ack K161

ALB ack K223

BGN ack K219

CLU ack K123

HBB ack K60

PRELP ack K277

CAST ack K43

HSP90AB1 p Y484QKI rme R242

COPA p S402PRRC2B rme

R1297

CTAGE5 rme R751

TPR rme R2163

HNRNPL kme K34

SNRPB rme R147DDX24 ack K17

POLR3B kme K1013

MARCKS ack K172

SPEN rme R3038

FBRSL1 rme R491PEF1 p Y133

HNRNPH1 p Y266

SYNCRIP p Y474TUBA1B p Y210NIPBL ack K907PLIN3 ack K257

CCDC59 ack K68

ST13 ack K364PTPN23 rme R1615

PCF11 rme R805

HNRNPUL2 p Y698

NCOR2 ack K1281

FAM120A rme R873

EIF4G2 rme R460

POGZ ack K871

UTP14A ack K304

EIF4B p S497

ARFGAP2 p T350

FUS rme R503

NCOR2 rme R1647

FNBP1L p Y291

IDH1 ack K81

RALGAPA1 p S740

DDX1 p Y628CNN2 p Y184

S100A4 ack K48

EIF4B p Y241

SRRT ack K720

TFIP11 ack K86S100A2 ack K27

TRMT1 rme R562

KRT8 rme R18

RBM12B p S839POGZ p S1364

NUMA1 p S1887KRT19 rme R51

ALDOA p S336RBM3 rme R99

AVL9 rme R588

FAM120A p Y431

BTF3 rme R13RSRC2 p S104

BAIAP2 p S336

PTPN6 p Y541

CRIP1 ack K77

HGS p T287

CCDC117 rme R60

RPS13 ack K39

PKM ack K422

MTHFD1 p T35

KHSRP ack K109

HSD17B4 ack K46

CBLL1 ack K29

EIF3L ack K465

NOP2 ack K91

DHX16 ack K210

NAV1 p S701BAG3 p T242

MERTK p Y754TMEM106C p Y40EDF1 ack K42

SLC25A5 ack K33

PKP3 p S95BRCA1 ack K1079

CNBP rme R25

EEF1A1 ack K330

LDHB p Y240

HABP4 rme R70

BCAR3 p S363

CNN2 rme R187

SERINC5 p Y345

RBM14 p Y645

CLDN3 p Y198

LURAP1L p Y227

G6PD ack K97

ANXA5 p Y94

EZR p Y270

TPI1 ack K43

CD46 p Y321

CHAMP1 ack K617

ZC3H14 ack K728

RBM4 p Y355UGDH p Y473ROCK2 p Y722

LDHA p Y10

PSMA2 p Y24RIN2 p Y77GARS p Y467

PDXDC1 p Y677EEF1A1 kme K79ESYT2 p Y824NUP98 kme

K1128

ACOT9 ack K292

FASN p S1174

SAFB ack K805

HSP90AB1 p Y155

HIST1H2BK p Y43

CANX ack K233

CENPT p T85

H2AFX p S139

EHHADH ack K280

SQRDL ack K372

LEMD2 p Y122

PTPRK p Y858

ENO1 p Y44

EPN2 p S182

MPP5 p Y528RAB13 p Y5

LPP p Y307

PTTG1IP p Y165

ANXA2 p Y238

SNRNP70 rme R201

SRSF1 p Y189

NUDT21 ack K23TAF15 rme R431

RPS29 ack K13DDX17 rme R100

NUDT21 rme R15

XRN2 rme R883SAFB2 rme R835

EZH1 kme K736

FLNB ack K476PLEKHA6 rme R445 SLTM ack K746

PKM ack K311MISP rme R6TPR rme R2327

GSTP1 ack K189

NPM1 ack K27

HNRNPA0 p Y145

CREBBP ack K1741ATRX p S84

CGN rme R188

HNRNPA3 rme R354 HNRNPA0 rme

R189

RBMX rme R172KHSRP rme R442

NBN ack K544

HNRNPA2B1 rme R350

LAS1L p S560

HNRNPA2B1 rme R325

HNRNPA2B1 p Y234

HNRNPA2B1 rme R203

DDX17 rme R684

TCERG1 rme R20

PSPC1 rme R507

ALB rme R281HNRNPU p Y260

ENO1 ack K326

KMT2D kme K4470

NUP133 rme R61

HSPA8 ack K348

SPTBN1 ack K1478 SMYD5 ack K212FLNB ack K2342

SFPQ rme R693TPR ack K748

SFPQ rme R706SIRT6 p T294

CPSF6 rme R194EEF2 kme K407XRN2 rme R946

RPS12 ack K84SNRPD3 rme R118

CIRBP p S148

KIAA1598 ack K51

COTL1 ack K75

FUS ack K332

RBM33 rme R1078

ANXA2 ack K204

UGDH ack K339

TAF15 rme R459

HNRNPUL2 rme R684 FLII p S436

PPP1R12A p S507HNRNPA2B1 rme

R266

SERBP1 rme R181

KRT8 rme R47HSPA8 rme R469TRIM33 rme R515

PELP1 p S1033PIK3C3 kme K287

ATAD2 p S1302DLD ack K420LSM14A rme R269

GAPDH ack K194PRPF4B p Y849

LARP4B rme R493

POGZ rme R238

HNRNPA2B1 rme R213

CTTN ack K235PRRC2A rme

R1012

PRRC2A p S619

XRN2 rme R933

ALB ack K229EPS8 p S685

RPL36A kme K53

MLLT4 p S1799

ATP5H ack K149

GPS1 p S474DYNC1LI2 rme

R397 HYPK ack K35

HSPA1B rme R469

KRT19 rme R43

UFM1 rme R15

LMNA ack K270TNKS1BP1 p

S1620 H3F3A kme K27RBM14 p S623

LSM14A p S178MYH9 ack K1445TALDO1 ack K314PKM ack K266

STAT3 p Y705

HNRNPD rme R272

PRRC2C p Y1218KRT7 rme R25

KIF14 p S1292FMR1 rme R474

UFL1 rme R433RBM47 rme R405HNRNPAB rme

R245 PNN rme R54

TBC1D4 p S588

PDXDC1 p S779ATXN2 rme R640

SMG1 p S3556MYOF p S731

EWSR1 rme R471

MYO9A p S1733

HNRNPH1 rme R233

SFPQ rme R681

GAPDH ack K227

HNRNPH3 rme R323

WDR36 rme R800FMR1 rme R471

EEF1G ack K220

CHTF8 rme R225L3MBTL3 p S608

AKAP8 rme R188PPIG p T358

CEP250 p S2229

SARG kme K252

LDHA ack K5

KRT8 p Y25FGFRL1 p Y502

HSPD1 p Y243

CHAMP1 rme R778

KRT8 ack K285TRIM25 p Y278

SPTBN1 p Y1171

SEC31A rme R411

UMPS p Y37

FRS2 p Y471RBM47 p Y283

SMCR8 p S498PSMA2 p Y101

ZNF638 ack K1430

PAK4 p S474

EWSR1 rme R615

RPS8 p Y117

HNRNPD ack K110ATIC p Y104

CIRBP rme R139

SNRPB p Y15; SNRPN p Y15

SLC19A1 p S225

ZNF638 p T483

BAIAP2L1 p Y163RNF26 p T327MVP p Y772

EPS15L1 p Y74

BRD4 ack K694

ARHGEF40 p Y242

PKP2 p Y119

RBMXL1 rme R91

FASN ack K2354

FASN ack K70

TP53BP1 ack K1360

GOT1 p Y71

FASN ack K2471

PDCD6IP ack K350

KHDRBS1 rme R289

LARP7 ack K431

HNRNPK rme R326

KCMF1 rme R149DYNLL1 ack K49RPS11 p Y92

HNRNPU rme R768

MAP2K1 p S218HBB ack K96

HBA2 ack K91

COL6A3 ack K1772

COL4A1 ack K1496

ALB ack K286

MAP2K4 p S257

RBM14 p Y576

TSEN34 rme R38

CDK11B ack K120

SPATS2L p S455

HNRNPA1 rme R370

CHD8 p T2050

HIST1H2AA ack K36

AGFG1 ack K326

EIF3E ack K425

TRAP1 ack K96

ASXL2 rme R607CNN3 ack K23GLIS3 rme R21BZW2 ack K24

LSM4 rme R90EIF3L ack K549

NCOA3 ack K620RBM15B rme R210

DNAJA1 ack K44

FASN ack K2438UPF1 rme R1019

NARR rme R125

RLIM rme R360PHIP rme R1804

SRSF2 rme R55

RPL31 ack K39

PLEC ack K1626

VIM p S56

AHNAK kme K1333

FXYD3 p T76

ALB ack K97

MFAP4 ack K100

HNRNPUL1 rme R173

RPL7A ack K97KIAA1671 p Y733

RBMXL1 rme R164FLNB ack K65

PLEKHA6 rme R326

TAF15 rme R584

UPF1 p S1107

TP53BP1 p T1214

STAU1 rme R108

SSB p T389

NCAPG kme K995NDNL2 p S60

EIF4B p S131

GTSE1 p S245

SUPT5H p Y787RB1CC1 p T646TOMM34 p S186

RBMX rme R101

FXR2 rme R399

KIAA1429 rme R1723

DOCK1 p S1743NCL rme R561

CALM3 kme K116

UIMC1 p S171

VIM rme R64

CHD8 p S2046

AHDC1 rme R891

CIRBP rme R121

TP53BP1 p S1216ATXN2 p S669

BCL9 rme R1254KHDRBS1 rme

R282

HNRNPA3 p Y188

FXR2 p S620

ARID1A rme R1276

STIM1 p S512PHAX p S364

AHNAK p S216

NEBL rme R96

IQSEC1 p S180KRT7 rme R13NEBL rme R795

RHBDF1 p S390TNKS1BP1 p

S1248 TUBB ack K379

ZNF652 p S197FLNA p S2158

KRT4 rme R56SH3KBP1 p S165RHEB p S175

AHNAK kme K2194

PSMD2 p S363

DMXL2 p S434

GPRC5C p S431

HADHA ack K735

TP53BP1 p S1219

CAMK2G p T287TNKS1BP1 p S1545

MBOAT2 p T474

TCEAL3 p S65

KCTD21 p S43KANK2 p S540

PPIL2 ack K482

RPRD2 p T517

SMARCC1 ack K854

RBM3 p S120

EIF2A p T512

LMNA rme R644WDR33 ack K46

DDX5 ack K501

RALY p T286

ALDH3A1 p S446

UBAP2 rme R166TAF15 rme R206

PTPN11 p Y584

GATAD2A rme R539

DSP p Y95

FIP1L1 ack K294

CHTF8 rme R494HNRNPA3 rme

R286 PABPC4 rme R509

NCOA2 ack K780

THOC5 ack K24ZFR ack K509

RBM27 rme R943

HCFC1 rme R524HCFC1 rme R855NCOR2 rme R1737 KRT7 rme R46

ARHGAP21 rme R574

SNX3 rme R43PABPC1 rme R419

GIGYF2 rme R149

SON rme R950

GAPDH ack K117PABPC4 rme R518MEF2D p S446NPM1 ack K229

HNRNPA0 rme R284

G3BP1 rme R435

RBFOX2 rme R297

RPS10 rme R119

ZC3H14 p S620YLPM1 rme R636GATAD2A rme

R293 PRRC2C rme R242

TARDBP rme R293

PRRC2C rme R2719

AIMP2 rme R26XRN2 rme R895

RBM27 rme R455

DNTTIP2 p T433

DAZAP1 rme R253

TPR rme R2111

AKAP8L rme R179SERBP1 rme R201

NCOR2 p S1181

DDX42 rme R12

BCL9L rme R680BAG3 p T285

HSPA9 rme R513

FAM195A rme R65

ILF2 rme R16

HNRNPA1 ack K52

EIF4G1 rme R694

SLTM rme R1017

KRT7 rme R77

OTUD4 rme R1050

G3BP2 rme R457MPLKIP rme R57HCFC1 rme R1219

TJP2 rme R1176

TMEM214 rme R29

BYSL rme R8 XRN2 p S455

CYSTM1 p Y64

NCL rme R656SRRM2 rme R2288

NCOR2 rme R1661

FOXK1 rme R161

BAG4 rme R108

SNRPA rme R152

PRDX2 p Y126

BTF3 rme R19STAU2 rme R131

CSTF2T rme R311

CHTF8 rme R172

BTF3 kme K46

PKP2 p Y166

NCOR2 p S1566

EIF4B p Y321

RBFOX2 rme R381

HNRNPL rme R343EP400 rme R1643

TSSC4 rme R240

SIRT6 p S338

PMM2 ack K202HMGCS1 ack K239TMED9 ack K160

ACTR2 ack K219ACTN4 ack K899

VPS35 ack K515ANP32E ack K68

NCL ack K95

CTNNB1 p Y716PYGO2 rme R130CLCN7 p S801 RUNX1 rme R319

ABL2 p Y231

PDIA4 ack K616HSPA5 ack K96DSTN ack K132

ERP29 ack K54FKBP3 ack K110

SPTBN1 ack K1913 SPTAN1 ack

K1274 NCKAP1 ack K63DHX9 ack K392

ARF1 ack K142TKT ack K102TRIM25 ack K273

KMT2C ack K2809

SSB ack K216TPM3 ack K169

COPA ack K517VDAC2 ack K120

IDH1 p S237

IQGAP1 ack K1174 HDLBP ack K536

PYGB p Y186

ANXA5 ack K76

HCFC1 rme R1244

ACSL3 ack K673

ACTN4 ack K214

PCID2 ack K133KRT8 ack K295

SCP2 ack K462PDIA3 ack K289TALDO1 ack K225TUBA1B ack K60

HMGB1 ack K43PDIA4 ack K335

UBE2N ack K94

LIG3 ack K907

PYGB rme R29

HNRNPM p S136

YWHAQ ack K212

SPEN rme R3027

SCP2 ack K432

HNRNPC p Y137ACTN4 ack K853

FAM103A1 rme R57 CBX8 ack K240

UBE2N ack K82ACTN4 ack K432

HSPA6 ack K350EP400 ack K2811

DOK1 p Y449

LPP p Y301

BCLAF1 p S259

S100A6 ack K47

MYOF p T1781MPP5 p Y243

SF3B1 p S308TP53BP1 p S1068

RASAL2 p S736CNN3 p Y261

KIAA0556 p T1175

HEXIM2 p T46

SARG p T92ALDOA p Y5

OAS3 p T365

MPP5 p S245

LYN p Y32

ZNF185 p T289

PDLIM2 p T257

SMC1A p T366

PAIP1 p T390PTK2 p Y397PRPF4B p T847GAB1 p Y259

LYN p Y508 EIF2A p S517FAM117B p T396FRMD8 p S408

TXNRD1 p Y302

G6PD ack K432

TST ack K24

RPS21 ack K16

HECTD1 p S1945

PCNP ack K89

C11orf58 ack K174

DCAF6 rme R364ADAR rme R114

NCL ack K70

ORC2 ack K105

KHDRBS1 rme R4

PTGES3 p S148

RANBP1 ack K154

P4HB ack K283

MTHFD1 ack K71

PSAT1 ack K117

XRCC6 ack K287

LMNA ack K417

SNRNP70 ack K162

EIF4B ack K223

TRIM28 ack K340

DTYMK ack K25

AHCY ack K188

EEF1A1 ack K450

LMNA p T224

HSP90AA1 ack K446

PYGB p Y52UGDH ack K264

PROSER2 rme R369

NAV2 p S311S100A6 kme K47

PYGB ack K521

RNF25 rme R422

TRA2B p Y226DLG5 p Y429TDRD3 rme R245

RBMY1A1 p T19GNPNAT1 ack K167

EI24 p S47

C10orf54 p S235

TMSB4X ack K4

NARS p Y539

PPFIBP1 p T603

EZR ack K253

SRCIN1 p Y268

BCAR1 p Y128

BRPF1 ack K896

DDX5 p Y202

LMNA ack K260

GAB2 p Y324

WIZ kme K1139

NFKBIL1 rme R291

CALR ack K286

ANKRD50 p S527

FASN ack K1704YARS ack K146CLIC5 ack K333;

CLIC6 ack K629

ZDHHC20 p Y312

NEDD9 p Y166IL6ST p Y915

ATG2B p S255DDX5 ack K33

CAMK2A p T286

SCFD1 p S637

G6PD p Y249

EEF1A1 kme K165

EIF3L p Y36

CIRBP p S146POR ack K291

AFF4 p S836

YWHAZ ack K74HSPA9 ack K653

G6PD ack K508

HSP90AB1 p Y56

PHF14 p Y886

PSMA3 p S250S100A11 ack K23

PLEKHA2 p T188

HNRNPU ack K543

WHSC1 kme K1207

PRKDC ack K3241FBN1 ack K666RPA1 kme K163TUBA1A ack K311

EPB41L4B rme R24

RACGAP1 p T580ZNF609 p S576GNB2L1 ack K130

NKX2-1 rme R127

TTC28 p S2398HNRNPAB rme R248

KMT2C p T2305TUBA4A ack K352ADRM1 p S211MARK3 p S583

MYSM1 p S110

JMJD1C p S652

PLK1S1 p S283FLNB p S1916PANK2 p S203

DPYSL3 p T64

FAM83H p S1125

BBX p T468

FIP1L1 p S559DDX3X rme R110

FAM120A p S513

UTRN p Y3197

LARP4B p T732KANSL1 p S1045

MDC1 p S372SASS6 p S304SPEN p S711

LSM14A p T384

CENPF p S3150TJP3 p S212

ELAC2 p T815 PIKFYVE p T253MSANTD4 p S191

MAST4 p S1449

DLGAP4 p T915

GNB2L1 p T50

AP2A1 p S567

CEP170B p S1179

BMP2KL p T264SORBS2 p S259

HBD ack K96

HSPA12B p T42

TAGLN rme R183

SLC20A2 p Y344

PARD3 p Y719MAP2 kme K1724

ITGA6 p Y1050

ZC3H7A rme R334

HNRNPF rme R218

CSNK1G1 ack K49

KPNB1 ack K191

GAPDH ack K5

HNRNPM rme R496

SFPQ rme R695

PGK1 ack K75PNN rme R63

INF2 p S1227

ACLY p Y682

AHNAK p T218

DYNC1H1 p S1230

LBH p S63

SPTBN1 p S2138

EPHA2 p S897

ELMSAN1 p S461PDIA4 ack K211

EEF1G ack K401

TAGLN2 rme R182

NME3 kme K29CUL1 rme R63

RBMX rme R298SON rme R964

SUMO2 ack K42

WASL rme R307

HNRNPD ack K129PSMC6 ack K206RBMX rme R164CCDC9 rme R102

ENO1 ack K406ELAVL1 rme R217

CCT4 ack K213

PKP2 rme R125HSP90AB1 ack

K204 SEC22B ack K43

PYCR1 ack K215

RBM15B rme R95

FAM103A1 rme R112

HSP90AA1 p S453

DDX5 rme R14AKT1S1 rme R51

HNRNPAB ack K215

UBE2K kme K18PEX6 rme R161

DDX17 rme R94RBM10 rme R902

CPNE1 ack K171

HSP90B1 ack K597

KIF23 p S943

PYGB ack K316

PSMC6 p Y207

PYGB p Y76

SERBP1 rme R160

HSPA9 p Y128

HMGB1 ack K128

NCOR2 p Y1378

SMC1A p S957

EIF4G1 rme R675

MDH2 ack K157

HADHA ack K353

HADHA ack K214

HADHA ack K326SSB ack K354

BAD rme R161DHX9 ack K16

PRDX1 ack K35

RRP12 p S1284

FASN ack K2186

PATL1 rme R385

ALDH3A1 ack K277

ANXA2 p Y24

LMNA p S22

LYN p Y194

NUP153 p S330

LPP p Y296

MBD3 p Y83

TNS4 p S350

WAC kme K79

LGALS3 ack K227

CLIC1 ack K183

GOT2 ack K302

TYK2 p S580EIF4A3 ack K152

ATP1A1 ack K843

P4HB ack K467

ALDH3A1 p Y443

THUMPD1 p S119

ELAVL1 p Y200P4HB ack K385

STAT5A p Y694YWHAE ack K50

YWHAB ack K214

AXL p Y702

CCT8 ack K440

RPL9 ack K174

AXL p Y703

CAST kme K261

NCOR1 rme R1589

EZR ack K79

HLA-A ack K267ALDH3A1 p T451

KRT18 rme R55

MKI67IP p S247PRRC2A rme R232

SLC12A7 p S96

NCL rme R694

HIST1H2BK ack K12

NAMPT ack K400DDX42 rme R814

EZR kme K564

HIST1H1E ack K106

NAMPT p Y188

DDX17 rme R81

VARS p Y428

ERBB2 p Y1248

IRS1 p S1101

CAND1 ack K40

NSFL1C p Y167

ZC3HAV1 p S322

RPS11 ack K58

MAPK7 p Y221

HSPE1 p Y76LPP p Y273

RALY ack K44

RBM3 rme R121

ARFGAP2 p S340

FASN p Y222

TKT ack K543

TPR ack K723AXL p Y866

PUS10 p S84RNF214 kme K136

SRSF9 p S211

ZNF185 p S512

SDCBP p Y46

ARHGAP21 p T481

LPP p Y275NFKB1 p S907

HSP90AA1 ack K209

MAP2 p S63

ACSL3 ack K699

PYGB ack K479

TPRN rme R210

PKM ack K162

DSP ack K1916

LRRC40 rme R6

ALB ack K257

DSP rme R27

KMT2A p S2098TMEM119 p S212

HIST1H3A ack K79RPS8 ack K148

TAGLN rme R197TCEAL5 rme R182

COX5A p T48

ALB ack K44

BASP1 p T196SCP2 ack K132

BRSK1 rme R498

SKA3 p S155SERPINA1 ack

K298 HIST1H3A kme

K23

SLC25A6 ack K33

TUBA1A ack K394

NCOA2 p T773

MAN1C1 p S164

ERBB2IP p S1239IDH2 ack K384

PKP4 p S395

NKX2-1 rme R121

TRIP6 rme R205

ACTB p Y218

UBE2D3 ack K133

ABLIM1 p S706

DPYSL3 p S75

ALB p T551

DPYSL3 rme R520

ATF7 p T337

PHAX p S368

CUX1 p S1312PPP2R5A p S49

MAGED2 p S194MTPN p T31

TTYH3 p Y439

CRTC2 p S447

SOD2 ack K130

UMPS p S172

MYH9 kme K199

DACT3 p S10

ATG16L2 p S304

HIST1H3A ack K14

XKR7 p Y553

SPTBN1 ack K1459 NCOR2 rme

R1633

SLC20A1 p S335

PYGB p Y405

SPTAN1 ack K1023

MARK2 rme R628TWF1 rme R340

G6PD ack K514PARD3 rme R294

SLC39A3 p Y147

YLPM1 rme R819

DDX3X p Y462

LDLRAP1 p S186

MAP7D2 p S315MAP7D2 p S304

TRIM25 p S158

ACADSB ack K284

PPP1R1B p S137

HNRNPC p Y105

ATAD2 p S1190

HSPA8 ack K3 CENPV ack K11

FBXL19 rme R367

MAML3 ack K480KHDRBS2 rme

R248

EEF2 ack K318

HIST1H2AA p Y39

RBM42 rme R130

RBM15 ack K762

PJA1 p T277

MCM5 ack K273PARP1 ack K400

PARP1 ack K418

DDX24 ack K24

PTGES3 ack K35

UBA1 ack K884

SAMD1 rme R104

SRSF6 ack K101

RPL3 ack K155STX7 p T78HSP90B1 ack

K410

HNRNPUL2 ack K273

RPL35A ack K15

ACAA2 ack K270

SRSF9 rme R209

DEK ack K87SRSF4 rme R8ATP5B kme K55

SDHA ack K179

SUPT5H rme R668

PRC1 rme R475RPL37A ack K13

RPL3 ack K373

ATP5O ack K26GATAD2A rme R249

PPFIBP1 p S610

SON rme R1039

PABPC4 rme R483SAFB2 rme R897SUPT5H rme R681TUBB4B ack K379

PRKDC ack K1612USP13 rme R4

ANGEL2 rme R44

SAFB p Y736

RGS12 rme R524

SUPT5H p T784

PVRL4 p Y502

MBP p Y148

HIST1H2AA kme K95

TRIP6 rme R25TEC p S308

AKR1B1 p Y190

COL18A1 p S1245DYNC1LI2 rme

R386 SH3GLB2 rme R196

RBM27 rme R411

NCOR2 rme R1571

TAF15 p Y218

FAU ack K51

HTATSF1 rme R380

MISP p Y350SRP9 p T85

XRCC6 ack K575

TTYH3 p S437

MYH9 p Y754

RPL30 ack K44

TRIP10 p S304

SRRM1 p S756

C1orf198 p S129

NAALADL2 p Y106

PKP4 p S438AHNAK kme K1791

PANK2 p S189USP6NL p S617

SAE1 p S185

FANCA p S1449ARHGAP5 p T1129

SUPT5H p T791

PGRMC2 ack K193

CPT2 rme R51

PIK3R3 p Y341

PHF2 ack K940

DSP rme R45

SPRY2 p Y55

CTPS1 ack K466

CBX1 ack K84

TBC1D1 p S237

RIPK1 p S320GLUD1 ack K527

HN1L kme K184LMNA p S307

AHNAK kme K1932

AHNAK p S5752NEK1 rme R472

PARD3 p S1335SDPR p T260AHNAK kme

K4529

PRKD1 p T746PPP2R5A p S41

SUPT5H rme R696TBC1D4 p S591FRMD4A p S901

DBF4B p S501

TRIM2 p S375

PCNP p S77

CKB p Y39

NBEAL1 p T2686

ARVCF p S345

CALML3 kme K116

WWC1 p S947

YLPM1 p T1043

CKB p T35

ZC3H18 p T796

CTTN p S113

IDH1 ack K29

TAF15 p Y558

DDX3X rme R622

SMC1A p S956

ANGEL2 rme R387

ZNF532 ack K266

PABPC1 rme R493

PCM1 p S378

AHDC1 p S93

NCOA5 p S162

HNRNPL p Y48

CHAF1A p T154

KIF14 p S937

C1D kme K119

NCK1 p Y105

HNRNPA1 p Y347

SRRM2 p S992

TAF15 rme R528

HNRNPA1 rme R218

SRRM2 rme R2221

IMMT p S126

HNRNPA1 p S361

KANK2 rme R105AKAP8L rme R237

TNS3 p Y601

SLITRK5 p Y945

LIMA1 p T57

PIK3R1 p Y580CRK p Y47 PDPK1 p T245

PRPF3 ack K519

PDZD2 p S920

ALB kme K558STX12 p S218

VPS26B p S327

ARHGEF12 p S1288

CTAGE5 rme R709

USP43 rme R1071

GSK3A p S278

SEPT9 rme R46

PPL ack K1718

NUPL2 rme R45

HELZ rme R1340CLOCK p Y331

MTMR10 p S758

USP54 p S1362CAPRIN1 p Y78

CBX5 p T188SNRPN rme R112PPL ack K12

RBM42 rme R225

MYO18A rme R43

VARS ack K433

GAB2 p Y476

G6PD p Y507

ITCH p Y420

GOLGA3 p Y329

DOCK4 p Y1906

CRIP2 p Y13

INCENP p S94

TAF15 rme R187

KIFC1 p S33

KHDRBS1 ack K169

XRCC5 kme K209

MYH9 ack K355

TNK2 p Y860

STAT1 ack K279

SRSF2 p Y110MYH9 ack K79

G6PD ack K497

PON2 ack K144

SZT2 rme R2474

TAF15 rme R320

GIGYF1 rme R267

MYH9 rme R1923

MYH9 ack K63

PYGB p Y263

SNRPN rme R181

GATAD1 ack K108BRD1 p S498

GAPDH ack K254

RBM3 rme R90

FXR2 rme R476

GPS2 rme R312KMT2B ack K926

SCEL p S68CEP170 p S636

RAB10 ack K129

DYNC1H1 ack K36

EHMT2 p S121

XRN2 p S451

NCKAP5L p T1171

TRIP12 p S424

ZBTB7B p S342

KRT7 rme R52HSPA9 ack K567

FOXK1 p Y463

PDLIM5 p S228

CSTF2T rme R461

SRSF2 rme R109DHX29 kme K26

IDH1 p Y391

KLHDC10 rme R13

SCEL kme K109

CCDC9 p Y264

ENO1 ack K420

BCAR1 p Y249

PA2G4 ack K287

SON p Y963

FASN ack K2426

PYGB p Y204

PYGB ack K811

NAF1 rme R375

CPNE1 p Y386

UBE2T p S184

HNRNPH3 rme R138

PPP1R16A p S60

HDAC3 p S424PTPN14 p T323

FLNA p T48PARP1 p S179PNN p T657

NT5C3A p S278

SRRM1 p S752

EPB41L4A p S445C6orf132 rme

R1127 CDH1 p S770

MYH9 ack K1642NCOR2 p S67

SART1 p S448KRT8 rme R23

PCNP ack K152

LPP ack K176

PUF60 ack K454MEPCE rme R377

TXN ack K96

NAMPT ack K331

NCOR1 p S79

MYH9 rme R1932

MYH9 ack K1260

MYH9 ack K1209SERBP1 p Y207

CLASP1 p S568EIF4G1 p T207

ALDOA p T9SYNJ1 p S1223

NUP133 p T28

TANC1 p S1503

NUP133 p S27

FUBP1 p T153

ARHGEF40 p T1074

BCAR3 kme K334USP8 p T577

GTPBP6 rme R242

SRRM1 p S414

RANBP2 p S128

LRP6 rme R1518

ECI2 ack K359

EI24 kme K335ATXN2L p S559HNRNPK rme

R256 SERBP1 rme R216HIVEP1 p S537

PKP4 p Y470

MYH9 ack K975

OCLN p S310PRMT6 rme R43CIC p T1398

PKP4 p Y421

PKP4 p Y1115

XRN2 rme R921

AHNAK kme K2463

NCL kme K96

ZCCHC11 rme R1624

CTTN p Y228

PRRC2A p Y1001

PRKDC p T2609

PHIP ack K1399NUP93 p S438

RBL2 p S639HNRNPD rme

R278 RBL2 p T642

GPI ack K142

PRKDC ack K3455

COPA p T286

ARID1A p T1599

INPPL1 p Y886

FASN ack K1911

MYH9 ack K1249

NFIC rme R354

PARD3B p Y1000

GAPDH ack K259

TAF15 rme R395

KIAA0101 ack K24

SCFD1 ack K126LAMB1 ack K1746

SAMD4B rme R570

STIP1 ack K237CBR1 ack K180

IDH1 ack K345

C6orf47 rme R12

C11orf58 ack K91TXN ack K81

HSPA9 ack K159

NCL p S563

CARD6 rme R798

ALB p S603

RALY rme R156

NPM1 ack K223SERBP1 ack K102

JAK2 p Y570VCP p Y495

FKBP2 ack K30

PNPT1 ack K55

SPATS2L ack K326

NDRG3 p S335

ASPH ack K336HINT1 ack K58

PSMB1 ack K184

MYH9 ack K961

SPTAN1 ack K1759

RPL8 ack K155

PYGB ack K81

RUNX1 ack K24

PYGB p Y821

EP300 rme R728

PARK7 ack K62

CBR1 ack K96

DTX2 rme R281CAST ack K606

SPTAN1 ack K662

SRSF1 rme R109

THRAP3 rme R115

LMO7 p S919CTNND1 p T799

RNF34 p S173

SPP1 p S215

MUC1 p S1227

PRKCQ p T536

CDC42BPB rme R671

HNRNPA1 p Y341FLNA p S2152

TNKS1BP1 p S1616

PDPR ack K854

RPS2 rme R34

SPTBN1 p S938

WHSC1 p T544

MTPAP p S493

TAF15 rme R185

BCAR1 p Y115

SIN3B p S266

TMEM245 p S30

WDR7 p T1163MLLT4 p Y374

PHKB p Y29

WHSC1 ack K317

THRAP3 rme R101

GAB2 p Y266

ZC3HC1 p S24

RAI1 p T1136

RALY p S295

KMT2B p T278

TRMT1 p T628

PLXNC1 p S978

BRD4 ack K317

SRRM2 p Y2390

CDK12 rme R1404

NUMA1 p S1225

XRCC6 p T455

GTPBP1 p S658

ZNF219 p S698

NBEAL2 p T2746

RAVER1 rme R534

PPL p S205

MYH9 p Y400

KRT7 p S38

PDCD11 ack K1363

BRCA1 p S1466

CFL1 p Y68

WASL p Y175

FAM120A p S933

EEF1D p Y238

OTUD4 p T509

TAB2 rme R173

HMGB2 ack K59

VCP p S784

EIF4B p S219

NCOR2 p S1487

HNRNPU rme R727

IQGAP1 ack K1261

SEC16A p S2107

UBA52 ack K88

PACS1 p S497HGS p Y216

IRS1 p Y612

GSTP1 p Y8

ELMSAN1 rme R447

MCM5 rme R280

BTF3 rme R3

CS ack K459

DDX3X ack K118

PKM p T195

DYNC1H1 p S4368

MYH9 ack K1614

PPP1R13L rme R82

CCT5 ack K284

SCAF11 rme R1151

CANX p S583

HNRNPA3 rme R246

NOLC1 ack K415PGRMC1 p Y113

PRDX1 ack K168

SDCBP p Y56SAFB rme R811

PTK2 p Y577

PCIF1 p S121

TSEN54 rme R316

LMO7 p T913

SRGAP2 p S209

C10orf12 kme K1037

TNFAIP3 p S592

HSP90AB1 ack K550

GSTP1 ack K55MGA p S449

FYN p Y213

SAFB rme R902

S100A11 p T10

DYNC1H1 ack K622

FASN p Y470NPM1 p S214

SNRPN rme R147

HNRPLL p S68

ALB p Y287

IRS1 p S348

FCHSD2 p Y677

ZC3H18 rme R239

ABL2 p Y668

U2SURP ack K88

PFN1 p Y129

PAIP1 rme R21

PDAP1 ack K172PABPN1 rme R259

ETFB kme K200

GTF2F1 ack K407

MAPK14 p Y182ATIC ack K524

RPL31 ack K115CFL1 ack K22

ENO1 ack K105FXR1 rme R453

SNRNP200 ack K46

TUBB ack K297

HIST1H2BB ack K120

NUMA1 ack K2032

CTTN p Y104

HNRNPD ack K161

HSP90AB1 kme K607

COPA ack K607

NCL ack K87

TCEAL3 rme R176

MYO1C ack K667

NCL ack K62

AHNAK p S220

HIST3H3 kme K37CSE1L ack K158

NCOA6 rme R1047

WDR1 ack K81

GLO1 ack K140

TJP3 p S368

BUD31 ack K125

HIVEP2 p S412

CTAGE5 rme R514

HNRNPD ack K98

HIST3H3 kme K28

SDCBP p Y50

CDKL5 p Y171

HNRNPC ack K39

SAFB p Y714

SAFB p Y780

PPP2R5E p S34

ATP1A1 ack K45

TFG rme R385

PGK1 ack K216

KHDRBS1 p Y440

VCL ack K276

EEF1A2 ack K330

SAFB rme R910

HSPA1B ack K88

ATP1A1 p Y260

KIAA1522 p S979VCL p Y822

MARCKSL1 p S104

RPS29 rme R12

TNK2 p Y827

PTPN11 p Y546

MLLT4 p Y1230

CAPRIN1 p Y665

HIST3H3 ack K80RPL26 ack K77

TBCB p Y98EGFR p Y1197

MET p Y1003

SAE1 p T194

KRT8 rme R40

HADH ack K132

SAFB ack K475

SMG7 rme R910

NARS ack K507

MARCKSL1 ack K106

FASN ack K1771

EGFR p Y1016

EWSR1 rme R506 PPP1R10 rme R665

LRPPRC ack K763

KAT7 ack K199

MDH1 ack K118NELFB ack K519

ACADVL ack K239

HNRNPK ack K179

SHMT2 ack K269

HNRNPA2B1 ack K22 GTF2I ack K372

TST ack K14

HIST1H2BK p Y41

EGFR p Y978

CHD1L p S607

RPL10A ack K91

HIST1H2BK ack K117

SUMO2 ack K33

PRKD1 p Y749

HCFC1 ack K1863

VAPA ack K52

YBX1 rme R242

PGK1 p Y196

PGAM1 p Y92DDX42 ack K806

CFL1 p Y140PXN p Y118

PTK2 p Y576

ATP1A1 p Y55

ADAM9 p Y769EIF4H p Y12

HNRNPK p Y323APLP2 p Y750

ACTB p Y53

CRK p Y251FER p Y402

SCAF8 rme R1120

NPM1 ack K141

PKP3 p Y84

TYK2 p Y292

PRMT7 rme R32

ADAM9 rme R772

WIPF2 p T212

MEAF6 ack K169

FAM20B p Y138CRKL p Y251

PTK2 p Y570

DDX3X p Y104

EGFR p Y869

PRDX1 p Y194ACOT7 p Y194TLN1 p Y436

RBM14 rme R657

CTTN p Y421

DOCK5 p Y1827

OSBPL10 rme R38

ASPH ack K370NCL ack K109

HNRNPK rme R246

PKM ack K206

SRRT rme R45WIZ kme K967

HNRNPK rme R325

YWHAZ ack K157

MPRIP p Y267

CTTN p S117

CTTN ack K147

RALY p T275

STAU1 rme R115

EEF1A1 kme K55

HSPA1B p T226PABPN1 rme R17

CTTN ack K161

YWHAZ ack K138TCERG1 rme R13

NCL ack K15CLTC p Y899

MYH9 ack K682

SRRM2 ack K1186

NPM1 p S125NUP133 rme R17TUBA1B ack K352ZC3H18 rme R249SSH2 p S1259

RANBP2 rme R1016

SYNCRIP rme R565

GSK3A p Y279

NCL ack K124CTTN ack K390

ALB ack K298DDX3X rme R592

MPLKIP rme R77

HSPA1B rme R458SF3B2 rme R245

ENO1 ack K92ME2 ack K272

MAGOHB ack K18CLIC1 ack K166

RPA1 ack K244TSNAX ack K14

FAH ack K241ADIRF ack K70

ANXA2 p Y333

CRIP2 ack K132

KRT7 rme R20

HIST1H2BK ack K109

NCOR2 p S1483

SRRM2 rme R2717

NME1-NME2 ack K250

HSP90AA1 ack K632

HNRNPU ack K213

HNRNPA2B1 p Y174

XRCC6 ack K526PDIA6 ack K216

CASKIN2 rme R851

KHSRP ack K122

EEF2 ack K648

LMO7 p Y697

CTTN p Y199CTTN p Y302

HCFC1 rme R504EEF1A1 ack K79

LSG1 rme R5

TUBA1B ack K311

CLTC ack K798

MAPK12 p Y185

HSP90AB1 ack K559

HSPB1 rme R12

ACTB ack K328

HIST1H2BK ack K121

ENAH p S125PEA15 p S116

P4HB ack K103ARID3B rme R361

PRKCSH ack K376

CSTF2 rme R373RPL37 ack K46HMGB2 ack K128

HNRNPK ack K34

TMEM201 p T440

EEF1D ack K15

ATP13A1 p S935

KHDRBS1 rme R10HNRNPH1 rme R259 RC3H1 rme R597

DDTL p S29

ACO1 rme R713SDHA ack K624

SON p Y935

LSM14A rme R456

CCAR2 rme R180NUMA1 p S388

CLTC ack K1264

ARID1A ack K1808

WARS p Y316

LRCH4 p S521

BRI3 p Y57

EEF1A1 kme K36

XRN2 p S448

FAM168B rme R88TAF15 p Y566

MRE11A ack K609

RPS10 p Y82SERBP1 p S203SP100 p S459

MYCBP2 p T3470CCT2 ack K284

RPL4 ack K259

MOB4 ack K140

DDX5 rme R478

TSSC4 rme R220EIF4B rme R251

BCOR rme R655

HSPA5 ack K547

DNMT3A rme R171

NUMA1 ack K2058

YWHAE p Y131VCP ack K754PABPN1 rme R269

RPS3A ack K109

MDH1 ack K107EEF2 ack K857PRRC2C rme

R2823 ALDH1A1 p Y481

ENO1 ack K281BPTF rme R40

KRT18 p S34RBMX p Y285

SDE2 rme R203CDK5 p Y15BCLAF1 rme R55

CRK p Y221PLXNC1 p S986

CTTN ack K87PABPN1 rme R279

SNRNP70 p Y146

SRRM2 rme R2274

MYO1E p Y698

PAIP1 rme R60SEC23A p S713

EEF2 p Y443

AHCY p Y193

SF3B2 rme R216TOM1L1 p Y109GPR126 p Y1184

ZNF598 p Y336

CSNK2A2 p Y13

TBCA p Y75ACACA p Y1370SEPT9 p Y278

HNRNPUL2 p Y706

PTPRF p Y1621

ARHGAP29 p S1029

BCLAF1 rme R794

RBM3 rme R145

FAM103A1 rme R62

SRCAP rme R1224

KRT19 rme R24

H3F3A kme K36

SPTBN1 p S2128ABLIM1 p S452TNKS1BP1 p

S1621 PRKD2 p S710

PRKAA1 p S496KIF13B p S1410

PDPK1 p S241LASP1 p S146

PPP2R5A p S38

AKAP13 kme K1670

MGA ack K798

RSRC2 p S105

UTP15 p Y166

PPP2R5A p S42

CREBBP ack K1744

KRT8 rme R32

ZCCHC6 p S132ABLIM1 p S450

NES p T338

PLEC ack K2309

KRT8 p Y374

PLEC p T4030

ALB ack K426

PML p S480

KANK2 p T552

ECHDC1 ack K217

FXR2 p S622

C6orf132 p Y1067IDE ack K899

HNRNPA3 rme R376

TPI1 ack K51

VIM ack K439

SYAP1 ack K110

HIST1H2BJ ack K35 ILF3 ack K540

PRDX6 ack K141

DYNC1H1 ack K1807

HSP90B1 ack K586

HNRNPA3 rme R216

HNRNPA3 ack K187

TMED4 ack K152

PYGB ack K520

COPA ack K46

MYO6 ack K56

EIF5A ack K67

HNRNPM ack K667DYNC1H1 ack

K2966

ANXA4 ack K184

HSP90B1 ack K455

SPTBN1 ack K1354

OAT ack K77

LDHA ack K90

CTTN p S224

DHX9 ack K1163

NCL ack K437

VTA1 p Y278

TARS ack K99

ZDHHC5 p S432

HIST1H2BK ack K86

PDIA3 ack K146

PYCR1 ack K107

CALR ack K151CFL1 ack K44

ATP1A1 ack K9

PDIA4 ack K484

COPA ack K619

MDH2 ack K26

DTYMK ack K51MYO9A p S1330

PPIA ack K131

RBBP5 ack K519

PTBP1 ack K266

SCP2 ack K454RPL12 ack K99

VIM rme R50

C6orf132 rme R1119

FEN1 ack K375EIF4G1 rme R685

EEF1G ack K294

ALKBH5 rme R359

TLN1 p S1201

NCK1 p S85CAPZB p T267

TBC1D14 p S91PLEKHM1 p S482

UBAP2L rme R829

UTRN p S2482

NEBL p S953FILIP1L p T986

PTRF kme K312

TBC1D2 p T290

KSR1 p S406

NEBL p S949

CEP128 p S331

GTF2F1 p T427

SAR1A ack K38

PHAX ack K183FTSJD2 ack K93

SF3A1 ack K486

BOD1L1 ack K2910

PHF3 ack K513SF3B1 ack K214

HSPA8 ack K357

HNRNPU ack K524

RPS6KA4 rme R743

OSBPL11 p S189NUMA1 ack K1121

HNRNPD ack K119

GATAD2B rme R527 STK3 p T336

USP3 p S210

HUWE1 p T2889

KANK2 p T168

SERPINA3 p T35

ZNF174 p T165ARHGEF11 p T668

PKN1 p T774

HSPH1 ack K68

RFC1 ack K15

PKP2 rme R193

GRHL2 ack K453

DIAPH1 ack K487

DHX38 ack K260

HSPA1B ack K500

ZNF292 ack K1117

TARS ack K583

PSPH ack K122

ECHS1 ack K115

DAZAP1 ack K135SORD ack K339

EIF3H ack K274HUWE1 p S2388

SLC25A12 kme K451

EHBP1 p S1058LRP6 p T1572

GGT7 p S79

RPS3 p Y120

TAF15 rme R326

HNRNPM ack K83

PHF3 rme R1911

COIL rme R393

FBL rme R15

EEF1A1 ack K180

RPIA rme R42

WDR33 rme R1315

RBM27 ack K142ZFP91 p Y76

ALDOA p Y3

INCENP p S93

FASN ack K1065SPTAN1 ack

K1911

BCLAF1 p S762

PRDX1 ack K27

YAF2 p S57

CDC5L p S417

HNRNPUL2 p Y743CLDN3 p Y214

CAND1 ack K262ALDOA ack K13

PYGB ack K575

NUMA1 ack K1624; PIP4K2A

ack K367

RFC1 ack K14ATP5L ack K66

NUP50 ack K275

WHSC1L1 ack K517

POLL ack K544

RPN1 ack K37CFL1 ack K92

TALDO1 ack K321

FASN ack K1847

RPL30 ack K26

PPP1CA ack K113YARS ack K335

PLEC ack K4570

PTPN11 p Y279

EIF1 p Y30

TJP2 p Y1118

CNP p Y110

HSPA1B p S254

PLEC ack K3053

ANXA1 ack K245

U2SURP ack K760

HNRNPF ack K224

HNRNPUL1 rme R645 BCR p Y177

SNRNP70 p Y126KRT8 p Y10

MED1 ack K1126

LASP1 p Y122

EP300 ack K1674PSPC1 ack K8

HYOU1 ack K530

THRAP3 ack K879

EEF1A1 ack K244EPHA2 p S570MEX3D rme R524

REXO2 rme R12DHX9 rme R1265EEF1A1 ack K30DYNC1H1 ack

K1649

IQGAP1 ack K1465

MAPRE1 ack K76SPTAN1 ack K2205

UFM1 p Y18 CISD1 ack K79

HSP90B1 ack K356

ILF3 ack K454FIS1 ack K46LMNA ack K378

TUBA1B p Y282LSR p Y406PTPN6 p Y276

SND1 p Y329SBF1 p Y1529PTPN12 p Y64

ZDHHC5 p Y91

CRK p Y108

NFXL1 p S835

CAT p Y84

SLC44A2 p Y9PTPN1 p Y46

ESYT1 p Y1009

BRIX1 ack K276

CPD p S1377

TUBA1B ack K401

PTPRA p Y271PKM p Y175ROCK2 p Y1255PTPN13 p Y2243HNRNPU ack K551

MYO1D p Y435

QKI rme R227

SKIL ack K446

BAG3 p S289CCDC86 ack K225

ACLY p Y131

PTPN6 p Y564NUCB1 p Y179HSPA1B ack K71

YWHAB ack K159

UBA1 ack K470STIP1 ack K32

ARPC2 ack K286

CCT5 ack K275

GARS ack K615

VDAC1 p Y195

XRCC5 ack K155

UPF3B p Y117

PKP2 p Y161

SLC44A2 p Y8

PHACTR4 p Y647PKP2 p Y876

CPSF7 p Y451LSM4 rme R117

LIMA1 p Y452

PITPNA p Y140

ESYT1 p S1011PKP2 p Y88

MYO1D p Y612PKP2 p Y631

KIAA1217 p Y424ECHS1 p Y35TJP1 p Y1191

PPA1 p Y193CBFB p Y85

PDCD6IP p Y319DOK4 p Y165C6orf132 rme

R1102

XRCC6 p S324

GPRC5A p Y347

SPTBN1 p Y831

PSMA3 ack K65

RBM14 p Y592EML4 p Y305

KRT8 ack K101

EIF4B ack K586RPS25 ack K66

GART ack K977

HSPA9 ack K646

GPBP1 p S49HSPD1 ack K96

CRTC2 p S86

HSPA9 ack K345

TPM3 ack K232

RALY rme R131

PTBP1 ack K259

RRP12 rme R1138

CGN p S332 MRPL1 ack K108

XRCC1 ack K169

ACTR6 ack K260

PHB ack K240

XRN2 rme R816RBM7 rme R229RPL6 ack K124

EEF1E1 ack K21

KRT18 rme R50

RPL3 ack K143

MRPL12 ack K163

PSMC1 ack K24DDX5 ack K470

ARFGEF2 p S1534

KRT78 rme R52PSMA6 ack K104

CGN rme R15

RPS8 ack K26

SCAF11 rme R965

KRT8 p Y286

VCP ack K502

SLC25A1 ack K21

RBM39 ack K119

RPL11 ack K67

HNRNPA1 rme R55

LMNA ack K450

ZNF326 rme R149

VDAC1 ack K109RAN p Y39SRRM1 p T872ARRB1 p Y63HSPA1B ack K77

C6orf132 p S381

TRMT1L ack K136

SNRPC ack K3

NAP1L1 ack K105

PPP1R10 ack K207TRIO p S1786LDHB ack K244

SNW1 ack K531

CTNNA1 p Y177 NAMPT p Y175KIF5B ack K801

CSTF2 rme R344; CSTF2T rme R352

HSP90AA1 ack K458

PRMT1 ack K173HNRPDL ack K212

CDC42 ack K153

PABPN1 ack K207

DDX5 ack K40

ACTN4 ack K779CYCS ack K74

RPS25 ack K43LMO7 p Y1672

HNRNPD p Y244

LRRC41 ack K375

HSPA1L rme R460

PARK7 ack K132

FTSJD2 ack K108

VDAC1 ack K28

MED8 ack K259PSMB6 ack K67

SFPQ ack K279HNRNPU ack K265CAPZB ack K95

RAC1 ack K133EP300 ack K1760

SEPT7 p Y30

EPHB4 p Y581

PTBP1 p Y127

HSPA5 ack K326PSMA3 ack K57

HNRNPA1 ack K15

SRCIN1 p Y272

UBXN7 p S285GAB1 p Y659

TRIP6 rme R179CDK1 p Y15

TNS2 p Y483

PTK2 p S574

VIPAS39 rme R114

STIP1 p Y354SYK p Y323CAPRIN1 p Y670

TNRC6B rme R1623

ACLY p Y1073

FAM120A p T428

ARHGEF5 p Y1370

GGCX p T10

OCLN p T305

ZNF185 rme R295

SAFB ack K356

PPP1R10 ack K261

MAPRE2 ack K156

NEBL ack K23

SAFB rme R818

DSP p Y28

ATIC p Y208

ZNF326 rme R175ALB p Y162

CLTC p Y1438CD2AP p Y88

SUPT6H p S1535

KRT7 p Y268

RB1 p S795

CAP1 p Y31

CIC p T1318

NSD1 p T2109

CTDSPL2 p T116

LMO7 p S318

C9orf169 p Y12

SUN2 p T9

NAV2 p Y315

TNKS1BP1 p S1328

ARID1A p S1602

MCFD2 p S34

SLC4A2 p T183

ARFGEF2 p S1528C9orf40 p S76

HNRNPUL2 rme R704

BCLAF1 p S262

SYNCRIP p S359

RLIM p T349

CASKIN2 p T853

EXOC2 p S432

SUPT5H p Y802

CHTF8 rme R266SRRM2 p T1531

KIF5B p S933

NFIC p S473

PSPC1 p S509DCAF5 p T500

MAP4K5 p Y401EEF1A1 kme K84

MYH9 ack K1793

PARP1 p S727

GPRC5C p Y387

YBX1 p Y145

DCP1A p T528

DDX3X p Y69ORC1 p T230

DLGAP5 p T329TPX2 p S310

KRT7 p Y205

HGS p Y286

CLDN7 p Y210CLTC ack K189

KIAA1217 p T1637

RBMX p Y234

GAB1 p Y406

MLLT4 p Y1189SEPT9 p T235

ALDOA p S46

AP1AR p Y165

SARG p T107

PTPN6 p Y536

TJP2 p T1054SMG1 p S1638TJP2 p Y257

RAPH1 p Y1226

ABL1 p Y185

DOCK1 p T1772 TNRC6B p S424

PKM ack K3EEF1A1 ack K20

BCL7C p S114

HSP90AA1 p Y627

CTTN p Y265

VCL p Y692

PKP2 p T162SEPT7 p Y141ABCF1 p Y250IST1 p Y43

PARP1 ack K654

FAM120A rme R886

BRAF p S447

PIK3R2 p Y453

FAM120A p S521

GIPC1 rme R240GSN ack K661

TAOK1 ack K820

HNRNPM ack K48

PPFIA3 p S264TNPO3 ack K594

EEF1A1 p Y141

NCK1 p S91

PRKD1 p S205KIF1C rme R1041

CAMSAP3 rme R823

FOXK2 p T634

HNRNPA1 p S95

FRMD6 p S525

PPP1R13L rme R344

ZNF326 rme R151

TJP2 p Y1179

CYB5R1 p Y84

PDLIM5 p Y247

ALK p Y1078G3BP2 rme R432

DCAF5 p T497

GRAMD1A p S263

SDC4 p Y197

CTTN ack K107NAA50 ack K34

HNRNPH2 rme R233

LMO7 rme R1488 CRIP2 p Y134

PAG1 p Y227LMO7 rme R312DLG5 p Y1344

YWHAE ack K12 PELI2 rme R36

CTTN ack K295

PYGB p Y197

PDAP1 ack K52PUM1 rme R580

TAOK1 p Y309DCXR p Y149

EIF4B rme R268

SPRY1 p Y89EIF2S1 p Y82

RBMX ack K30

ENO1 ack K81

MAF1 p S75

ENO1 ack K193

ALDOA ack K147RSF1 p T1305

RSF1 p S1310

WDR33 rme R1262

HNRNPA2B1 ack K59

MAN1C1 p S169

KANK2 p Y100

IRS1 p Y632

ITPA p Y113

TRIP6 rme R238

OGFR p S420

CTTN rme R119

WIPF2 p Y74

BCLAF1 ack K338

SHB p Y272SNAP29 p Y160

YLPM1 rme R1563

SEPT7 ack K313

PRKCD p Y313

EPS8 p Y602

G6PD p S132

CLTC p Y883

HNRNPA2B1 rme R153

G6PD p Y503

FAM120A rme R1006

LARP4 rme R443

SON rme R936

CHTF8 rme R429

FUBP1 rme R363

MRE11A rme R604PIK3R2 p Y464

YLPM1 rme R619

IDH1 p Y135

PAG1 p Y359KRT7 ack K331

SON p Y928

WDR1 ack K115

KRT7 p Y55

LYN p Y397

MAPK13 p T185

TRIP6 rme R186

BAG3 p S291

PIK3R2 p Y449PARD3 p Y1127EGFR p Y1172

PARD3 p Y489

PIK3R1 p Y467

S100A11 p Y30

PVRL1 p Y468

EGFR p S995ACTB p Y294

SOCS4 p Y30EIF4B p Y270

SLITRK6 p Y833

EGFR p Y1092

KRT7 rme R458EGFR p Y998

GARS ack K426

HDAC1 ack K438

LYAR ack K283PSAT1 ack K127

CDC37 ack K154ERF rme R329RPL31 ack K31

HIST3H3 kme K24TCP1 ack K532

GBAS ack K143

RPS29 ack K54

EPPK1 p S1548

SIN3A ack K865

EIF4G3 rme R673COX7A2 ack K33

RPS2 ack K257

CYB5R3 ack K120

PHB2 ack K147TARS ack K243

PRRC2A rme R698

ATP5A1 ack K434

CSNK2A1 ack K49

PES1 ack K152TRIM28 ack K377

SAT2 ack K29

PRRC2A rme R1066

TAF9B rme R128

NFIB rme R335

CHTF8 rme R146

PKP3 rme R261

PKP3 p Y195

PSMD9 ack K123

TCERG1 ack K1035

EEF2 ack K314

PFKM ack K678

GSTP1 ack K209

AHCY ack K103

IPO5 ack K800

CDK1 p T14FBXL18 rme R446

SRSF4 rme R83HNRPDL rme R25

FOXRED1 rme R12

RBMX rme R317

SCEL p Y58

PEAK1 p Y635

PUS7 rme R450

TONSL rme R797

UGDH p Y108

PRRC2C rme R1186

MPDZ rme R1170

HMGN2 ack K90

NCOA2 rme R1261

CTAGE5 rme R557

NAMPT ack K48

PNPT1 ack K289

RPL4 ack K239

CBX4 ack K149

LRPPRC ack K613

ERF rme R224

RPL27 ack K107

SNRPB ack K8; SNRPN ack K8

ILF2 ack K109TUFM ack K88

TMC5 p Y55HSPA8 ack K88

PPAN rme R426

TARS p Y298LDHA p Y239

TNK2 p Y859

TJP1 p Y1524

NSUN2 ack K640

PRPF4B ack K170

CDC37 ack K60

EEF1E1 ack K138ST13 ack K353

FEN1 ack K200

NAT6 rme R234

UQCC2 ack K71

SF3B4 p Y16

MIF ack K67

HIPK1 p T351

PLEC p Y4611

ZNF511 p S230

EIF4G1 rme R65

HSF1 p S136

EP300 ack K1704PPM1G ack K383

EIF4A1 ack K146RCC2 ack K377

YWHAE ack K123

EEF1A1 p Y177

RRP9 ack K25

MPZL1 p Y263CTNND1 p Y208

LSR p Y551GRB2 p Y209

EEF1A1 p Y29

CNN2 p Y231

WASL p Y256

ATXN2 p S667

DHX9 ack K497

RAN ack K38

HNRNPA1 rme R371

HADH ack K81

PHF6 ack K227

INCENP p Y73

ACLY ack K17

TMEM154 p S115

SDHA ack K92

FAHD2A ack K234

CLTC ack K507

LMNB1 ack K474

SET ack K172

PSPC1 ack K99

RPL7 ack K161

ATP5A1 ack K498AHCY ack K405

HSPD1 ack K292

PTBP1 ack K485

RPL7A ack K101

TRIM28 ack K366CLTC ack K367

IDH3B ack K135

FDPS ack K123

MATR3 rme R51

FAM120A rme R884

CFL1 p Y82

CSTF2 rme R475

FRK p Y46

GDI2 ack K210DDX3X p Y283

PLCH1 p Y907

SRSF4 ack K95VTI1B p Y115

KIAA1217 p Y244

GOLGA3 p S878; KRT1 p S254 PLXND1 p Y1673

EIF2S2 p Y298

PGK1 ack K156

XPOT ack K634

NARR rme R42

VWA5A p S92

SMARCD2 rme R529

TNKS1BP1 p S221ABI1 p S222

TKT ack K232

HSPA1B kme K561

RBM7 rme R201

C1orf106 rme R554

CIC rme R599

TAF15 rme R498

PRPF4B p S32

RBM3 rme R47

KIAA1143 ack K36PPFIBP1 p S540

ELMSAN1 p T468

LAMTOR1 p Y40

TRIP6 rme R111

HNRNPU rme R755

SAFB p S627

AHNAK kme K4859

RAN p T32

HNRNPUL2 rme R716

PRDX1 ack K16

KRT19 rme R7

RPL11 ack K154

CLK2 p S50

FASN ack K1591

STIP1 ack K395

EZR ack K64

IDH3A ack K77SOD1 ack K71

TNKS1BP1 p S920

MTHFD1L ack K189

ATP5A1 ack K239

EEF1D ack K107

ATP5J ack K41RAD54L2 rme

R1433

PSMB2 p Y146

EEF1A1 kme K318

API5 ack K487

SLC25A5 ack K92

KIF5B rme R956

NCOA1 ack K632HNRNPF ack K200

PCNX p Y580

NCOR2 ack K2412

ALYREF ack K86

MED1 ack K1309

SRSF9 rme R88

WBP11 rme R192

RBMX p Y272

DDR1 p Y484

NUCKS1 p T222

NUCKS1 ack K188

TAOK1 p Y610

DYRK1A p S324

ZAK rme R670

DGCR14 ack K408

SETD1A rme R1227

VDAC1 ack K61

QSER1 rme R1171

WDR70 rme R573

HIPK3 p Y359

KRT8 ack K11

PARD3 p Y1080NCOA2 ack K640

NCOR2 rme R1719

NACA ack K2005

PTTG1IP p Y174

EDF1 kme K25CLDN4 p Y208

RPS8 ack K128

NUCKS1 ack K35

CYC1 ack K318

MAGOHB ack K33

DNAH2 p T616

RPS4X ack K37

ERBB2IP p Y1042EGFR p Y1110

ITSN2 p Y553

PKP4 p Y372

EIF3D ack K412

MLLT4 p Y1656

HSP90AB1 p Y276

HMGB3 ack K12

RPL10A ack K106

SCRIB p Y1360

PRRC2B rme R1097

NCBP2 ack K151

TXLNG rme R24

PDPK1 ack K304CDYL kme K185

EIF4H rme R191SIN3A ack K875HNRNPM ack K698

CTTN ack K309HNRNPUL2 rme

R747 CAPRIN1 ack K74CFL1 ack K114

PTMA ack K103RECQL ack K613

HMGB3 ack K165

SMEK1 ack K655

HSP90AA1 ack K436

TRIM33 rme R535

HNRNPA1 rme R140

XRCC6 p S319

CAPRIN1 rme R633

RSF1 p S1345TERF2IP p S203PPFIA3 p T714

AKAP10 p S187VGLL4 p S52

G3BP2 rme R468WDR33 rme

R1257 MEAF6 ack K69

STMN1 ack K53CMAS rme R16

CASKIN2 p T848EHBP1L1 p S462

FASN ack K1239ALDOA ack K200

ESYT1 p Y822SLC25A5 kme K166

PGK1 ack K291

RABEP1 p S407

PPIA ack K82EIF4A1 ack K174

HSPA8 ack K246

CAPZA1 ack K19

EIF4H rme R166

SERBP1 rme R195

HNRPDL rme R408

EIF4H rme R174HNRNPUL2 rme

R720

DHX9 rme R1235SRRM2 rme R2384

PPP1R10 rme R705

KHSRP rme R411

TRIM24 rme R469

CASKIN2 rme R862

GATAD2A rme R273

C11orf68 rme R237

VPS13C rme R3526

HNRNPF rme R212ZNF827 p S14

GTPBP6 rme R55

TUBA1B p Y103HSPA1B ack K246RPS15A p S31

CTNNA1 p Y419

LRRC40 rme R13

MPRIP p S301

GPD2 ack K634

HNRNPK rme R377

SMG6 p T479

HNRNPK ack K461

SNRPN rme R108

ARPIN p Y5

PRRC2A rme R1022

EIF3G ack K212

PLEC p S2361

GAB1 p Y627

CNNM1 p Y856

WDR33 p S1210

AFAP1L2 p Y54

PUM2 rme R694

RPRD2 ack K862

IFT43 p S78

EIF2S3 ack K90

RPL5 ack K220

DCUN1D5 ack K26

NPM3 rme R27

PRPF31 p Y205HNRNPR ack K366TROAP rme R199

DDX3X rme R632SRRM2 rme R2342

CAPRIN1 rme R667

CHTF8 rme R387DDX3X rme R600G3BP1 rme R460PABPC1 rme R432

CD3EAP rme R162

SNRPC rme R21

SPEN rme R3312

MAPK3 p Y204

TWF2 p Y309

KRT9 rme R487

FAM120A rme R986

HNRNPH3 rme R121 HNRNPK rme

R316 FOXK1 rme R191

VDAC1 ack K174

DST rme R7402

HIST1H2BK ack K35

NQO1 ack K61HNRNPAB rme

R253

SRRM2 p T274

EIF3A ack K196

FBRS rme R408

PRRC2C rme R747

HNRPDL p Y295

TUBA1B ack K163

HSP90AB1 ack K275

SLAIN2 rme R538

TUBA1B ack K394

ALDOA p Y204

SNRPD1 rme R98

PEBP1 ack K150

NQO1 ack K90

HIVEP1 p S703

NQO1 p Y20

CTNNA1 p Y619

CTTN ack K272

CCAR2 p T484

FANCE p S204COL4A4 ack

K1688

RAD54B kme K226

IGF2BP3 p T217

CAMK1 p S176

ANKZF1 rme R252HSP90B1 ack

K682

PPFIBP1 p T798

PPIA ack K125

DARS2 ack K454

NOP58 p S109

MPLKIP p T51

EZH2 p T487

NFIC ack K280

SCEL ack K602

FAM103A1 rme R78

FAM120A rme R982

RPS26 ack K66

ABLIM1 p T451FAM120A p T42

TK1 ack K220

NUP214 p S974

PDHA2 p S293

ANXA2 p T19SLC45A4 p S424

LAMA5 ack K2481

SYAP1 ack K70

BAZ1B p S345

TRA2B p S264

CHAMP1 p S382

PEBP1 p Y181

EIF3A p T574

EIF3A rme R1026

S100A11 ack K103

KRT19 p Y130

EEF1D p Y182

MAPK1 p Y187

SRRM2 p Y18

TUBB4B ack K252

HSPA5 p S448

RPS15A ack K19

PHF3 p S1796

SEC62 p Y46

EIF4B rme R292

SSB ack K328

ATIC ack K266

DCPS ack K142

ZNF638 rme R81

KIRREL p Y647

CAV1 p Y14

RIN1 p Y295

CDH1 p Y797

ATP8B1 p Y1217

DSG2 p Y968

PHB2 p T155

SON p Y949

DNAJC17 kme K264

PPA1 ack K228PRMT1 ack K124

C12orf10 ack K40

SERBP1 ack K320

BCAP31 ack K72

LDHA ack K243

C12orf57 ack K101

EIF3A ack K850

RPS11 ack K45RBM39 ack K111

DYNC1H1 ack K4204 HSPA8 ack K71

CCT2 ack K204RPL23 ack K75

HNRNPM ack K672HSP90AB1 ack K64

IMPDH2 ack K109TWF1 ack K135

LASP1 ack K121

RPS29 ack K33CAP1 ack K279XRCC6 ack K461HSP90AB1 ack K624

VBP1 ack K52HSP90AB1 ack

K428 RPL23A ack K78

PSMA4 ack K239

TPM1 ack K168NPEPPS ack K163

SRRM2 rme R2246

CFL1 ack K152YWHAE ack K215

GANAB ack K462PDCD6IP ack K269

SYNCRIP ack K42

PKM ack K135

ACO2 ack K520

NONO ack K467

KIAA0907 ack K553

DHX15 ack K17PRDX2 ack K26SEPT7 ack K208

NELFA ack K255

ECHS1 ack K118RPN1 ack K516

CALR ack K143

CIT rme R2003

YWHAG ack K217CANX ack K127

ELAVL1 rme R205

PLEC p Y4393

SLC4A7 p S407

SART1 p T764

FAM21A p T437

SZT2 p S1651

RIF1 p T1518

KIF22 p S455DIS3 kme K331

CLDN2 p Y194

ATXN2L rme R417

OCLN p S313

SEPT7 p Y319TMEM2 p Y27MSN p S384

KHDRBS1 rme R325

KIAA1429 rme R1741

HNRNPH3 rme R301

VIM rme R36

DYRK3 p Y369BYSL rme R40

BRIX1 rme R9

ZNF292 p S820

ZNF24 p S317

ZKSCAN4 p S217

PRPF40A p S748TBCB p T33

LATS1 p T735

HNRNPM p S432CAD p S1267

SIPA1L2 p S1478

HGH1 p T223

PRPSAP2 p S227

RBM15 p T568

SSX2IP p S540IARS p S1049

HSPA9 ack K654

PCBP1 p S43

IDH2 ack K69

HNRNPH3 p T17

BCL11B p T376

IRS2 p S306

MYO1B p S572

MAP2 p T1440

MSN ack K79

TLN1 p T931VIM p Y276

SARG kme K308

PDZK1IP1 p Y99

MSN p S429

AHNAK kme K2396

SHB p Y114

PRDX1 kme K192EPHA2 p Y594

BAIAP2L1 p Y274PAWR p S233

TXNRD1 kme K138

MYO9A p T1738

TLN1 kme K428

KRT6A rme R42

ATXN2L rme R361

TRMT5 p T494

RILPL1 p S259

OCRL p Y133

MYOF p T1070

KMT2A rme R32AHNAK kme

K3404

HECA p S250GAK p S73

DCLK1 p Y74

UBTF p S484

NCAPH2 p S492

ARAF p S547

RPL5 ack K43SND1 ack K366

RPS28 ack K10RPL26 ack K2

RPL35 ack K79

RPL23A ack K134RPS25 ack K98

RPL23A ack K115

RPL18A ack K151

NME1-NME2 ack K154

KPNA3 ack K97

SRRM1 p S874

SAFB2 rme R842

SNRPB ack K57

PPP1R7 p S24

RPS28 p S23

FYN p Y185

FASN ack K1582

RPL4 ack K234

RPL30 ack K87

KLF10 ack K427; SP3 ack K679

PUM1 rme R796PAPD4 rme R73NME1-NME2 p Y167

GNB2L1 ack K183

FABP5 ack K72

ALDH1A1 ack K329

RANBP2 p S1835

TPX2 p T369 EPRS p T467

GTF2I p S674

EPRS ack K1389

RPS25 ack K57

EIF2S1 ack K154RAN ack K71

SSR3 ack K103RBM7 rme R190

FKBP4 ack K181GSPT1 ack K108

DYSF rme R79C14orf166 ack

K58

XPR1 p S676

NEK7 p S195

PKP3 p S180

MME p S6

TUBB ack K252

GARS p S335

ZC3HC1 p T28

KANSL2 p S135

CNN3 p T224

MKI67 p T391ALDH4A1 ack K93

RPS9 ack K93RPS6 ack K143

RBBP6 rme R877TSN ack K78DNAJC8 rme R243

DNAJC8 p S81DCTN1 p T122

DSP p S22

APOA1 ack K157

RICTOR kme K1367

PHB2 p S151

TOP2A p S1469

HIST1H1C p T31

CECR5 p S77ERI2 p S302

SORBS2 p S301

KDM1A p T104

SART3 p S769SLC4A1AP p S82PRR12 p T738

EPPK1 rme R4739SRSF6 p T146

ROCK1 p S574

TNKS1BP1 p S1631

TNRC18 p S2771

NAV2 p S1970

INADL p S455

PPP6R3 p T631

KIDINS220 p S1555

THOC2 p S1234DCP1A p S525

RSRC2 p S30

CUL1 p S6

CHD8 p Y2516

CHD7 p T2551WAC p S64

MARK1 p S666

HIST1H4A ack K8

TLK2 p T72

MARK1 p S671

RAPGEF5 p T207

EP400 p T2294

MARK1 p S633

MAPKAPK2 p T334

CTR9 p S941

CSDE1 p S123

SPAG9 p Y713EPS8L1 p T187

LPIN1 p S162

RABEP1 p S416

RPS6KA3 p T231SLK p S189

MKNK1 rme R455

KRT19 p S35

CGN p S131

ACTB p T318

POLR3C p S204

YTHDC1 p S515

USP39 p S97

RECQL p T605

CCT2 p T23

IRS2 p S523

EIF4G1 p S704

FOXK1 p S441PHF3 p S1952

FIP1L1 p S554

NOP56 rme R342

RECQL p T190

JMJD1C p S1748

STK11 p Y36

KRT1 rme R602

SAMSN1 p S7 MPLKIP p S124

SMCR8 p S489

TACC1 p S44

APC p S2724

TNS2 rme R816

CHTOP rme R97STX7 p S81MRE11A p S678

ZYX rme R253

HBS1L p S225

FRMD6 p S522

XPR1 p S668

SPEN p T3236

LRCH1 p T568

LOC113230 p S208

CCND2 p T280

CCND2 p S279C10orf12 p S273

ARHGEF12 p T1286

PDCL p T229DBN1 p T335

NCOA2 rme R489

ALB ack K205

MAST2 p S931SPECC1L p S868

NES p S1175

AHNAK rme R330

PLEC ack K4504GTF3C1 p S746

FKBP15 rme R520MCM7 p S401

CIT p S902PLK1 p T498

ATAD3A ack K539

MAP4K4 p S649

SPEN p T3139

TLE3 p T312

FASN p S1411

COBL p S269

SF1 p T253

CELF1 p S52

HBA2 ack K12

C11orf58 ack K13TANC2 p S430KANSL2 p T131AVEN kme K230

LASP1 ack K23

MAPK11 p Y182NAA30 kme K102AHNAK kme

K1461

LUZP1 p T993NARR rme R71

PITRM1 ack K946

KRT6A p Y341

USP5 ack K353

RPS16 ack K131

IFNGR1 p Y304

CERS2 p S348

ZFR p T202

PFKP ack K574SQSTM1 p S366

PVRL1 p Y396KRT6A rme R24

BCAR3 p Y212ASXL2 rme R639

FAM65A p S351

FAS p T241BCAR1 p Y306

CAD p T1946TAF15 rme R512

PRDX6 p T177

EP300 p S1897

CNOT2 p S143

MTSS1L p T260

ATXN2L p T681C19orf43 kme

K128

KLC4 p S590

FH ack K66

EPHA2 p S892

CAV1 p Y42

CDC26 p S78KRT6A rme R16

NFIC rme R451

AXL p Y481

SRC p Y187SCYL1 p S676

BRD8 p S694

PTK2 p Y194

RASAL2 p T741

TPX2 p S252

CLTC p Y900

SSBP3 p S355

LPP p Y300

ASH1L p S167

TCEB3 p T397

MTMR10 p T583ZFPM1 p T653

PRKAA1 p S498ITIH4 rme R56

VTN ack K443

HBB ack K67

ALB rme R34

RBM7 p S204

FOSB ack K166

LYN p S196

MAP4 kme K871

FAM129B p S609

STK38L p T283

TPR ack K755

RBM33 p T757

EGFR p S1081

DENND6A kme K510

GGA2 p S400

GAB3 p Y560

RBM15B p T532CXorf23 p S139

AHNAK2 rme R327

GTF3C1 p T514

FAM156A p S13

ESYT2 p S691

EFHD1 kme K234 AHNAK p T4100

AHNAK kme K1794

EZR ack K254

KDM1A p S80CAST p S57

GTF2F1 p T437

IKBKG p S17RGS12 p S937BLM p S422

NCF2 p S213

HAUS6 p T858

RPL3 ack K366

SPIDR p S252FAM208A p

T1049

DNM2 ack K562

RAI1 p S1135

SRRM1 rme R16PNN p S658

TMX2 p T283FUBP1 rme R361

DIEXF p T15YARS2 ack K367

HMGN4 ack K90

L3MBTL2 p S73

PSAT1 ack K318

TICRR p Y1133

RBBP6 p S1444

FAT4 p S4655

FAM117B p S208

DNAJC30 p S44

SLC4A7 p S403

DLC1 p S856SLITRK4 p S663

SLC12A7 p S40ATXN2L p S111

ALB p Y108

FNIP1 p S292RAI1 rme R249

PRR3 p T26

MAPK1 p T181

CENPF p S3019

BCL11B p S256

ATP5A1 ack K240

MYBBP1A p T1196

AHNAK kme K4011

PRKCI p T416

RECQL p S608SCAMP1 p S112

PPFIBP2 ack K502

ALB p T379

USP36 p T629

EPN1 p S454

MAP2K1 p S377

SPEN p S2101

HMOX1 p T252

TFAP4 p T37

HOMEZ p T451

LARP4B p S736

EIF4G1 p T211

RANBP9 p S477

MTA2 p T534

NOP58 p T34

PARD3 p T1347

PUS7 p T610

IK p T42

DARS2 p S242

CCDC9 p T83AHNAK p T3716

FUS rme R514

EPS8 p T317

EPS8L2 p T303

EPN1 p S473

MDM1 p S314

CDC42EP4 p S174

RBM26 p S127

CCDC6 p S254

SLC12A7 p T30

AUP1 p S354

ZNF280C p S80

SPECC1 p S847

NONO p T450

RNF19B p T698

RACGAP1 p T606

NUP98 p T670

NUMA1 p S2003

MKI67IP p T223

CCDC86 p S18

ARHGEF2 p T679

ASH2L p S623

PCBP2 p S50

RPTOR p T714

PEX14 p S232

C2CD5 p T285USP6NL p S585AP1M1 p T223

TSC2 p T23

N4BP2 p T1210

DTNA p T504

POLA2 p T130

ENO1 ack K256

HNRNPUL1 rme R685

SEPT9 p T49 SEPT9 ack K62HNRNPH3 rme

R343

SEPT9 rme R10DDX3X rme R88

SLK p Y195 NOP2 p S812DIDO1 p S1974

LASP1 p T104EEF1G p T46

RAD51C p S20 SURF2 p T190

WNK1 p S1978

TSC22D4 p T57

ARHGEF12 p T736

ZCCHC11 p S104

TAP1 p T545

RB1 p S794

CNN3 p S285

CDK13 p T494

ANLN p S323

PLEC ack K2652

LARP1 ack K367SCAF8 rme R1139

LIMD1 rme R428ALDH1A1 ack

K367

EIF3C ack K332

SON rme R957

IGF1R p Y1165RPL3 ack K115PGRMC1 ack K105SAP130 rme R453

ACTC1 ack K70

C19orf43 ack K72

COPA p Y249

RBMXL1 rme R113PTPRF p Y1381

SETD1B rme R292

NOP58 ack K418

TNS3 ack K450

VDAC1 ack K201

FOXK1 rme R177

HIST1H1E kme K26

PRKACA p T202

GSE1 rme R232

EIF4H p S230NCBP2 rme R146

HNRNPUL1 rme R671

UBN2 ack K1148AKAP8L rme R185

MIF ack K78

ENSA ack K114

RNASEL ack K684

RHBDD1 p S314

TJP1 p S1111

EEPD1 p S16

DBI ack K55

ABLIM1 p S455

U2AF1 rme R211

RBM12B p S591

HIPK1 p Y352

SF3B2 rme R884

DDX3X rme R617

USP39 rme R22

DDX3X p Y301

POLR3E p S162

ACTR8 p Y424

TOP2B p S1550LMO7 p S1597

ZBTB34 p Y211

ESYT2 p S699

PLEKHA1 p S380RPGR p S961

HIRA ack K114

MATR3 p T150GATAD2B rme

R286

FOXK2 rme R144DOCK6 ack K1871

PUM1 p T112

PCNA ack K80

EIF4G3 rme R692

KRT18 ack K167COPA rme R965

ESRP1 rme R582

UQCRH ack K85

MTMR14 rme R638

LARP4B rme R419HIST2H2BF ack

K21

PPIG ack K555

LDHB ack K7PSMF1 rme R231

ATRX ack K967

DHX15 ack K786

ARHGAP32 rme R1695

ACTB p S33

PPP1R14D p S34

FHDC1 p S883

EPB41L4A p S448

TBC1D30 p S114

ARHGAP18 p T158

EPS8L3 p S557

EEF1G p T43

PLEC kme K4480

SAMD9 ack K1261CCDC50 p T310EPB41L1 kme

K463

AFAP1L1 p S584

PKP3 p S104

AFAP1L1 p S583

DDX5 rme R486

TMPO p T154

SETD1B p S961

PARP1 kme K508

SMARCA4 p T609

FAM169A p T489

KAT6B p S1048PRR12 p T744

EXOC4 p T237

STK4 p S307

MYO9B p T1252LRRC41 p S276

ENO1 ack K262

COL17A1 p S93

CEP57 p T58

CTNND1 p Y296

ALB kme K223

SF3B1 kme K240

FAM117B p S180

NEK4 kme K622PLIN4 kme K89

SSH3 kme K598

ANXA8 ack K297

BRAF p S428

ABLIM1 p S669

SLC25A22 ack K83 CCS p S267

ZZEF1 p S1518

MAP1B p T704

NUP88 ack K592NDRG1 p T346

MDC1 p T150PHB p T91

CDK13 p S358

RICTOR p S1302MAP2K6 p Y203

SRRM1 p T220

SARG kme K511SSH2 p T870

CHAMP1 p S386UBXN4 p T489

DMTN p S152BIRC6 kme K1250

BAZ2A p T1621

LRRC16A p T1228

RPS10 p T101XPC p T169

ZSWIM8 p S1092

CENPV p S47MAP1B p S747

DUT p S11

AKAP10 p S52KMT2D p S4822

SAFB rme R820

LMNB2 ack K520

TTN ack K1054

DBN1 p T346CIR1 p S365

RBAK p S78TPR p T653VRK2 p S447

SLC25A6 kme K147

PPFIA1 p S1139RSRC2 p S32

HDGF p S206

RNPC3 p S108WDR33 rme R1071

FHOD3 p S345AHNAK p S5793

AHNAK kme K3229

CCNY p T75

EXOC5 p T122NUSAP1 p S247

NUP35 p T106

CCNY p S73

AHNAK kme K3681

TBX18 p T131

PRKCQ p Y545

DOCK5 p S1742

HIST1H1E ack K32

TXLNA p S218

HDGF p S202

GOLGA3 p S878

PRKAR2A p T54KIAA0930 p T293

SUPT5H p S797LMNA p T24

PEX1 p S1216

DDX1 p S362

CHD8 p T2522

BTBD1 rme R79

FARP2 p T22DCAF10 rme R134

PRPSAP2 p S198

ZDHHC5 rme R617

PITPNM1 rme R1230

TLK2 p T78

TSSC4 rme R139

AKAP8 rme R233GTF2F1 p S377

RB1 p T252

SSBP4 p T355

WBP11 kme K169

RB1 p T821

RANBP10 p S365

INCENP p S481

ARHGAP5 p S1124

EPS8L2 p S240

PLS3 p S339KRT7 rme R48

EPN3 p T495

KRT7 rme R329

LSG1 rme R14

KHDRBS1 rme R284

SCPEP1 ack K393

DIDO1 rme R1882

DOCK1 p S1751

HIST1H1B ack K35

CDC42EP1 p S192

PAK4 p T478ERRFI1 p S330

ARPP19 ack K109

FAM129B p S603HMGA1 p T53

ARHGAP21 p S1098 C17orf49 p T161

CHD1 p T1704

S100A8 ack K92

PPIL4 kme K460

SLCO4A1 p T37

PRCC kme K225KHDRBS1 kme K432

FLNC p S2646

GSTP1 p S135

SREK1 p S435WWC3 p S925

NT5DC1 ack K171

SEC16A p T415

DOCK6 p T182EEPD1 p T134

DDX5 p T507

CEP170B p T413BIN1 p S333

AFF1 p T697

MYO9B p S1267SKA3 p S152

TP53BP1 p S580

MCPH1 p T120

PCNP p S14

PNPO p S172KIAA0754 p S496

NACA p S2049

MKI67IP p T234

EPRS p S330

KANK3 p T300

NGEF p S696

PABPC1 kme K188

WDR37 p S31

FLNC p S2233

HBB kme K18

SPRY2 p S97

RB1 p S249

APOA1 ack K131

TRAF7 p S91

FAM129B p T606

PRKD2 p Y717

SYNJ1 p S1225

PROSER2 p T167C10orf54 p S305

EXOC2 p T440

AHNAK p S5782

AHNAK kme K2322

ADD1 p T724

XRCC6 p Y322

LASP1 ack K205

UTP14A kme K298

RPS10 p Y127

DDX3X rme R99

MYH10 p Y13

ERBB2IP p Y1293

ZC3H18 p S795

PCF11 rme R855MSI2 rme R228

CTNND1 p Y213

SNRPA1 ack K3

HSPA8 ack K187PFN1 ack K126

DAZAP1 rme R393

HNRNPA3 ack K36

LSM14A rme R401

GDI2 ack K174

CLTC ack K1074AHCY ack K401

PABPC4 rme R530

SSB ack K360

PRDX1 ack K68

KRT8 ack K122NQO1 ack K209

CSDA rme R169

NCL ack K16

XRCC6 ack K317

PTGES3 ack K48

RPS3 ack K10

TRIM25 kme K437

ALDOA ack K342

XRCC6 ack K123

SFPQ ack K518RAC1 ack K96

YWHAQ ack K157SAMD1 rme R284

PPP1CA ack K305HSPA4 ack K674

EEF2 ack K308

WDR7 p S1154MARK2 p S621

NUMA1 p S991CTDSPL2 p S9

RNF111 p S898

RBM14 p S620

KHDRBS1 rme R302

SRP54 p S453

FAF1 p T580

AHSG p S138

TAF12 p S51

CBL p S833

PRR12 p T224

GSK3B p Y216

CCDC14 p S96

TRAF3IP1 p S476

PAFAH1B2 p S2

PHIP p S683

PEA15 p S104

ACLY p S451

ATN1 p S168

PRKDC ack K4048EIF4G2 p T508

ZCCHC8 p S658

PDIA3 ack K466

INTS1 p S87

DCP1B p S283

ACAT2 ack K170

RABEP1 p T480

STAT1 p S727

PPIP5K1 p S1152

TMPO p T160NFKB1 p S903

IRF2BP1 p S436

GTSE1 p S435

SEPT9 p T38

NDC80 p S69

MSH2 p S717

SPTAN1 p T1552

HN1L p T76MAP1B p S1797

GOLGA3 p S107

EPRS p S910

USP24 p S1285

LRCH4 p S513VCL p S574

BCAR1 p S694

LMNB1 p S23

ALDOC p S45

XRCC5 ack K443PRKDC p S3290

EIF5B ack K275

EEF2 ack K638

THRAP3 rme R513

YWHAE ack K153

DIDO1 rme R1775

BPTF rme R68

STXBP5 p S700SLC25A6 ack K92

DLD p Y153

SMCHD1 p Y1932POSTN ack K426

DMTN p S372

ITPR3 p S1832

HIST1H4A ack K5

ALB ack K460

YWHAZ p S110

SDPR p T33SARS p T501

TDRD3 p S409

PPIA p S110

SYNM p T386

LAMA5 ack K3099

DCN ack K280

ARFGAP1 p S234

FRS2 p T132

RALGAPA1 p S775

GEMIN7 rme R23

TOP2B p S1552

PDPK1 p S45

TOR1AIP1 p T20

SLCO4A1 p S43MMADHC ack K203

TMEM194A p S368

GAPVD1 p S769

CUL4B p T85

COBL p T291

CAMSAP1 p S371

JMJD1C p T650

RB1 p S350

PLEC p S4390

MEX3C p T455

ZHX2 p T207

GTF2F1 p S436

ZC3H18 p T809

DMAP1 ack K86

CCDC86 p S255

NCBP1 p S22

SURF6 p T184

FUBP1 p T151

PDHA2 p S291

ASPH p S374

DISP2 p S1270

ETV3 p T157

RASA1 p T462CIC p T305

TLK2 p S73

AHNAK kme K5725

POLR2B p S467ARHGEF12 p T699NXF1 p T85

TUBB p T290

CEP128 p S950

FAM83A rme R419

NUPL1 p T445PLEKHA5 p S549

BCLAF1 p S276

ADAR ack K1115

RAB44 p T157

NCL rme R660NSUN5 p T462

TRA2B rme R238C2CD5 p T278 EHBP1L1 p S964

FOXK1 p T436

FARSA p S301

RBM15B p T631

RRAGC p T394

CENPT p T27

FAM65B p S37PPFIA1 p S708

MCM4 p T23ANP32A p S17

ERF p T526INCENP p S275

REM2 p S68

NUP210 p T1844

TCF20 p S1792

RBM12B p S575

NEK6 p S206

IWS1 p T725ATR p T1989

SPAG1 p T409ERBB2IP p T485

LIMCH1 p S589

PDE4D p S362AHNAK p T490

RBM27 p T888

ADAM9 p S733

RNF4 p Y107

OPTN p S198ZC3HAV1 p S302

VIM rme R69

GAPVD1 p S766LIMA1 p S346

GAPDH ack K27

CIT p S1350

SYNPO2 p Y925

PNN p S114

POGZ p T1368ATAD2 p T1152

ATAD2 p T1158TSC22D4 p S49

MLLT4 p S239NUMA1 p S1792

TJP2 p S978

AKR1B1 p Y40

ABLIM1 p S587

DOCK7 p T186

FAM129B p S605CSPP1 p S904

TERF2 p S365

NUP107 p T45

PLEKHA6 p Y471

BRPF3 ack K449

STAT1 p Y701

ERRFI1 p T127

ZDHHC5 p Y533

APRT ack K167

SNX1 p S368

MAF1 p S73HIRIP3 p S370

PAK2 p Y194

AP1B1 p Y6

ITGB1 p T544

FGA p T505

RPL17 p Y63

TRIM47 p S461

PRPF40A p S192MCFD2 p S38

GDI2 p S396SMARCA4 p T1428

YES1 p Y446HNRNPA1 rme

R196

SHMT2 ack K469CHEK2 p T383

SARM1 p T553

NUMA1 p S1847

NACAD p S148

MYO9B p S2049

MSI1 rme R197

HNRNPU ack K592

BRPF1 ack K383

MAP2 p S1545

MAP2 p T1616

AUTS2 p T119

REPS1 p S186

WDR62 p T1053

PDE4D p S59

NDE1 p S231

FOXM1 p T620CHD9 p S550

CKAP2L p T648

HAUS6 p T584

SYNPO p T856

TPI1 kme K231

PUF60 p T60ARHGAP11A p

T508

TJP2 p Y1178

HDLBP p Y437

ERBB3 p Y1307

PKP4 p Y1168

CTNND1 p Y257 EHBP1L1 p S1257

CBR1 ack K211

GNL1 p S68

ITSN2 p Y968

ACOT9 ack K103 RALY ack K165

SNIP1 p S128

CDK9 p S347

FRYL p T1959

ARID1A p S1609

NHP2L1 ack K21

PPP1R7 p S27

GPS1 p T479

ACTR8 p S412

PML p T409

PKP3 p Y176

SHB p Y268

KIAA1217 p Y393

FHOD1 p S357

ITGB4 p Y1207

ERRFI1 p Y394ITGB1 p Y783

ERBB3 p Y1328

EPHA2 p Y575

RPS9 ack K116

MAGED2 p T72

TRMT1 p S623

NCOR1 p T568RPS9 p T15

NDE1 p T228

CTDP1 p T391CCDC86 p S219

PCMTD2 p T274

NCBP1 p S7MICAL3 p S1221

SRRT p T544MDC1 p S1570

KIAA0754 p T122

MGA p S924

UBE2C kme K18

RPS6KB1 p S447

KHNYN p S10

ELAVL1 rme R206

PSMC2 p T426

XRCC6 ack K468

PINX1 p T164

PRDX6 ack K215

TOMM70A p T85SLX4 p S1185

PGD ack K316

HNRNPUL2 rme R666

SRSF1 ack K174

AKR1C1 ack K201

LSM4 rme R125

PCF11 p S494

SLC30A6 rme R440

DHX16 p S348PHF10 p S50

CDV3 p Y244

CCDC94 p Y31

AKR1C1 ack K9

PPP2R5C p S520

FAF1 p S582

XRN2 rme R824TJP1 p S125

TRIM33 p S1119

RCOR1 p S257ACTR3 ack K244

CSTF2 p T317

ZDHHC5 p Y456

TUBB p S115

RNF4 p T110

CSTF2 rme R319

ZNF219 p S114

RALY p S106

PSMA7 p S216

MTCL1 p S1514

CSTF2 rme R381

ANKHD1 p T2323

MTMR10 p S751

MED14 p S617 HSPE1 ack K99

RPS3 ack K108

SLC25A24 ack K336

FAM129B ack K507

CD44 p S697

CYB561 p S250

LMNB2 p T34

VCL ack K444

SLC2A1 p S490

PSAP ack K414

VCL p S357

AP1M2 p T223

REPS1 p Y275RAI1 p S1164MTA2 p S548

RUVBL1 ack K171

CIC p S1402

C9orf142 p S148PPM1H p T227

NUP98 p S1060PPP1R13L rme R200

ZBTB34 p S209YWHAZ ack K11

STMN1 p S25

YBX2 p S189MCMBP p S298

HGS rme R557

BCLAF1 p S268

HNRNPL rme R46

PARD3 p Y388

TRA2B p Y260

KRT18 p Y13

RECQL4 p S27

KRT8 p Y267

F11R p Y280

MARVELD2 p Y14

PKP4 p Y425

CTNND1 p S244

NONO rme R256

CXXC1 ack K250

RPRD2 p S487

LPP p Y412

PTPRF p Y1321

EPB41L1 p Y864

BAG3 p Y247

MYH9 p S1943

OTUD4 p Y439

BAG3 rme R261

SYNJ1 p S1063

HBB ack K83

INTS1 p S1363

TBC1D30 p T119

BDP1 p S1317

ANXA2 p Y318 KDM1A p T59STMN1 p S38

ICE1 p S960

MAP2K2 p S293

GIGYF2 p S258SLC7A11 p Y15

EPS8 p Y525

PLEKHA7 p Y1011

SND1 p Y109

MAPK13 p Y182

KRT7 p Y40

ANXA2 p Y30

LUC7L ack K357

SPTAN1 p Y1073

PSEN1 p S357

PBK ack K12

PXN p Y88

LARP1B p T454

LSR p T327

HSPA5 ack K617

MOGS p T18

ITGB4 p Y1492GOLGA4 p Y2148

PSMA7 rme R163

SCYL1 p S679

UMPS ack K162

NONO ack K295FAM120A rme

R984

SCP2 ack K443

RPL29 ack K56

THOC5 p T328

NKX2-1 rme R10

VIM ack K188

FAM120A p S511

MST1R p Y1238

MBIP ack K301

UBR4 ack K1084UBN1 p S493

HSP90AB1 ack K347

VDAC1 ack K96

MEF2D p S444

CAP1 kme K287

SMC6 p T1083

SPTAN1 ack K1486

PRRC2C kme K27

KMT2C rme R886

HNRNPUL1 rme R179

RUVBL2 p S220

KMT2C ack K2769AHNAK p T5796

PPP1R12A p S802

HLA-A p S356

HIST1H4A p Y98

SFPQ rme R242

HSPA1B ack K348

ATAD5 p S621

PLEKHA2 p Y185

GLUD1 ack K457

PKP4 p Y494

GMIP p S919GATAD2A p T20

PHF14 p S294PHC3 rme R837

GAPDH ack K139

EEF1B2 p Y182GATAD2A rme

R213 CFL1 ack K132

PHACTR4 p S131

EEF1B2 ack K176

E2F2 p S123

APMAP p T19

RSRC1 p S5

DOCK5 p S1869

NCL ack K348

PHC3 p S315AKAP2 p S152MYL12A p S28DBNL kme K164

PRDX1 p S126

SLC4A2 p Y73

KHDRBS1 rme R331

HNRNPA3 rme R214

SLC4A2 p T309

PRKAA1 p S494

HSP90AA1 p Y492

ALDH1A1 ack K362

HLA-A ack K170

PPIG p S636

SFPQ p Y602

SFPQ p Y698

HIST1H2BK ack K44

HIST1H1C p S36

HNRNPL p Y47

GMIP rme R874

GTF3C2 p S165

SF3B2 rme R222

MISP p S394

SET p Y146

EPS8 p Y45

SERPINA1 ack K258

LXN ack K55

SAMD4B rme R602

CRK p Y136CPSF6 rme R202COL4A2 ack

K1494

PTPLAD1 p S135 PRKCI ack K175

PPP1R13L rme R167 MED12 ack K80

NCL kme K80

TLN1 p Y2239

PRKCI p Y136

GALK1 p T103

SHMT2 ack K464

MFF p T137 TC2N p Y154

SRSF1 rme R97

THRAP3 rme R66CNBP rme R79

IRS2 p T314NARR rme R178

ALDOA p T52

TBC1D5 p S730

CCT2 p S260

PRKAA1 p Y500

MYL12A p T18

PLEC p S4400

ABLIM3 p S504

RPS3A p Y133

RARS p Y338LRBA p S1787

SYNCRIP ack K576

LDHA p Y83

CAV1 p Y6

TRIP6 rme R236

PPP1CA ack K141

S100A11 p Y32

RPS8 p Y188

DLG1 p Y753

ATP5B p T60

TRA2B rme R233MDH2 p Y161

TPM3 p Y163CAV1 p Y25

RPL35A p Y34

FILIP1L p S992

C19orf43 ack K124

PIP4K2B p S131PHLDB1 p S583PKP4 p T432 PDIA3 ack K94

ARID1A p S698

DCP2 rme R319PARP1 ack K700

TPX2 p S292

PARP1 p S874

ERBB2IP p S1242

USP34 p S3406PHF3 rme R1785

PAK4 p S488

DNAJA3 ack K134

AASDHPPT ack K151

FUBP1 ack K218

FLNB rme R262

EFNB1 p Y313HSPH1 ack K648

CSRP2BP ack K292 COL6A3 ack K228

FAM129B ack K479

ARPP19 p Y59; ENSA p Y64

EIF4B p S406

NPM1 p S217

MYO18A p Y1140

NECAP1 rme R180

MDH1 ack K298

ARHGAP32 p Y1927

SRRM2 p S1729RBM4 ack K139; RBM4B ack K139

RAN ack K60

SPTBN1 p T2320SRGAP1 p S497

RAD50 p S635

KIF1C rme R958

SUCLA2 rme R106

HSPH1 ack K221

TAF6L rme R555

TAF15 rme R570

HNRNPH1 rme R224

MAP1S p T521KRT7 ack K122

CACYBP ack K85

DAB2IP p S101

QKI rme R219BRD3 ack K307

BPTF p S822MAPT p T470MAPK13 p T180AKAP12 ack

K1548

YBX1 rme R192WDR77 p T5WDR1 ack K180FUBP1 rme R359

ZMYM3 p T826ZNF185 p Y581 VPS37B rme R206HSPH1 p S304 VGLL4 p T46APLP2 p T754

HMGB1 ack K172

NUP153 p S333

RBMX p Y335

SRSF2 rme R117

NUMA1 ack K2040

RBMX p Y266

PABPC1 rme R475

RBM47 rme R394RBM4 rme R358

ARHGAP32 p Y1520

SRXN1 rme R16

CREBBP p S2361

RPL13A ack K191

SRSF6 rme R85PPP1R13L rme

R180

EML4 p Y226

LMNA ack K420

RIN1 p Y36

PRDX1 ack K109

MAP7D1 rme R326

ATG3 p Y18

CHERP ack K879

TBL1XR1 ack K102

RPS13 p S48MTOR p S2454

RPL15 p T197

PECAM1 p Y713

RPS6KA3 p Y234

AKAP8 rme R109

SLTM ack K803 PRPF38B p S481SRSF2 p Y115

SRSF4 p S402

RAI14 p T297RPL34 ack K36

SRSF1 ack K179

MFAP1 p S132

CTR9 p S943CSDA p Y287

CSDA rme R220

PAIP2 ack K123

CEP170 p S1019

CASP2 rme R22 MDH1 p S111

C6orf132 p Y1045

NUP153 rme R1465

CCDC104 p S201

NUMA1 p S1601ARFGAP3 ack

K498

CDC5L p T424C6orf132 rme

R1038

BGN ack K288

ARFGAP3 p Y356AKAP12 p S698

CALD1 p T546 PCBP2 p Y236

DDX42 rme R875

PDIA4 ack K506

DNMBP rme R480

DNMBP p T1462DDX42 ack K650

BPTF p S817

WIPF2 rme R119

HNRNPA3 rme R377

HJURP p S448

KIF18B p S645

WDHD1 p S1058

GTSE1 p S243FASN ack K1871SF3B2 rme R502

CCDC88C rme R1877

ZDHHC5 p Y630MSH6 p S14

OXSR1 p T189TJP2 p Y261

ZDHHC5 p T348DLD ack K277

CINP p T10

SIRT7 rme R388

ZNF511 rme R240TJP2 p Y249PRRC2C rme R281BRWD1 p T687

PSMC1 p T434

SLC25A4 kme K147

SPAG9 p S268

SCAF11 rme R1096

SP3 ack K593

PPHLN1 ack K180DLG3 p Y673

C12orf5 ack K50

STMN1 ack K119SRSF1 p Y72LPIN1 p S166

HSP90AB1 p Y301

AFP p Y377

EIF4H rme R145

FLVCR1 p Y22

DAZAP1 p T86MYH10 rme

R1930

MYO6 ack K750

MOB4 ack K155

MLLT4 p Y584

APLP2 p Y757

FAM103A1 rme R70

CTTN p Y453

ACTR8 p S132

HSPD1 ack K31

MATR3 p S533

HNRNPA1 rme R352

TAGLN2 rme R196

GOLGA3 p S983

SFPQ ack K314NPM1 kme K223

HCFC1 rme R847TAF15 rme R403

MYC ack K148

FLNA p Y775

SPATS2 rme R449KHDRBS1 rme

R442 ECHS1 ack K261NUP35 p T280

HNRNPH3 rme R116

SRRM2 p S908

THRAP3 rme R825

TAF15 rme R535

THOC5 p T30

HSPE1 p S37

INCENP p S97

PRKCI ack K134

HMGB1 ack K59

FH ack K80

CDC25B p S151ICE1 ack K1218

HSPA4 ack K631

GMPS p T318

CAV2 p Y19

TLK2 p Y70TIMP3 ack K68

EIF4G1 rme R1042

TIMM44 p S180

HBA2 ack K17

TNK2 p Y284

PRKDC p S3294

MAGI1 p Y373

LSM4 rme R109

KRT81 p Y282

EHMT2 p S115

DCBLD1 p Y665

TYW1 ack K396 MPLKIP rme R126DDX5 rme R20

CAPZA2 ack K19

MISP rme R496

TRIM33 rme R591

CHD8 p S2518

TUBB ack K58TRIM28 ack K254

ANP32B ack K68

BRCA2 p T2035MISP p S397

CALR p Y109

LMNA p S406 MAP7D2 p Y301CRK p T228FRS2 p Y306

MAP3K11 p T755

APBB2 p T62

BCL10 p T52CDK18 rme R463PPM1H p S223

CCDC92 p T201ACLY p T447

SMTN p T315

WBP11 p Y236

TFPT p T207UBAP2L p S416ENAH p T489

PABPC1 rme R436

KDM3B p T614FAM21A p T437; FAM21C p T437

CFL1 p T25

PCNXL3 rme R274

SMTN rme R642

WNK1 p S1838

MACF1 rme R7361

SARM1 p S548

ANK2 p S1940

NEK6 p T210SASH1 rme R920

PITPNM1 rme R1211

SRRM2 rme R2207

BRIP1 p S116

RRAGD p T395

FRMD8 rme R219MYLK p T1624

SCAF11 rme R969

SSBP2 p T333CSTF2 rme R344

CTAGE5 rme R560

STAU2 rme R137

TAGLN2 ack K88

HADHB ack K181

TPM4 ack K132

NFIA p S287

KAT6A ack K90

NOLC1 ack K33

TNRC6B rme R1315

CAPZA2 ack K86

ATPIF1 p Y58

FZD6 p S606

TJP2 p Y506

RAB1A ack K61

SATB1 p S633

EPHA2 p T593

DCDC2 p S433

C12orf75 p Y42

C11orf52 p Y78BAIAP2L1 p Y16

ACTN4 ack K622

PIK3R1 p Y556

DDR1 p Y796MYO1E p Y971

EPB41L1 p S650

C12orf75 p S47

PLEKHA1 p Y345UBE2E2 ack K52

HSPA1B ack K524

NCS1 p Y115

FAM83F p Y327

EIF5A ack K85RPS18 ack K94

LGALS4 ack K83

CD2AP p S233

ANKZF1 p S361

FAM83H rme R496

HNRNPA1 ack K166

RAVER1 rme R477

TPM1 ack K248BCL7C p S126

TAGLN2 p S185

RBM14 p T206

HBB ack K145

ENAH p S136

SLC25A3 kme K112

THRAP3 p S444

CNNM3 p S673

SPTAN1 p S1550

PYGB p T210

HBA2 ack K100ABLIM1 p S458

XPC p S351

DYNC1I2 p S97

RBM14 p S562PHACTR2 p S23INF2 p S433

MTM1 p S593DYNC1LI1 p S207

LMNB1 p T575

SLK p T193

MYO9B p T1271

LIMA1 p S490LASP1 p S82

FAT1 p T152

NUMA1 p T2099ZC3H7A p T210

TMPO p S354

CGN p S134

SRGAP2 p S206

PDPK1 p Y248

PARD3 p S1337

TNS3 p S850

NBEAL2 p S2739

SF3B2 p T201

RPL13A ack K53LMNB1 ack K483

GAGE1 rme R13; GAGE4 rme R13

AKAP13 p S2498

MSI1 rme R199

SND1 ack K541

TMEM100 p S121

PNPLA2 p S404

PRKDC p T1733

INCENP p S208

SUGP2 rme R212

PAK6 p T99

DYSF p T184NUP35 p S279

MARCKSL1 p T61

MDC1 p T242

MYCT1 p T219

IGF2BP3 p S248

PHF10 kme K206

DLST ack K277

RYBP p T215

LIMK2 p T278

PSMC1 ack K258

SHANK3 p T1234

PRKCI p T412

GSE1 p S857

DHCR7 ack K454

FAM73A p S147NANS ack K52

REPIN1 p T510

SLC7A2 p T467

NAA50 ack K140

FOXK2 p T389

PCBP2 p S107

KIAA1211 p S878

FAM156A p S11

KMT2A p S449

VPS13C p S2071

RPL27 ack K117

RAPGEF1 p T1071

RASAL1 kme K399

KDM2B p T1004

ANKZF1 p T364

ALMS1 rme R2668

RBM39 rme R109

TFPT rme R68

KHDRBS1 rme R340

TRA2B rme R241

ZNF326 rme R235

YBX1 rme R199

HCFC1 rme R1253PYGL p S524

VDAC2 p Y184

PYGL p S517SMEK1 p T685

TPI1 p Y246

EEF2 p Y265

RPL5 p Y183

EEF1D p Y26

SRSF5 rme R88

CCT7 rme R53

CCT4 rme R19

SRSF9 rme R93

EIF4E2 rme R241

KHDRBS1 rme R320

ALYREF rme R50

VIM p T202

TPI1 p Y105

TUBA1A p T349

TNPO1 p T35TXNDC5 p S292

SF3B2 p S778

GAPDH p T246

VDAC2 p T199PLN p T17MVP p S563

COX7C p Y19PPM1G p S183

TCOF1 p S1410

TACC2 p T2387

VIM p Y383

CCT4 p Y24

HMGB2 ack K43

SAT1 ack K26

XRCC5 ack K534

KHSRP ack K653

ST13 ack K186

PFKP ack K688

MDH1 ack K73

JADE2 ack K298FASN ack K1158CANX ack K458

MDH2 p T179TKT p Y321

NPM1 ack K157

SLC25A10 p S93

GGCT p S56

PRDX1 p T156PLEC p T1859

EI24 p S56

DDI2 rme R108

RPS7 ack K178RANBP1 ack K183

CTTN ack K263

KHSRP rme R413

PGK1 ack K322

NAPG ack K195

HEXB ack K382

DSTN ack K44

TPT1 ack K130SF3B3 ack K787

PPIB ack K129

IDH1 kme K87; IDH2 kme K127

EEF1G ack K434

CLTA ack K242YWHAZ ack K49YES1 p Y426

MICALL1 p T318

MGA p S534

PLEC p S4389

SIRT1 p T530HSP90AB1 p Y619

DIS3L2 p T15

DDX56 p S526BRD1 ack K523BCL2L12 p T171

PROSER2 p T146

KIAA1522 p S161

PRKDC p T2603

H1FX p S31

GAGE2A p T39

ZRSR1 p S425

GAGE2A p S114

ZNF318 p S709

PBRM1 p S16

EPN1 p T470

SRRM2 p S1329

FAM21B p T342

DDHD1 p S11

ZMYM4 p T217

UQCRFS1P1 p T46

RCSD1 p S351PML p S408

PAPOLG p S708

MED13L p T1050

CHD8 p S2519

EHBP1 p S710

FAM129B p S574

SP110 p S244CRKL p Y207

FXR1 p T511

TWISTNB p T322

TNS1 p Y1404

NFIA p S280TNS1 p Y366

SIPA1L1 p Y159

VAV1 p Y844

CCNL1 p S445

HSP90AA1 p Y284ARPP19 p Y59

ARHGEF17 p S914

ZNF106 p S1328

MTOR p S2448SRRM2 p T983

SIPA1L3 p S158

SF3B1 p T313RNF219 p T60

MAP2K1 p S222

LYAR p S276

LSR p S464

HBD ack K60

BCLAF1 p S264

EIF5B p S182

MYBBP1A p S1241

SPEN p T1619

CRTC2 p S433

RANGAP1 p S442CENPF p T3045

HN1 p T54

TLN1 p S1227

TLN1 ack K1221

BEGAIN p S246

TLN1 p S1333

ING5 ack K154

ETFA ack K232

FH p T85

ALB p Y164

TAF15 rme R464

TAF15 rme R195

PRPF38B p S475

TNKS1BP1 p S851

TAF15 p S180TCOF1 p S1350

C5orf30 p S132

PABPC4 rme R442

EEF1A2 kme K318

TCEAL2 rme R205

HIST3H3 kme K38

SLC15A4 p S298

TAF15 p Y156

TAF15 rme R467

AHNAK2 kme K3744

AHNAK2 p S317

ZNF318 ack K1866

PRPH rme R72

PRPH p S75

SSBP1 kme K122

ANKS1A p S887

TRIM9 p T41

UCHL1 p T205

ZNF24 p T195XKR7 p T558

AHNAK2 kme K3414

UBA1 p S293KPNB1 p S50

RPS20 p T25ZNF239 p T190

MKI67IP p T238

KARS p S81

EPB41L2 p T20

RBBP6 p S1695

BAG3 rme R258

JMJD1C rme R897

AHNAK2 kme K2417

TKT ack K6

ITGB5 p Y766

EEF1A2 ack K79

HSPA8 p T226

AHNAK2 kme K1757

HMGN3 p S6

POM121C p T424

DLGAP5 p T326

FN1 p S1122VCL p S579

SRRT p S21

MPDZ p T1609

CSTB p S45

ATXN7L3B p S92

MFAP4 ack K246

SECISBP2L p S344

PABPC1 rme R481

NARR p T69

RRS1 p S329

ZC2HC1A p S247

MARK3 p T507

INTS1 p S82

MYOZ1 p S116

MICAL3 p S1640

TP53BP1 p S830

MED1 p T1440

CLINT1 p T462

TCF12 p T335

MAGED1 p S457ZBED1 p S9

RPL26L1 ack K41

DARS p S192

RTCB ack K496

SP3 rme R611

SART3 rme R906

SNF8 rme R4

POLR2B kme K1052

RRP12 p S1049

RPS17 p S115

PDS5A p S1278

EPB41 p S92

GPR157 p T328

CLSPN p S1147 WDR33 rme R1035

WWC2 p S1002 WDR33 rme R1144 SVIL rme R1203

ZGPAT rme R370

SUV39H1 p S391

EIF4H rme R19FANCD2 p S1401

API5 rme R500

PYCR2 ack K47

RBM14 p T572

TAGLN p S186

NIPSNAP1 p S156

ECT2 p T444

TNS2 rme R555VCL ack K992

LDB1 p S410

BOD1L1 p S2128

RELB rme R16

PDGFRA p Y988

BCL9L rme R994VHL rme R79

FMNL1 p T1020

DOCK7 p S900

CSRP1 ack K108GPBP1 p S55

AKAP12 p S887

PDGFRA p Y613

VIM ack K236

VIM p Y117

PDGFRA p Y762

DNAJC30 p S39

PRR14 p S207

PLEC p T1235HADHA p T185

PPIB p S150HADHA p T167

VDAC1 p T188

PPP1R13B p T676

TICRR p T1127

EEF2 p T724CSE1L p S269 RASSF1 p Y259

PRKD2 p S198

MYPN rme R810

WDR33 rme R782

SYNCRIP rme R526

EPB41L2 rme R72

HSPB1 p S83

TNS1 p S769

ZBTB20 p S353TJP3 p S342

PHACTR2 p T20PKP3 p S115

FAM195A rme R27

PDE12 p S219

TRMT1 p S625

METTL15 rme R395

WNK1 p S382CCDC82 p T227

YES1 p Y222

NRK p Y217

XRN2 rme R936

WDR20 p S347

NUP98 p T1772

FAM129B p Y593

CTTN p S417

TUBA1A p Y108

CLIC1 p Y214LMNA ack K378; LMNB1 ack K379

PFDN1 p S78PFN1 p Y60

PDIA4 p Y264

ARHGAP5 p Y1109

TMPO p T355

GOLGA3 p T110MIOS p Y761

LMNA p S403

RABEP1 p S410PERP p Y190

NDRG1 p T375

EPN3 p S498

PLEC p S4037

ABLIM1 p T670

RRP15 p T104

FLNA p S377

STK10 p T14

RNF213 p T302

RPL19 p S12

DLGAP4 p S666

C10orf12 kme K140

ARHGEF5 p S657

CTNND1 p Y174

LMO7 p S1207

TRIM47 rme R184

TAF1C rme R728

TJP1 rme R1151

PDLIM2 rme R169

BCAR3 rme R442AHNAK p S5784

AHNAK ack K4074

AHNAK ack K3356

PPP1R21 p S653 EPN1 rme R534

TYRO3 p Y685TAF15 rme R415

LCK p Y192

AKAP13 p T2391

PPP1R14A rme R21

TPM4 ack K212MYH10 ack K1256

TUBB3 ack K58LATS1 p S909

MYH9 ack K74

MYO1E p S980

PDCD4 p S457

AHNAK p S212PRKCDBP p S62

TWISTNB p S316

C15orf39 p T364RBM12B p T640SLCO4A1 p S40

C10orf12 p T1218

CEP164 p S544KIAA1462 p S931

MYOF p T228

BRD9 p S138

PPP1R13B p S681

AIM1 p T524

PABPC1 p Y513FAM129B p Y565

ARHGAP12 p Y355

DSG2 p Y775ERBB2IP p Y1164

C11orf52 p T101

ACTR3 p T119

CEP170 p S1029

EHMT2 p S118

ELMSAN1 rme R177

EEF1A2 p Y177

CCT7 rme R537

TPR p T2137

RPS4X p T196

ZNF185 p T513

EIF3A p S1188

CTDP1 p S841C6orf132 p T297

SURF2 p T195

SDHA p S321

HSP90AA1 p Y61

CHCHD6 p T153BTBD7 p S1012

PARP4 p S1335

TJP2 p S163

PKM p T412

SCLY p S129

EIF4B p S230

SHROOM3 p T1205

POLR2M rme R45

TAF15 rme R580

CRKL p T228

NUP107 p S37MET p Y1235

MST1R p Y1239NUDT9 ack K319

REPS2 p Y558

PUM2 rme R454

PPFIBP1 p S794

CLDN7 p Y195

CHTOP rme R87

UGDH ack K107PUM2 rme R462

MYO15B rme R1068

TFIP11 ack K155ITIH2 ack K190EEF1A1 ack K255

APCS ack K98

PFN2 p S92SCAF11 p S830

DOS p S319

RBM14 p S571SEC22B p S35

RPL18 p T42

ARL3 p S58

MED13L p T1053

TMEM48 p S445TANC2 p S1740

CNN3 p S215

SORBS3 p S539

USP15 p S229RANBP2 p T1399

SIRT1 p S525

GAS2L1 p T474

SMC2 ack K330

ECT2 p T359

ACAD9 p Y611EML4 p T160

TTF1 p S240

ROCK1 p S580

ZNF185 p T505

SEPT9 p S41

CPNE8 p S260

IRS2 p Y675

C12orf43 p S53

MED13 p S504

ANXA7 p Y350NUP214 p T416

PROSER2 rme R378

EZR ack K60

SPAG9 p T1264

SZRD1 p Y95

RBL1 p T997

ACSL3 p T688

CASK p Y321

ME2 ack K74

NT5C3A p T105

HIST1H1B ack K149

SON rme R929

PHKA1 p S758MATR3 p S188

MAP1B p S336

CEP170 p T644

AQP4 p S285

FAM120B rme R885

BCL11A p S711

MCM3AP p S538

AHNAK rme R270

C19orf47 p S154CPEB3 rme R308

TTC26 rme R12

MTCL1 p T1417

DHCR24 p T373MAP1B p S1400STXBP5 p S692

SORBS1 p S325

ZNF318 p S1896

HIST1H2BK kme K21

TCEAL5 rme R185CBX8 p S256

SRRM3 p T116

EXOC2 p S435

BCKDHB ack K294

AP2A2 p S566

MAP3K10 p S830

RBM20 p T1104

FARP2 p T413

LARP1 p T1071

ZDHHC5 p S380

DDX17 rme R2

MAP2 rme R1552

DOCK4 p S1717

SMARCC2 p T322

CAPN15 p S456

BTG1 p S159

PWWP2B p S206PSMD2 p S367

GSG2 p T112

DCN ack K130

MAPKAPK5 p T182

RAB39A ack K63

CLASP2 p S523

EEF2 ack K259

CLIC5 ack K333AHNAK kme

K4603

TP53BP1 p S1067

STAG2 p T1146HBA2 p Y25

MAPK13 p T265

FAM129B p T611

UHRF1BP1L p S1081

CDC42EP4 p T188

CCT7 ack K67ATP1A1 p Y542AP2B1 p Y6

KRT6A ack K173

SPTAN1 p S1231

TAGLN2 p S11

WDR47 p S297

FANCE p S210

PPIA ack K151

NUMB p T436ROCK2 p S550

MICAL3 p S649

KRT6A rme R40

AKT2 p S474

HP1BP3 p T51

DLD ack K273 RTKN p S106

WEE1 p T644

GPRASP2 p S521

RNF214 p T546

DSP p S1926

PSMD14 p T266

COPB2 p S604

SORBS1 p S495

KHNYN p T413

AP2B1 p T245

HSP90AA1 ack K567

FAM193B p T669PPIL4 ack K460

BAG3 p S279

ARID1B p S632

KIDINS220 p S1559

ARFGEF1 p T1072

PKN2 p T814

DHRS13 p T264

MYO18A p S1843

SNX4 p T210

BCAT2 ack K229

SRSF6 rme R94

H1FX ack K195

BRD3 ack K304

HIST3H3 kme K10

FBL rme R70

HNRNPK rme R249

DHX33 rme R43

HIST3H3 kme K80

RPL15 p Y59

ANKRD54 p S63

KCNK5 p S266

LDLR p S849

KIAA1109 p S1312

RBM12B p S710THRAP3 p S243

RPL29 kme K5 HNRNPK p S284

ANP32B p T244

ZSCAN18 ack K366 PPP1R12A p S509

CBL p Y674

GOT2 ack K59

SEPT6 p S411

FLNB p Y2502

BAG3 p S284

RPS3A p Y256

GFPT1 p T263

CHD8 p S2551

AAK1 p Y28

OCLN p Y337

EPS8 p Y485

IFI16 p T435CTNND1 p Y865PLEKHA5 p Y436

OCLN p Y368

NUCKS1 p S14CPSF6 p Y520

KANK1 p S312

RBMX p Y310

NOM1 p S15AKAP2 p S405

RAB27A rme R64C10orf12 p T825

CPSF6 rme R216

RBBP8NL rme R365

TRIO p S1632

BOD1L1 p T2956

GPS1 p S483

DCTD p S35

RPL34 p Y78

YWHAZ p Y48

TUBB p Y159

SNX27 p T215ACAT1 ack K230

HDAC7 p S155

CCT7 rme R535

HNRNPL ack K34

APOE ack K260

SNRPB rme R108

WBP11 ack K13

PDIA3 p Y445

STIP1 p Y468

AHNAK kme K3553

SMARCAD1 p S132

MLH1 p T495RASSF7 rme R125

IGF2BP1 p T446 RIF1 p S1542

MTCH1 rme R29PRKAA1 p T382

PABPN1 rme R263

RBMX rme R125ACLY p T434

HIST1H3A kme K37

TACC2 p S2389COL8A1 ack K637

ABLIM3 p S503

UTRN p S1415

HSD17B4 p T265

CEBPB p S231

CDC42EP5 rme R38

U2AF2 p S79

SNX16 p T100

AAK1 p T389

MAP1B p T1788

SPIDR p T248MKI67 p T844

SRRM2 p T1492

NCOR1 p S2120

ZNF638 p S193

SREK1IP1 p T146

NUMA1 p T2000

ENAH p T493

WDR33 rme R1067

SLC25A5 kme K52

TUBA1A p Y161ZMYM3 p T817

NUP214 p T1312

STK38L p S282SRSF3 p Y13CD46 p Y357

IRS2 p Y742

IRS2 rme R412

HIST1H3A kme K36

IRS2 rme R569

HIST1H3A kme K9

HIST1H3A kme K27 IRS2 p Y576

HIST1H3A ack K4

CLASP1 p S646

RPL27A ack K47

SCP2 ack K546SKIV2L2 ack K51RPL19 ack K153

RPL15 ack K179

QARS ack K421

PARVB ack K24EIF4B p Y237IRF2BP1 p T377

EIF4B rme R308

FAM103A1 rme R85

EIF4B p Y285

GAS2L1 rme R642

BARD1 p T299

RAPH1 p Y667

IRS2 p S577FLNA p Y2571

IRS2 p Y111

FLNA p S2370

DVL3 p S622

ERP29 p Y66FAM21C p T437

KIAA0556 p S673PRDX1 p S196

DCP1A p S523PSMC5 ack K222

SAMD4A p T424GAPDH ack K66

HSPD1 ack K218

LGALS8 kme K204

PSMF1 rme R205CKAP2L p T742

RBM25 ack K283

LSP1 p S204

TICRR p T1119

ACTB p Y91

OTUD7B ack K505

MTDH p S295CEBPB p S237

ACTB ack K68

MAPK14 p T185

TNRC6B p S421SLC38A2 p Y41

DHX9 p S125

ARHGAP21 p T1073 RNF213 p T303KANSL1 ack K180

PPP4R2 p T173MAP1B p T1853

TJP3 p S338

SRSF12 p S148

AKAP13 p S1898

KRT8 p Y282KRT18 p Y94INPPL1 p Y1162

PTBP1 p Y430

HNRNPA1 p Y167

PTBP3 p Y127

FSCN1 p Y111

DERA p Y302

PGK1 ack K48

RAC1 ack K153

NONO rme R135RBPJ ack K8

CAP1 ack K81

CUTC p S17

RB1CC1 p S644

MADD p S813

AFAP1L2 p Y383

CRK p Y239

TNS3 p Y855HSP90AB1 p Y305SMC3 p S1067

CFL1 p Y117

TUFM p Y92

TOP2A p S1474

FOXO1 p S256

ACTB p Y198

TACC3 p T59

RBL1 p T369

RPL19 p S122H2AFX ack K5

KIRREL p Y625

IWS1 p S720

EPRS rme R1152PRKDC p T2620

TJP1 p T354

CDK9 p T350

PTK2 p Y688KANK2 rme R243

LIX1L rme R18

PPP1R13L rme R185

TWF1 p Y309VIM rme R12

TRIP12 p T152UBA1 ack K671

TRIOBP p Y2325EIF4A1 p Y70

HNRNPK p Y280

GTF2F1 p S203

AHCTF1 p S1900RPL26L1 ack K77

RPS10 p Y12

KMT2D p T2332

RPL11 p T47

AAAS p S541

MAF1 p S85 MARCKSL1 p S151

IGBP1 p Y277SHB p Y336 RPS28 p T28HMGB2 ack K182

SEMA4B p S825

HUWE1 p S2391

PRX p S1439

HUWE1 rme R3138

TPX2 p S486

HNRNPA2B1 rme R352

LDLR p S846REPS1 p S709

PLEC p S4396

EWSR1 rme R486

SAFB rme R749

SYTL1 p Y304TFG rme R400

NUMA1 p T2015

MYO6 p Y1146

EIF4G1 p T205

ALDOC p T52

SPAG9 p T365

NUP93 p S783

PDZD8 p S538

PLEKHA6 p Y341PKP4 p Y114

SUPT5H p T806

KIAA1522 p T162

CDK1 p S39

CD46 p Y354

RPL10A p Y11BZW1 p Y244 YBX1 p Y72RPL35 ack K43CTDSPL2 p S104

ARHGAP21 p S476

EPS8L1 p S549FGFR1OP p S156

EIF4B p T427

KANK3 p S293

RTN4 p S107

RPS10 rme R160AHNAK p T5798

GANAB p S190SLC25A5 p T233

PKM p Y390VTN ack K194

CRK p S85

HSP90AA1 p Y197

CDK2 p T14

SH3BP5L p S233ADD1 p S726

HNRNPR ack K584

MIEF1 p T61 SART1 p S89

NAA15 ack K95 SCARF2 p T840

MTOR p S2450

TKT ack K352

KIAA0430 p S66

SF3B2 rme R205

RALGAPA1 p T743

EPB41L2 p Y623

MAP1B p T1949

SUPV3L1 ack K220

MAST4 p S1950

CBX8 p T234

BAZ1A ack K1277

RPS17 p T123

EP400 ack K345; EP400NL ack

K334

HSP90AB1 ack K354

CBX8 rme R103C11orf58 ack K49

AKR1C1 p Y81

SHC1 p Y427

SEC16A p S164

TNKS1BP1 p Y202

TNKS1BP1 kme K1644

RBM19 p S489KIAA1522 p S929

EPHA2 p Y772

TNS4 p Y150

TPR p S2155

TNS4 rme R209

RBL1 p T332

CAMK2G kme K301

OTUD4 kme K1040

UTP14A p S437

EDC4 p S1248

SPAG9 p S705

ATP5O ack K172

ALYREF rme R204ACAA2 ack K137

EIF4H rme R146

MYH9 p T391

RBL2 p T404HIPK1 p S1200

TPX2 p T72

SUPT5H p S804

YRDC p S37

AHNAK p T5794

TXNRD2 ack K153

CDC42EP1 rme R53

PRKRA p S18

PRPF4B p S36

NNT ack K100

IDH2 ack K106

SARG kme K480

SHMT2 ack K103

ACOT13 ack K127

KIAA1522 p T531PPP1R12A p S525

TARS p T374

KRT7 p S45

BCL9L rme R675

BCL9L p S987

LOC113230 p S174

RBM8A rme R38

PAPD4 rme R131

SP2 p T192

ELF2 rme R494

SRRM2 rme R2370NUP107 rme R60

ILF3 rme R815

EEF2 ack K272

SNTB1 p Y200

SHB p Y96

MDC1 p S598

PKP4 p Y420

PLEC p Y26SNRNP70 rme R180

KIF20A ack K770

EIF4H rme R22HSDL2 ack K49

TALDO1 ack K269

TALDO1 ack K258TTC7A p S679

NNT ack K394 AKR1C1 ack K84

FAM83B p Y896MINK1 p Y706

MTMR10 p Y708SLC9A1 p Y683

PACSIN3 p S383

ZNF609 p S413

JUP p Y660

ARHGAP32 p Y1557

CASC3 p S66

KLF11 p S124SPARCL1 p S295

ZNF446 p T327

HTATSF1 kme K234

MAP1B p Y1938

EEF1G ack K52

CHAMP1 p S87

STK10 p S191

CAMK2D kme K301

ZMYM4 p T212

GSTP1 p Y50

CASP9 p T125

PCBP2 p T65

PTPN2 p S304

ZC3HAV1 p S257

GANAB p T214CASC5 p S32

PCNXL3 p Y279

TP53BP1 rme R1338 PPP1R13B p Y202

ROBO1 p Y1224

CLASP2 p S529

NES p S1489KANK2 p T176

FCHSD2 p S681CEP170 kme

K1077

TCOF1 p S1407FASN ack K298 USP9X p S588

DDX39B ack K188

KRT81 ack K345

CSRP1 ack K112

PNPT1 ack K285

DNAJA4 ack K44

AKAP8L rme R208

NAA50 ack K37

VCP ack K696

DSTN ack K127

OGFR p S378

CERS2 p S341

PPA2 ack K216

RABL6 rme R508COX5B ack K121

ADRA1B p S470

PTPRK p Y916

UVRAG p S493

MED1 ack K1354

LMNA ack K171

SNW1 ack K170

KRT18 ack K372

MPRIP p T542

GBAS p Y74

RAB1A p T153

PRRC1 p T152

ATP2B4 p T1181

GCLC p S8

SART3 p S778

SUB1 kme K53

TP53BP1 p T855

ALB ack K183

WTAP p S306

USP54 rme R535

SRP9 ack K30

AHNAK kme K5307

TCOF1 p T249

GPRIN3 p S57

PI4KA p S262

FOXK2 p S381UGDH p T185

SPTBN1 p S333N4BP2 p S1216

GOT2 ack K52

EPRS p S335PHLDB1 rme R512

UBR1 p S1593

UBA1 p S13

AJUBA p S69

RANBP10 p S367SLC9A3R1 ack

K34

ANXA2 p T61

PLEKHA4 p T296

PIK3R1 p Y463

AHNAK p S135

TPD52L2 p T173

TMEM163 p T16

CHD7 p T2554

PIP4K2C kme K390

SCAF4 p S1037ANXA3 p S167

TFIP11 rme R166

NUFIP2 rme R291

MLH1 p S477TAF15 rme R450

SMG8 rme R835

FUNDC2 p T16

TPD52L2 p S134

LARP1 p S1067

KRT19 rme R32

MTHFSD kme K41

CEBPB p T235

MYH11 ack K1256

RHBDF2 p S113

SON rme R943

LMNA p S407

CHTF8 rme R186

ANXA1 p Y207

MCMBP p S154

UBAP2L rme R168TMEM245 p T36CDCA8 p T106

CARHSP1 p S58

DENND4B p T1052

CAPRIN1 rme R608

TES p Y126

VPRBP p T706

TES ack K286

DPYSL3 p T85

TES p Y111

PRDM2 p T1529

DHX38 p T1217

TES p Y251

ADO rme R28

NCOA3 ack K687

CTNND1 p Y904

NUP35 p Y300

PACSIN2 p Y388

MET p Y1234LDHA ack K118PPP1R12A p Y766

CTTN p Y154

PPP1R18 p Y230APP p Y757

ZNF609 p T829

SCAF11 ack K1354

KRT8 ack K352

WDR70 ack K509

TJP2 p Y269

TES p Y293

SMARCA4 p S1422

ZNF609 p T823

BAZ1A p T1367

KHSRP ack K266

ECI2 ack K92

NASP ack K417

TPR rme R2106

RPS27A ack K104

PPM1G ack K519

CHRAC1 ack K102

SSBP3 p T360

CCM2 p S393MARCKSL1 p S71

BRD4 p S1117

RBM15B p S237

NASP p T390

ESYT2 p S18

TBC1D5 p S732

SUN2 p T107

TMPO p T164ABCC5 p S67

RRBP1 p T954

SEPT7 p T228

KRT19 p Y391

GAPDH p Y140

PDIA4 p S351

PKM p T41

ALB p T263

ANXA4 p Y165

RICTOR p Y863

PVRL2 p Y454

KIAA1522 p Y241

ZC3HAV1 p Y410

PLEKHA5 p Y590

PNPO p S165

ADD1 p Y35

EPB41L5 p Y476

ADD1 p Y24

NEDD9 p Y317

MARCKSL1 p T148

TJP2 p S325

TLK1 p S37

HNRNPK rme R258

EPS8L2 p Y487

PLEKHA5 p Y804

AKAP8 p S323

CLASP2 p S525

MYH9 kme K1918GPS1 p S468

ACSS2 ack K418

CTNND1 p Y248

CTTN p Y334

MRE11A rme R587

SRRM2 p S2740HGS p Y334

PALLD p Y1348

IRS1 p T335

EPB41L2 p Y773

COBL p Y867

HSD17B4 p S304

EZR p S539

TJP3 p S203

SYTL1 p S216

HECTD1 p S358

MYCBP2 p S3467

TLK1 p S38

ERBB3 p S686BMI1 p S299

TLN1 p T144

ZNF185 p T447

RCCD1 p S268

LAMTOR1 p S69

TUBA4A p T349

AMPD2 rme R99

SRGAP1 p T501

ZNF503 p T223

NCOR1 p S2184

TOP2B p T1431

TMEM163 p S12CTDP1 p T843

PAICS p T238

PHF20L1 ack K737

NAV1 p S1190

CDK17 p S165

GTF3C2 p T486 GRPEL1 ack K94CARKD ack K140FRS2 p S226

SON ack K16

EEFSEC rme R556

KLC2 p S582

NCL kme K71

ANXA2 p S22

EHMT2 p S119

IK p T330

GNL3L p S465SYNRG p T1100

CIC p S1397

HBB p Y146

CIT p S1343

FAM50A rme R13

DVL2 p S170

ZFC3H1 p T766

LZTS2 p S175

ACIN1 rme R624

HNRNPU ack K635

ILF2 ack K186

SRRT ack K526

VDAC2 ack K235

ISOC2 ack K26SOWAHA p S244

HDAC5 p S259

TRIM33 p T1102

DOCK9 p Y1237

HNRNPD p T134

GAPDH p T237

ZYX ack K279

HIST1H1D ack K169

RPS13 p S12

REPS1 p S274

STK26 p T178CAV2 p S23

SMC1A p S360

MATR3 p S14

BOD1L1 p S2121

TPD52 p S144

LMNB1 p T76

CWC15 p S24

ZC3H18 p T162UBE3A p S218

HIST1H3A ack K23

ARIH2 p S353

MTHFD2 ack K44

HNRNPUL1 rme R181

VDAC2 ack K39

SART3 rme R918

TPR ack K713C9orf142 p T145

DLAT ack K473ATP5B ack K522

SREK1IP1 p S149

CNN3 p T288

PPP1R18 p S145

EIF4B p S422

YES1 p Y194

SCRIB p S1285BOD1L1 p S1710

ANXA1 ack K242

TNS1 p Y903

GOPC p S280

HGSNAT p S239

SSFA2 p S737

TAGLN2 p T190

SHROOM2 p S422

TESK2 p S367

HP1BP3 p T85

TAGLN p S166

PERP p Y188

EEA1 p S18

OPTN p T202

SIGLEC7 p T411

HMGCL ack K324

LARP1 rme R285

PRKAA1 p T183

SENP3 p S307PLEC ack K187

PCBP2 p S111

FAM54B p S103

TMPO p T279

PRKAA1 p T490EIF4ENIF1 p T769RASAL2 p S739

ABI1 p S323

HBA2 ack K41

SCRIB rme R1527

SCRIB p S1276

DNPEP p S109

TJP1 p S404

DPYSL3 p S265

ARHGAP23 p S647

CHTF8 rme R214

NCOA4 p S237

OXSR1 p T185

NDRG1 p T366

CARHSP1 p Y63

HSPA5 kme K585

SNRPB rme R172

TIMP3 ack K99

HSPA5 ack K352

HSPA5 ack K268HSPA5 ack K113

NRGN rme R68

PPP2R5D p S90

PRKCI p S411

VIM ack K294

PROSER2 rme R252

HNRNPM rme R503 NDRG1 p S367

FLNA ack K578

GTF3C1 p S748

PRKDC p S2612

HIST1H3A kme K4

HDGF p T200

NOL7 p S126

DIDO1 p S2238

H1F0 p S66

MATR3 p S11

EEF2 p S38

IGHG1 ack K205

ARHGEF11 p S35VPS26B p S330

RAPGEFL1 p S302PRR12 p T884

UBAP2L p Y602C10orf12 p T727

SRRM2 p Y1049

ARL6IP4 p T224

KRT18 rme R45UTP11L p T90

PEAK1 p Y531

DDX17 ack K109RAB5A p Y82

KRT18 rme R14

PROSER2 rme R320

PTPN23 rme R1595

DAB2IP p S1140ARHGAP35 p

S1106

KRT19 p Y256

ERBB2IP p Y1104

SEC16A p S1149

PPP1R14B p Y29

PRKCD p Y374

ADD3 p Y35

EFHD1 kme K9

SON rme R997

CTTN p Y162

CTNND1 p Y241

SAFB rme R751PLCG1 p Y1253

FLOT1 p Y203

RALGPS2 p Y420

CTNND1 p Y217

PHLDB1 p S461

KIAA1522 p T932

SEC16A p S428

SEC16A rme R1036

DNAJC30 p T37

PRPF38B p S529

CSPP1 p S901INTS4 p S600

PSMC1 p Y439

MRE11A p T597

CCDC50 p S340

SIN3B p T262

ATP7A p T327

ATP7A p S330

FBXL19 p T225

TBCA p Y94

LIG1 p T233

TMPO p Y351EPRS p T898

BCAR3 p T130

POU2F1 p S267

TAF4 p S1036

PLEKHG3 p S475

TCOF1 p T983DHX36 p T994

LASP1 p Y57

PHIP p T1482RASEF p S393

TET2 ack K948

EWSR1 rme R455

HNRNPH3 p Y100

LDHA p Y172

RPL11 p Y92TNKS1BP1 p T854

HSPE1 p Y88

TNRC18 ack K1554

EWSR1 ack K641

EIF1AX p Y106

C17orf85 p S516

DOCK11 p T1352

ENO1 ack K422

ZFP36L2 p S147IKBKG p S31

GAPVD1 p T390

CENPL p S53

XRCC5 ack K703

FUNDC2 p S10

HIRIP3 p S196

KDM1A p S45ADRB2 p S246

HIST1H2BC ack K121

TPI1 ack K92

DCP1A p S534

HIST1H3A kme K79 HEYL p T256

DES rme R37

COL6A3 ack K2532

CDK1 p Y19KHDRBS2 rme

R240

TMEM230 p Y29

CLASP1 rme R660

BASP1 p T190

LAMB1 ack K1736

S100A14 p Y32SQSTM1 p S272

EIF4B p S425

RSL1D1 p T340

EEF1A1 rme R166

IRS2 p T527

ARHGEF40 p T371

DDX47 ack K448

MAF1 p S89SPAG9 p S265

RNF167 p T288

KMT2C rme R4162

SPAG9 p S238

EML4 p S151

NOP10 ack K19

CDH1 p Y755

FANCD2 p S319

ABCC5 p S64

RCC2 p T74

STK4 p T340MAP3K9 p S693

TBC1D14 p S93

ARHGEF11 p S38

DCTN2 p Y6

LMNA p S18

TCF4 p S318 KRT18 p Y36

DLG1 p Y760TBCC p S80

PDS5B p S1369EPN2 p S511

STXBP3 p Y521RIPK1 p Y384

BAZ1A p S1546

DYNC1H1 p T1885

TIMP3 ack K112FUS rme R371

TLN1 p S1725

BGN ack K111

RAB3GAP1 p S927C17orf85 p S500

TNKS1BP1 p S1331

PPP2CA p S26

HSPA4 p S54

ARHGEF17 p S940

LCMS/MS analysis

TMT peptide quant

LCMS/MS analysis

TMT peptide quant

LCMS/MS analysis

TMT peptide quant

LCMS/MS analysis

TMT peptide quant

LCMS/MS analysis

TMT peptide quant

Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6

Proteolytic digestion

TMT labeling Mix samples

A

B

C

IP pY peptidesIP pS/T peptidesIP meK peptides IP acK peptidesIP meR peptides

Fig. 1. Data acquisition and analysis. (A) A CFN was created by using a machine learning, pattern recognitionalgorithm (t-SNE) to identify which PTMs clustered together, filtering PPIs (red edges) to retain only those betweenproteins whose PTMs coclustered. (B) Outline of TMT mass spectrometry coupled with immunoprecipitation (IP) usingmodification-specific antibodies. Phospho-Ser/Thr (pS/T) peptide IP was accomplished inmultiple steps with AGC/PSD-family kinase substrate, AKT (v-akt murine thymoma viral oncogene homolog 1) substrate, AMP kinase substrate, andATM/ATR (ataxia telangiectasia mutated/ATM related) substrate antibodies (see Materials and Methods). Phosphopep-tides were also further purified on a TiO2 column (81).m/z, mass/charge ratio; LCMS/MS, liquid chromatography–massspectrometry. (C) Bird’s eye view of the CCCN derived from PTMs from 15 independent experiments, each with sixmultiplex samples, from comparison of 45 lung cancer cell lines [12 derived from from small cell lung cancer (SCLC)and 33 from non–small cell lung cancer (NSCLC)] to normal lung tissue, and selected cell lines treated with anticancerdrugs. This disconnected network includes threshold-filtered Spearman correlations among t-SNE–clustered PTMs(yellow edges are positive correlations; blue are negative correlations). Also shown are negative correlations amongdifferent modification types within the same protein, which are useful for revealing antagonistic relationships amongPTMs. Node size and color reflect total of all PTM ratios in the data set (fold change key). This network is available fordownload as data file S1 and on the NDEx repository (https://doi.org/10.18119/N9F59Z). This network combined withthe CFN that contains filtered PPI edges may be explored at https://cynetworkbrowser.umt.edu/.

3 of 16

PKMEPHA2

T

FASNEGFR

EPHB4

LYNEP300

RAC1

MERTK

CLTC

PRKD1PTPN11

PIK3R1

D1

GAB1

PTK2

ERBB2IP

CRK

HSPA1B

DDX5

HSPA8

ROCK2HNRNPA2B1

EEF1A1

GAPDH SRSF9

PPP1CACCT2

HNRNPK

HSPD1HSP90AA1

VDAC1 GSK3AHSP90AB1

ACTB

COPA

CLASP1

TUBA1B

CDK1CDK13

ILF3ARF1

PGK1

HNRNPM

SRRM2

LMNA

BAG3

PDPK1

CHD8

PPP2R5A

BCR

DDX3X

PRPF40A

WNK1

ALDOA

CAD

TALDO1

MAP2K1

NUP133ARHGEF12

YWHAB

PRKAA1AHNAK

MARK2

PVRL1ATP1A1 PABPC1

PARD3

SF1HNRNPD

HSPA5

VDAC2

SPENHNRNPA1 ENO1

MAP4K4

EIF4G1

SNW1 TNK2

MYL12AEIF4A1

TPM3

ATXN2

FER

RIPK1

TPREIF5AP4HB HNRNPA3

XRCC6 SF3B1YWHAG

MAPK3

DLG1

DSTN

MAPK1

CFL1

CTTN

Phosphorylation (PSP)

20 40

hange

itinib

70 p Y146 p Y30

p T275 p Y194AB1 p Y276AA1 p Y492

PD p Y244p Y44p Y453p Y228p Y162p Y104p Y899p Y883p Y1206 Y82 Y140 p Y3

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an unexpected relationship between phosphorylation and acetyla-tion. Filtering PPIs by PTMmodification clustering highlighted linksbetween cytoskeletal proteins, RNA binding proteins, and heat shockproteins in lung cancer cell lines.

HSP90 proteins, together with CDC37, act as chaperones for a largenumber of kinases, including RTKs, and are required for regulation ofactivity as well as their initial folding (42). The mechanisms of action ofthe HSP90 inhibitor geldanamycin are not well understood comparedwith the other anticancer drugs used in this study. Heat maps showingPTMs affected by more than twofold by geldanamycin revealed that, inaddition to heat shock proteins (HSPs; Fig. 3A),many proteins involvedin regulating endocytosis (Fig. 3B) and cytoskeletal dynamics (Fig. 3C)were affected by geldanamycin. This is consistent with reports that gel-danamycin affects endocytic membrane trafficking and cytoskeletaldynamics (43–45). Examination of the shortest paths between HSP90proteins, the known targets of geldanamycin, and proteinswhose PTMswere affected by geldanamycin included acetyltransferase EP300 inter-

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

acting with HSP90AA1 (Fig. 3D). As mentioned above, proteins thathave high betweenness are likely to be hubs in the network, that is, con-nect many cell signaling pathways (fig. S7). These included HSP90AA1and several other proteins linked to it in the geldanamycin subnetwork(Fig. 3D), including the 14-3-3 proteins YWHAQ and YWHAZ, theRNA binding protein NPM1, and the heat shock proteins HSPA8,HSPA1B, and b-actin (ACTB). Geldanamycin treatment also affectedphosphorylation of the RTKs ALK, AXL, EGFR, ERBB3, and IGF1R(insulin-like growth factor 1 receptor), of which phosphorylation wasdecreased for all but AXL and ERBB3 (Fig. 3D).

These results suggest that geldanamycin may affect the balance be-tween phosphorylation and acetylation by influencing EP300 throughinteraction with HSP90 proteins. This in turn affects endocytosis (asindicated by phosphorylation changes in DYNC1I2, EPS8, CAV1, andclathrin heavy chain CLTC), microtubules, actin, and other cytoskeletalelements (as indicated by several PTMchanges in spectrin SPTAN1andkeratins KRT7 and KRT8) (Fig. 3). Protein methylation may also be

ME

CTNN

CDH1

GIPC1

SCRIB

ACTN4

KRT8

NDRG1

HSP90AA1

RAC1

ACTN1

IRS1CTNND1

CTTN

MET

APP

ALK

HIST3H3

RPS4X

SEPT9

HSP90AB1

HSPA5

EIF4B

TJP2

CTNNA1

CCT2

ACTR8LASP1

DOCK1

NPM1

ACTB

YWHAB

KRT18

YWHAE

ATP1A1

HSP90B1

STIP1

SRRM2

HSPA8

PSMA3EEF1A1

ACACA

GAB2

MPP5

RASA1

IRS2GAB1

EPHA2

SHB VCL

HSPD1

GRB2

TNK2PIK3R1

CRK

CFL1

CDK1

EGFR

SRC

CLTC

ATXN2L

MLLT4

MAPK1PTPN11

HNRNPA1

MAPK14

CEBPB

UBA1KHDRBS1

INPPL1

CRKL

PPP1CA

BCAR1

LYN

ERBB3

PTK2

TNS3

STAT6

DOK1

C

Up

Fold change

Down

–40 –20 0

Fold c

Crizotinib Gef

H32

55.m

ean.

cont

rol

H32

55.1

hr.1

uM

H32

55.3

hr.1

uM

H32

55.6

hr.1

uM

H32

55.2

4hr.1

uM

SNRNPSEPT7RALY PRDX1HSP90HSP90HNRNENO1 CTTN CTTN CTTN CTTN CLTC CLTC CLTC CFL1 pCFL1 pALDOA

chaange

H32

55.m

ean.

cont

rol

H32

55.1

hr.1

uM

H32

55.3

hr.1

uM

H32

55.6

hr.1

uM

H32

55.2

4hr.1

uM

SNRNP70 ack K162SEPT7 ack K313SEPT7 ack K208RALY ack K165PRDX1 ack K27PRDX1 ack K168HSP90AB1 ack K559HSP90AA1 ack K446HNRNPD ack K129ENO1 ack K358ENO1 ack K105CTTN ack K309CTTN ack K235CTTN ack K147CLTC ack K1264CFL1 ack K92ALDOA ack K342

gefit

inib

gefit

inib

gefit

inib

gefit

inib

gefit

inib

gefit

inib

gefit

inib

gefit

inib

10

–10

A B

FpwEke

4 of 16

ig. 2. Networks derived from composite shortest paths from drug targets to drug-affectedroteins. (A to C) Graphs showing the sum of shortest paths from each target to each proteinhose PTMsweremore than twofold affected by theMET and ALK inhibitor crizotinib (A) and theGFR, ERBB2, and ERBB3 inhibitor gefitinib (Iressa) (B) in H3255 cells treated for 1 to 24 hours. Aey defining node shape and border colors and edge colors is shown bottom right. Directeddges are shown with arrowheads; these indicate one protein acting on another protein (for

example, kinases phosphorylating substrates). Undirected edges without arrowheads indicate various other types of interactions. Edge line thickness is proportionalto the strength of interactions, as defined in PPI databases. Node size and color are proportional to the changes in PTMs for each protein in response to indicated drugtreatments (see scale bar; yellow indicates positive change; blue, negative; green, no change). Many yellow nodes represent overall increases in acetylation in these graphs(C). Fold change for individual PTMs in response to indicated drugs is plotted using heat maps on a blue-yellow scale (see scale bar). Several proteins exhibited phos-phorylation decreases (represented by blue on the heat map) and concomitant acetylation increases (represented by yellow) in response to gefitinib.

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involved. Changes in methylation were also observed in response togeldanamycin, and phosphorylation of the histone lysinemethyltrans-ferasesWHSC1/NSD2 andNSD1was reduced (Fig. 3). TherewereCFNlinksbetweenEP300 andkinases, phosphatases, another acetyltransferase(CLOCK), methyltransferases (PRMT1 and ASH1L), and the actin-regulating proteins RAC1 and CDC42 (Fig. 4A).

Specific PTM relationships in the pathways that connect EGFR toEP300 can be visualized by showing PTMs and their correlation edgeson the CFN graph (Fig. 4B). In the graphs in Fig. 4, node size and colorindicate comparison of individual PTMs, or the sum of all PTMs for aprotein, in cell lines compared to normal lung tissue. The same graphsindicating fold change in response to drug treatments are shown in fig.S11. Individual PTMs on EP300 changed in response to different con-ditions, and these changes occurred concomitantly with PTMs on otherproteins that coclustered with EP300 PTMs (fig. S12). For example,EP300 phospho-S1897 was down-regulated in lung cancer cells com-pared to normal lung tissue along with two phosphorylation sites onBCAR3 (fig. S12A, bottom), whereas EP300 acetylation sites K1674and K1760, along with RAC1 and CDC42 acetylation sites, were

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

increased by gefitinib treatment (fig. S12C, top and middle left, respec-tively). These data indicate that EP300 likely plays a central role in cy-toplasmic signaling in addition to its previously described role as ahistone acetyltransferase. The inverse relationship between phosphoryl-ation and acetylation on EP300 (fig. S12) and other proteins (Fig. 2)gives rise to the hypothesis that there is an antagonistic relationship be-tween particular sites of acetylation and phosphorylation on cell sig-naling proteins. These sites may be indicators of mutually opposingmechanisms or pathways.

Evidence for antagonistic relationships among PTMsThe hypothesis that there is an antagonistic or dueling relationship be-tween phosphorylation and acetylation sites leads to two predictions.First, we should expect to find negative correlations between a subsetof phosphorylation and acetylation sites for proteinsmodifiedwith bothPTMs. The distribution of correlations between phosphorylation andacetylation sites on the same proteinwas significantly different than thatof dual phosphorylation or acetylation (Fig. 5A). We found 269 suchphosphorylation and acetylationmodificationswith Spearmancorrelation

TPM3

TPX2

KIF23

LMO7

NUMA1

DLGAP5

FZD6

PPP6R3

USO1

KRT8

FASN

HSPD1

CLTCKRT18

LYNPAG1

PTK2

LASP1

DOK1

TYK2CRKL

ACTB

HSPB1

CRK

STAT3

SHB

KRT7

GAB1

EGFR

EPS8

YBX1

DYNC1I2

IRS1

NFKB1

ALK

GSK3BCAMK2G

AXL

WHSC1

TUBB NCL

PKM

PPP2R5ARPL10A

PDIA4

ERBB3

TUBA1A

PDIA3TPR SUPT5H NEK1

HNRNPA2B1EIF4A1

SHC1HNRNPK

EPHA2

PDPK1

IRS2DOCK1

HIST3H3

MAP4K4

SPEN

SRRM2

NSD1

YWHAG

BCAR3

MAP1B

BCAR1

SEPT9

SPTAN1

SQSTM1

ZNF185

CAV1

MYH9

VCL

RPL3

HNRNPA1

IGF1R

SF3B1

DDX5

BAG3

RPL23A

NOP58

HSP90AB1

FKBP4

WDR33

EP300

ACTR2

EEF1A1

HSPA1B

DSTN

CAP1

SNW1

CTTN

YWHAB

EIF3A

HSPA4

HSPA8

MKI67IP

ALYREF

RAC1

NOP2CCT2

YWHAQ

ENO1

RANBP2

RBM3

MKNK1 HNRNPA3EIF4G1

AXIN1

HSP90AA1

NPM1

TUFM

YWHAZ

VDAC1

H22

28.C

ontro

l.Sta

rved

H22

28.C

ontro

l.Uns

tarv

edH

2228

.15h

r.100

nM.g

elda

nam

ycin

H22

28.2

4hr.1

00nM

.gel

dana

myc

inH

3122

.Con

trol.S

tarv

edH

3122

.Con

trol.U

nsta

rved

H31

22.1

5hr.1

00nM

.gel

dana

myc

inH

3122

.24h

r.100

nM.g

elda

nam

ycin

CCT2 p T261NPM1 p S218NPM1 p S217HSP90AB1 p Y192HSP90AA1 ack K567HSPA8 ack K348HSPA1B p T226HSPA8 p S329HSPA8 ack K88HSPA1B ack K246HSPA8 rme R469HSPA1B rme R469HSPB1 p Y133HSPA1B kme K561HSPA4 p Y636NPM1 kme K223HSP90AB1 kme K607HSP90AB1 ack K354HSP90AA1 p Y627HSPA8 ack K567HSPA1B p T265NPM1 ack K267NPM1 ack K154HSPA1B rme R458HSPA1B kme K568

H31

22.C

ontro

l.Sta

rved

H31

22.C

ontro

l.Uns

tarv

ed

H31

22.1

5hr.1

00nM

.gel

dana

myc

in

H31

22.2

4hr.1

00nM

.gel

dana

myc

in

CTTN p Y84KRT7 p Y205CTTN p Y302CTTN ack K147MARK1 p S671ROCK1 p S118CTTN p Y162MAP1B p S1797CTTN p Y199KRT7 rme R329PKN2 p T816PRKCI p S411CDCA8 p T106NEDD9 p Y317NPM1 p S217ACTB p Y53KRT8 p Y267MAP1B p T1788HSPB1 p Y133KIF23 p Y582KRT7 p Y268ABL2 p Y718MAP1B p Y1904KRT7 p S45CCT2 p T261MTPN p T31NPM1 p S218CTTN p S224PKN2 p T820NEBL ack K23NEBL rme R96KRT7 rme R48NPM1 ack K267PTK2 p S580PEA15 p S104KRT8 p S39NPM1 kme K223LCK p Y505NEK1 rme R472KRT7 rme R20NEBL rme R795NDRG1 p T366NPM1 ack K154CTTN ack K235PEA15 p S116KRT7 rme R13KRT8 rme R47KRT7 rme R25ZNF185 p S523ZNF185 p S519KRT8 p Y10

R3RAR

B

V1

H22

28.C

ontro

l.Sta

rved

H22

28.C

ontro

l.Uns

tarv

ed

H22

28.1

5hr.1

00nM

.gel

dana

myc

in

H22

28.2

4hr.1

00nM

.gel

dana

myc

in

ACTB p Y53PCM1 p S121CLTC p Y900ABL2 p Y231MAP2 p S63ABL2 p Y718MAP1B p T1788PTPN23 rme R1595PTK2 p Y194PTK2 p Y861CDCA8 p T106MAP1B p Y1762ABL2 p Y668CTTN p Y421NEDD9 p Y345NEDD9 p Y223CTTN p Y228RAB8A p Y5CCT2 p T261CTTN p Y104MAP1B p S1764NPM1 p S218MAP1B p S1899LASP1 p Y122MAP1B p Y1889KRT7 p Y205MTPN p T31NEBL ack K23NPM1 kme K223LASP1 kme K75ACTB p Y198NPM1 p S217NPM1 ack K267NEBL rme R96PEA15 p S104MAP2 p T1440PEA15 p S116KRT8 p S39NPM1 ack K154KIF23 p Y582ZNF185 p T289ACTB ack K328KIF23 p S943DYNC1I2 p S97ZNF185 p S519KIF23 p S912NDRG1 p S364CTTN ack K161KRT7 rme R25TPX2 p S310KRT8 ack K101TPX2 p T374TPX2 p T369TACC3 p T59HAUS6 p S826DYNC1I2 p T95DLGAP5 p T329

H31

22.C

ontro

l.Sta

rved

H31

22.C

ontro

l.Uns

tarv

ed

H31

22.1

5hr.1

00nM

.gel

dana

myc

in

H31

22.2

4hr.1

00nM

.gel

dana

myc

in

CAMK2A p T286RUFY1 rme R12SUN2 p T9PIK3C2B p Y1401EGFR p Y869TBC1D5 p S732GIPC1 p T238SNX6 p Y245KIDINS220 p S1555CRKL p Y251VIPAS39 p Y11SUN2 p T107RAPGEF6 p S1070CORO1A p Y25SHC1 p Y427PRKCI p S411CAMK2G p T287LCK p Y505SNX3 rme R43ITGB5 p Y766NDRG1 p T366HSPH1 p Y653EZR p T358VPS37B rme R206SNF8 rme R4VPS37B rme R218HBA2 ack K100

H22

28.C

ontro

l.Sta

rved

H22

28.C

ontro

l.Uns

tarv

ed

H22

28.1

5hr.1

00nM

.gel

dana

myc

in

H22

28.2

4hr.1

00nM

.gel

dana

myc

in

NRP1 p Y899CAV1 p Y25RUFY1 rme R12PTPN23 rme R1595CRKL p Y132OCRL p Y133TJAP1 p T351CLTC p Y900PCM1 p S121PACSIN2 p Y388PML p S480TBC1D5 p S730PKN1 p T774WASL p Y256SUN2 p T107ARHGAP32 p Y1520CHMP7 p Y164ATP1A1 p Y260ATP1A1 p Y55JAK2 p Y570ATP1A1 p S60OCLN p Y287SYK p Y526CD164 p Y194EGFR p Y1016RAB35 p Y5NUMB p S438RAB8A p Y5EGFR p Y869ITSN1 p S687RAB5A p Y82M6PR p Y255GGA2 p T319CAV1 p Y6CAV1 p Y42CAMK2A p T286CAMK2G p T287MMP14 p Y573SHC1 p S426TF p Y536TF p Y534HSP90AA1 ack K567HBB ack K145HLA-A ack K170NDRG1 p S364SHC1 p Y427HSP90AA1 p Y627HBA2 ack K100SQSTM1 p S272SQSTM1 p T269ANXA1 ack K161C

H22

28C

Up

Fold change

Down

D–40 –20 0 20 40

Geldanamycin

10

–10

A B

Fig. 3. Heatmaps andnetwork showing PTMs affectedmore than twofold by geldanamycin. (A toC) Heatmaps of PTMs of HSPs (A), proteins involved in endocytosis(B), and proteins involvedwith the cytoskeleton (C) in each of two lung cancer cell lines cultured with serum and either untreated or treatedwith geldanamycin (100 mM for15 or 24 hours) relative to serum-starved, untreated cultures. Scale bar (B) indicates fold change on a blue-yellow scale. (D) Network graph plotted as in Fig. 2 showing thesum of shortest paths from HSP90AA1 and HSP90AB1 (center) to each protein whose PTMs were more than twofold affected by geldanamycin in H2228 or H3122 cells.Node size and color indicate the sum of PTM changes in response to geldanamycin in both cell types (refer to the key in Fig. 2).

5 of 16

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lower than −0.5 in 112 proteins in the lung cancer cell line PTM data(highlighted in blue in Fig. 5A). Both tyrosine phosphorylation andserine/threonine phosphorylation exhibited negative correlations withacetylation (fig. S13). Negative correlations can be visualized as blueedges on a combined CFN/CCCN (Fig. 5B), which revealed proteinsthat are involved with endocytosis and the actin cytoskeleton that areaffected by geldanamycin. Cortactin (CTTN), for example, had a largenumber of phosphorylation sites negatively correlated with its acetyla-tion sites that are affected in opposite ways by geldanamycin [Fig. 5, B(upper right) and C]. Clathrin is another example where phosphoryl-ation and acetylation sites were negatively correlated, although not allsites were affected by geldanamycin, or detected in the drug treatmentexperiments. Cliques of highly correlated coclustered PTMs were alsorevealed in the CCCN (Fig. 5D, identified by yellow edges). For exam-ple, EGFR pTyr869 clustered with MET pTyr1003 in one clique, whereasdifferent EGFR phosphorylation sites clustered with proteins involvedwith endocytosis (EPS8 and CLTC) in the other clique (Fig. 5D).

The second prediction of the hypothesized dueling relationship be-tween certain phosphorylation and acetylation sites is that there shouldbe interactions between acetyl-binding proteins containing bromo (orBET) domains, which bind to acetylated lysine moieties, and kinase

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

signaling pathways (5). Such interactions were observed in the CFNamong dually phosphorylated and acetylated proteins, kinases, andbromodomain proteins (Fig. 5E; bromodomain proteins are coloredlight red). Bromodomain-containing proteins weremore likely to inter-act with dually phosphorylated/acetylated proteins than acetylatedproteins in general, or proteins modified by phosphorylation ormethylation (Fig. 5F). That there were more CFN interactions betweenbromodomain-containing proteins and dually phosphorylated andacetylated proteins compared to all other groups of proteins (Fig. 5F),combinedwith the fact that gefitinib (Fig. 2, B andC) and geldanamycin(Fig. 3) caused decreases in phosphorylation and concomitant increasesin acetylation for a large number of proteins, strongly supports the hy-pothesis that certain phosphorylation and acetylation sites play antag-onistic or mutually opposing roles for proteins identified in this study.

The data suggest the hypothesis that the intracellular location of pro-teins may change when their phosphorylation and acetylation rates goin opposite directions. To test this hypothesis, we performed cell frac-tionation experiments that effectively separate organelles including en-dosomes and lysosomes, and membrane compartments distinguishedby resistance to nonionic detergents (lipid rafts; Fig. 6A) (10, 46, 47).Geldanamycin treatment caused changes in the intracellular location

MAPK11KAT7 ack K199

WHSC1L1

KAT7

CLTC ack K507SRC

CDK12

PPM1G

GSK3A

CDK12 rme R1404

CLOCK p Y331

CLOCK

EPHA2

PRMT1 ack K173

EP300

PRMT1

PPP1CA

GSK3A p S278

EP300 rme R728

EP300 ack K1760

CLTC p Y900

EGFR

EGFR p Y978

EGFR p Y1092

EGFR p Y1016

CLTC p Y883

EGFR p Y998

EGFR p Y869

EGFR p Y1172

EGFR p Y1197

EGFR p S995

MAPK11 p Y182

SRC p Y187

ASH1L p S167

ASH1L

CLTC

CLTC ack K367 PPM1G ack K383

CDC42

ACTN4

KIF5B

CAPZB

RAC1

PPM1G

HSP90AA1

PPP1CA EP300

KAT7

GSK3APRMT1

SRC

CLOCK

ASH1L

PTK2

BCAR3

MAPK11

BCAR1–40 –20 0 20 40

Fold change

A B

Fig. 4. EP300 interactions with PTM-modifying enzymes. (A) Shown are links in the CFN between EP300 and kinases, phosphatases, acetyl- and methyltransferases,and the actin polymerization–governing GTPase (guanosine triphosphatases) RAC1 and CDC42. In cases where there were more than one type of interaction betweentwo proteins in the PPI databases (see the key in Fig. 2), to simplify graphs, white edges represent the composite of these interactions with the edge weight summed.(B) EP300 interactions with CLTC and enzymes that modify clathrin and govern EGFR endocytosis. The graph shows PTMs linked by black edges to the parent protein,and correlation edges (yellow, positive; blue, negative) between PTMs in the PTM CCCN, which depicts PTMs that cocluster with edges representing Spearman cor-relation greater than the threshold of |0.543|, as defined in fig. S9. Node size and color (refer to the key in Fig. 2) indicate ratios of PTM changes in lung cancer cell linesto those in normal lung tissue; see fig. S11 for responses to drugs. The combined CFN/CCCN graphs show the individual PTM response and the sum of all PTMsrepresented in the parent (gene) node.

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of proteins with negative correlations between phosphorylation andacetylation, determined by mass spectrometry (Fig. 6, B and C) andWestern blotting (Fig. 6, D and E, and fig. S14). Many dually modifiedproteins increased indetergent-resistant lipid raft fractions (raft2 to raft4),

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

including HSPs and chaperones (HSP90AA1, HSPA4, HSPB1, andCCT2), 14-3-3 phosphoserine-binding proteins (YWHAZ, YWHAE,YWHAQ, YWHAH), cytoskeletal proteins (ACTB, CTTN, TUBB4A, andMTPN), membrane traffic-associated proteins (CLTC andNDRG1),

p p p ac ac ac

0.0

0.5

1.0

–1.0

–0.5

0.0

0.5

1.0

Cor

rela

tion

A B

EP300 ack K1794

CLTC p Y1438

CLTC ack K507

CLTC p Y1096

EP300 rme R728

EP300 ack K1583

EP300 ack K1760 EP300

EP300 ack K1674 EP300 p S1897

CLTC ack K189

CLTC p Y899

CLTCCLTC ack K798

CLTC ack K1074

CLTC ack K367

CLTC ack K1264

CLTC p Y1206CLTC p Y900

ANXA2 ack K169

ANXA2 p T61

ANXA2 ack K204ANXA2

ANXA2 p Y238

ANXA2 p Y30

ANXA2 p Y24ANXA2 p Y333

ANXA2 p Y318

NCOA3

NCOA3 ack K620

ATAD2 p T1158

ACTB p T318

ATAD2 p S1190

ATAD2 p T1152

ATAD2

EPS8 p Y525

ACTB p Y218

ACTB ack K215

ACTB ack K61

ACTB p Y91

TLN1 ack K1221

TLN1 p S1333

EGFR p Y1110

ACTB

ACTB p Y53

EGFR

EGFR p Y1197

ACTB p Y362

ACTB ack K68

TLN1

EGFR p S1166

ACTB ack K328

TLN1 kme K428

EPS8 p S685

EGFR p Y1092

EGFR p Y1172

EPS8

EGFR p S995

ACTB p Y294

EPS8 p Y485

CLTC p Y883

EGFR p Y998

EPS8 p Y602

CTTN p Y265

CTTN p Y228

CTTN p S224

CTTN ack K124

CTTN ack K235

CTTN ack K107

CTTN ack K87

CTTN p Y199

CTTN p S113

CTTN ack K147

CTTN p Y302

CTTN ack K390

CTTN ack K263

CTTN p S417

CTTN ack K161

CTTN p Y421

CTTN p Y104

CTTN p S117

CTTN ack K309

CTTN p Y154

CTTN ack K295

CTTNCTTN p Y453

CFL1 p Y140CFL1 ack K22

MET

MET p Y1235

CFL1 ack K114

MET p Y1003

MET p Y1234

TLN1 p S1201

CFL1 ack K92

CFL1 p Y117

CFL1 p T25

CFL1

CFL1 ack K44

CFL1 ack K152

CFL1 p Y82

CFL1 p Y68

CFL1 p Y89

HSP90AB1

HSP90AB1 ack K428

HSP90AB1 ack K559

HSP90AB1 p Y484HSP90AB1 p Y56

HSP90AB1 ack K64

HSP90AB1 kme K607

HSP90AB1 ack K624

HSP90AB1 p Y619

EGFR p Y869

EGFR p Y1016

TLN1 p S1725

EGFR p Y978

TLN1 p S1227

TLN1 p Y436

AHNAK kme K5725

AHNAK kme K1794

AHNAK kme K3229

AHNAK kme K3553

AHNAK p T4100

AHNAK kme K1461

AHNAK kme K3681

AHNAK p S5793

AHNAK p T5794

AHNAK p S220

AHNAK ack K3356

AHNAK kme K3404

AHNAK p S5784AHNAK ack K4074

AHNAK p S212

AHNAK

AHNAK p T3716

AHNAK p S216

AHNAK kme K4529

AHNAK kme K2194

AHNAK ack K2299

AHNAK p T218

HSP90AB1 ack K275

HSP90AB1 ack K204

CCT8 ack K318

CCT8

CCT8 p Y30

CCT8 ack K440BRD2

BRD2 ack K345

HSP90AB1 p Y155

AHNAK kme K2322

AHNAK kme K2396

AHNAK kme K1791

AHNAK kme K1932

AHNAK p S5752

AHNAK kme K4603 AHNAK p S5782

me only

p only

All except p ac

All except ac

All ac

p ac neg

p ac

Bromodomain interactions per gene

0.00 0.04 0.08 0.12

F

CTTN p Y265

CTTN p Y228

CTTN p S224

CTTN ack K124

CTTN ack K235

CTTN ack K107

CTTN ack K87

CTTN p Y199

CTTN p S113

CTTN ack K147

CTTN p Y302

CTTN ack K390

CTTN ack K263

CTTN p S417

CTTN ack K161

CTTN p Y421

CTTN p Y104

CTTN p S117

CTTN ack K309

CTTN p Y154

CTTN ack K295

CTTNCTTN p Y453

234

C

k K189

98

TAD2 p T1158

ACTB p T318ATAD2

8 p Y525

EGFR p Y1110

ACTB

ACTB p Y53

EGFR

EGFR p Y1197

ACTB p Y362TLN1

EGFR p S1166

ACTB ack K328

TLN1 kme K428

EPS8 p S685

EGFR p Y1092

EGFR p Y1172

EPS8

EGFR p S995

ACTB p Y294

EPS8 p Y485

CLTC p Y883

EGFR p Y998

EPS8 p Y602

CFL1 p Y140CFL1 ack K22

MET

MET p Y1003

MET p Y

CFL1 p T25

CFL1

CFL1 p Y

CFL1 p Y89

EGFR p Y869

EGFR p Y1016

EGFR p Y978

TLN1 p Y436D

E

Fig. 5. Dually acetylated andphosphorylated proteins: In-teractions with bromodomainproteins and kinases. (A) Cor-relation between different PTMsites on the same protein: differ-ent phosphorylation sites (p p);phosphorylation and acetylation(p ac); and different acetylationsites (ac ac). Homo-PTM correla-tions (ppandacac) are comparedto heterologous (p ac) PTMs (bothP<2.2× 10−16,Welch two-samplet test). Individual PTM-PTM corre-lations are plotted in gray underboxplots (top). Correlation densi-ty between phosphorylation andacetylation sites on the same pro-teins is also shown (bottom). Sim-ilar plots in which tyrosine andserine/threoninephosphorylationare compared to each other andeach to acetylation individuallyare shown in fig. S13. Negativecorrelations selected for displayas edges are highlighted in blue.(B) Combined CFN and PTMCCCN for selected proteins modi-fied by both phosphorylation andacetylation. In addition to correla-tion edges, negative Spearmancorrelations less than −0.5 areshown as blue edges (plotted asin Fig. 4B, except edges connect-ing proteins to their PTMs arelight gray). (C and D) Selected re-gions of (B) expanded for clarity.(E) CFN interactions betweentyrosine kinases, geldanamycin-affected dually acetylated andphosphorylated endocytic andcytoskeletal proteins, and bromo-domain proteins (colored lightred). Node size and color (refer tothe key in Fig. 2) are in responseto geldanamycin for (B) to (D).(F) Comparison of the numberof interactions of bromodomain-containing proteins with duallymodified proteins both phos-phorylated and acetylated (p ac);those with negative correlationsless than−0.5 (p ac neg); all acety-lated proteins (all ac); all proteinsnot acetylated (all except ac); allproteins except those both phos-phorylated and acetylated (all ex-

cept p ac); and proteins only modified by phosphorylation (p only) or methylation (me only). CFN interactions between bromodomain-containing proteins and these groups ofproteins were retrieved, and the number of edges was divided by the number of proteins in each group to obtain bromodomain interactions per gene.

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C.H

3122

.raft.

1.m

C.H

3122

.raft.

2C

.H31

22.ra

ft.3

C.H

3122

.raft.

4YWHAZYWHAQYWHAHYWHAGYWHAEYWHABTUBB4ATRIM28SMARCA4PEA15PDCD6IPPBRM1NDRG1MTPNMAPK12MAPK1LASP1KRASHSPB1HSPA4HSP90AA1GRB2GIPC1FASNCTTNCRKLCRKCLTCCCT2BAZ1BBAZ1AATAD2ACTB

geld

.H31

22.o

rg.1

geld

.H31

22.o

rg.2

geld

.H31

22.o

rg.3

geld

.H31

22.o

rg.4

.mge

ld.H

3122

.raft.

1.m

geld

.H31

22.ra

ft.2

geld

.H31

22.ra

ft.3

geld

.H31

22.ra

ft.4

YWHAZYWHAQYWHAHYWHAGYWHAEYWHABTUBB4ATRIM28SMARCA4PEA15PDCD6IPPBRM1NDRG1MTPNMAPK12MAPK1LASP1KRASHSPB1HSPA4HSP90AA1GRB2GIPC1FASNCTTNCRKLCRKCLTCCCT2BAZ1BBAZ1AATAD2ACTB

1

Amount in cell fraction

0

CRKL

Organelles Rafts

4 1 2 3 4 l Geldanamycin

1 2 3 4 1 2 3 4 Control Geldanamycin

CLTC

LASP1

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and signaling adaptor proteins (GIPC1, LASP1, PEA15, CRK, CRKL,and GRB2) (Fig. 6 and fig. S14). CLTC also decreased in endosomefractions (org2) in response to geldanamycin, whereas other proteins

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

increased, including mitogen-activatedprotein kinase 1 (MAPK1), MAPK12, andKRAS (Kirsten rat sarcoma viral oncogenehomolog) (Fig. 6, C to E). Although therewas a geldanamycin-induced increase inphosphorylated MAPK3/MAPK1 in raftfractions, phosphorylated CTTN de-creased in the same fractions (p-ERK1/2and p-CTTN; Fig. 6E and fig. S14). Con-comitantly, several bromodomain-containing proteins (PBRM1, ATAD2,BAZ1A, BAZ1B, and SMARCA4) de-creased in the same lipid raft fractions(raft2 to raft4; Fig. 6, B and C). These dataare consistent with previous work showingthat geldanamycin influences the intra-cellular localization of signaling proteins(43–45) and support the hypothesis thatthe changes in modification state that weobserved in response to geldanamycin(Fig. 3) have functional consequences forintracellular localization.

A total of 295 proteins were identifiedthat had negative correlations betweendifferent types of PTMs on the same pro-tein (table S1). Examination of relation-ships between protein methylation andother PTMs revealed that the distributionof correlations between methylation andacetylation sites on the same protein wassignificantly different than correlations ofthe same PTMs (Fig. 7A). There were 50proteins with 95 dual acetylation andmethylation PTMs that had negative cor-relation less than−0.5 (highlighted in bluein Fig. 7A). These include RNA binding,cytoskeletal, heat shock proteins, tran-scription factors, and acetyltransferases,including EP300 and NCOR2 (table S1).Note that none of this group were his-tones, which were dually modified, butcorrelations were mostly positive or notsignificant. There were also groups ofmethylated and acetylated proteins whosePTMs clustered together and were allhighly correlatedwith one another. An ex-ample clique of these highly correlated co-clustered PTMs (Fig. 7B, identified bymultiple yellow edges) revealed severalRNA binding proteins and transcriptionfactors, including the methyltransferaseEZH1, acetyltransferase CREBP, deacety-lase SIRT9 (which was phosphorylated),and proteins whose methylation and acet-ylation sites were inversely correlated.These data suggest that there aremolecular

interactions governed both synergistically and antagonistically by meth-ylation and acetylation in proteins to regulate RNA processing andtranscription.

A

C

C.H

3122

.org

.1C

.H31

22.o

rg.2

C.H

3122

.org

.3C

.H31

22.o

rg.4

.m

D

high

relative phospho-peptideamounts

low

8

Fold change

–8

org1

org2

org3

org4

raft1

raft2

raft3

raft4

BAZ1BSMARCA4BAZ1AATAD2PBRM1TUBB4AGRB2CLTCACTBTRIM28YWHAHYWHAQCTTNHSP90AA1FASNCCT2HSPA4LASP1YWHAEYWHAZPDCD6IPYWHAGYWHABMAPK12KRASCRKCRKLHSPB1PEA15MTPNGIPC1NDRG1MAPK1

org1

org2

org3

org4

raft1

raft2

raft3

raft4

LASP1.H3255LASP1.H3122YWHAZ.H3255YWHAZ.H3122CRKL H3255CRKL H3122CCT2.H3255CCT2.H3122p-CTTN H3255p-CTTN H3122CTTN H3255CTTN H3122p-ERK H3255p-ERK H3122ERK.H3255ERK.H3122CLTC.H3255CLTC.H3122ACTB.H3255ACTB.H3122

B

1 2 3Contro

E

Fiz(Agtomtoimpraetrfrode

ig. 6. Geldanamycin induces changes in lipid raft local-ation of dually phosphorylated/acetylated proteins.) Outline of cell fractionation experiments that separate or-anelles including different populations of endosomes (org1org4, top) and detergent-sensitive and detergent-resistantembranes including lipid rafts (raft1 to raft4, bottom). Org1org3 contain lysosomes and endosomes with different sed-entation velocity, respectively; org4 contains soluble, cyto-lasmic proteins; raft1 contains detergent-sensitive proteins;ft2 to raft4 are detergent-resistant fractions of decreasingquilibrium density (10, 46, 47). (B to E) H3122 and H3255 cellseated with geldanamycin (“geld.”) or not treated (“C.”) wereactionated, and total protein amounts in each fraction [fourrganellar fractions (“org.”) and four raft fractions (“raft.”)] wereetermined in three separate experiments by mass spectrom-try (B and C, H3122 cells) and, for a select few, by Western

blotting (D, H3255 cells; E, cell type indicated). Mass spectrometry data [expressed as heat maps in (B)] and Western blotdata (D, and fig. S14) were used to calculate the amount of each protein in each cell fraction as a proportion of the total inthe whole cell, which is the sum of protein amounts in all cell fractions. The heat maps in (C) and (E) show fold changeabundance in treated cells relative to control cells for each fraction for mass spectrometry and Western blot data, respec-tively. One hundred sixty-eight of 218 dually phosphorylated and acetylated proteins with negative correlations betweenthese PTMswere detected in this experiment.Many exhibited changes in the raft2 fraction (P=0.05394,Welch two-samplet test). Forty-five of 108 proteins whose PTMs changed significantly in response to geldanamycin (Fig. 3) were detected bymass spectrometry in this experiment; collectively, their amounts increased in the raft2 fraction (P = 0.01457). Of the sixbromodomain-containing proteins detected, most decreased in the raft2 fraction (P = 0.04832 for all the bromodomain-containing proteins). Mass spectrometry data expressed as the amount of proteins in cell fractions are in table S2.

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Similar to other dual modifications on the same proteins, thedistribution of PTM correlations among 96 dually phosphorylated/methylated proteins was distinct from homologous PTM correlations,with 211 modifications having negative correlation between phospho-rylation andmethylation less than −0.5 (Fig. 7C). Many of these coclus-tered PTMswere found onRNAbinding and RNA-processing proteins.We also identified a clique of PTMs among phosphorylated andmethy-lated RNA binding proteins that included links to methyltransferasesand kinases (Fig. 7D). The core clique of proteins whose PTMs all

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

clustered and correlated included proteins involved in RNA splicingand processing, similar to the clique of methylated and acetylated pro-teins above (Fig. 7B) (48). The extended group contained other proteinsinvolved in RNA binding, cytoskeleton, chaperone activity, andtranscription regulation. HNRNPA2B1 displayedmultiple negative cor-relations between its tyrosine phosphorylation and argininemethylationsites. Note that the methyltransferase EZH1, the RNA-processing pro-tein XRN2, and the RNA binding protein RBMX were linked to bothclusters (Fig. 7).

p p p me me me

0.0

0.5

1.0

–1.0

–0.5

0.0

0.5

1.0

Cor

rela

tion

me me me ac ac ac

0.0

0.5

1.0

–1.0

–0.5

0.0

0.5

1.0

Cor

rela

tion

PRPF4B p Y849

SFPQ ack K518

SMG1

PRPF4B

SMG1 p S3556

CLK2

ABL1

TRIO p S1632

CPSF6

CPSF6 rme R194

CPSF6 p Y520

CPSF6 rme R216TRIO

SFPQ p Y602

SFPQ rme R681

SFPQ rme R242

SFPQ

SFPQ rme R706

SFPQ rme R693

HNRNPA3 ack K187

HNRNPA3 ack K36

HNRNPA3 rme R216 HNRNPA3

HNRNPA3 rme R226

HNRNPA3 rme R214

HNRNPA3 rme R286

HNRNPA3 rme R376

HNRNPA3 rme R354

HNRNPA3 p Y188HNRNPA0 p Y145

HNRNPA0 rme R284

EZH1 kme K736

SFPQ rme R695

EZH1

PPP1CA ack K305

PPP1CA

CAMK2A

CAMK2A p T286

KHDRBS1 rme R340

KHDRBS1

KHDRBS1 rme R320

KHDRBS1 p Y435

VRK1

VRK1 kme K5

KHDRBS1 rme R331

XRN2 rme R946

XRN2 rme R883

XRN2 rme R895

XRN2 ack K641

XRN2 rme R921

HNRNPA2B1 rme R213

HNRNPA2B1 rme R325

HNRNPA2B1 rme R266

HNRNPA2B1

HNRNPA2B1 rme R238

HNRNPA2B1 rme R203 HNRNPA2B1 rme

R350

HNRNPA2B1 rme R153

HNRNPA2B1 p Y234

HNRNPA2B1 p Y336

PTPN14

EHMT2 p S119

PTPN14 p T323

EHMT2

HNRNPA2B1 rme R228

CDK17 p S165

HNRNPA2B1 p Y174

EHMT2 p S121

CDK17

RBMX p Y272

MEPCE

RBMX p Y260

RBMX rme R298

RBMX ack K30

MEPCE rme R377

RBMX rme R339

PRKDC p T2609

KHDRBS1 rme R4

PRKDC ack K3455

PRKDC

RBMX p Y266

RBMX rme R317

RBMX rme R164

HNRNPA0 rme R189

RBMX rme R172

RBMX

RBMX p Y335

HNRNPA0

XRN2

XRN2 p S448

XRN2 rme R933FBL

XRN2 p S455

XRN2 p S451

SERBP1 rme R160

SERBP1 ack K102

EWSR1 rme R455

EWSR1 ack K439

EWSR1 rme R615

EWSR1 ack K641

SERBP1 rme R216

XRN2 rme R883

KHSRP

KHSRP ack K653

KHSRP rme R413

KHSRP rme R442

KHSRP rme R415

TCERG1 rme R20

RPS29 ack K13

TCERG1

RPS29

TCERG1 ack K1035

RPS29 ack K54

RPS29 ack K33

TCERG1 rme R13

SERBP1 rme R195

SERBP1 ack K320

RPS29 rme R12

DDX17 rme R94

HNRNPA3 rme R354

HNRNPA3HNRNPA3 rme

R246

HNRNPA3 ack K36

RBMX ack K30

RBMX rme R164

RBMX rme R339

RBMX rme R317

RBMX rme R298

RBMX

CREBBP

HSPA8 rme R469

HSPA8

SIRT6

CREBBP ack K1741

SIRT6 p T294

RBMX rme R172

XRN2 ack K641

XRN2 rme R921

DDX17 rme R81

XRN2

XRN2 rme R895

HNRNPA3 ack K187

HNRNPA3 rme R216

HNRNPA3 rme R286

HSPA8 ack K348

HSPA8 ack K71

SERBP1 rme R181

SERBP1

SERBP1 rme R188

HNRNPU ack K213

HNRNPU rme R755

HNRNPU rme R727

HNRNPU

RBMX p Y335

RBMX p Y266

HNRNPU rme R702

EWSR1

EWSR1 rme R300

HSPA8 ack K187

HNRNPA3 rme R226

EZH1

EZH1 kme K736

DDX17 rme R684

DDX17 ack K547

DDX17

DDX17 rme R100

XRN2 rme R946

A

C

B

D

Fig. 7. Clusters of proteins dually modified by different PTMs. (A and C) Correlations between different PTM sites on the same protein plotted as in Fig. 5A. Homo-PTM correlations (me me; ac ac; p p) are significantly different from heterologous PTM correlations (me ac; p me; P < 2.2 × 10−16 in all cases). (B and D) Selected proteinsmodified by (B) acetylation and methylation, and (D) phosphorylation and methylation are shown with CFN links to PTM-modifying enzymes, as described in Fig. 4B.These figures highlight two cliques of PTM CCCN edges that coclustered and had a high Spearman correlation. Negative correlations between different PTMs on thesame protein are indicated by blue edges. Node size and color (refer to the key in Fig. 2) reflect total of all PTM ratios in the data set.

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Connections to aberrantly regulated genes in lung cancerLast, to assess the functional significance of upstream signaling events’influence on global mRNA gene expression by PTMs, we examinedhow cell signaling pathways inferred from the CFN analysis may regu-late basal gene expression patterns in lung cancer cell lines. Among themost commonly differentially regulated genes from the gene expressiondata that we obtained from lung cancer cell lines from the Cancer CellLine Encyclopedia (CCLE) (49), SMARCA4 andNKX2-1 were also de-tected in the protein modification data (Fig. 8A) (50). SMARCA4 is themost down-regulated gene, and its inactivation is thought to promoteNSCLC aggressiveness (51). NKX2-1 is one of the top 10 differentiallyregulated genes in this set of cell lines. NKX2-1 plays a key role in lungdevelopment; its loss causes a failure of lung cell differentiation andleads to malignant transformation in lung adenocarcinoma (52–54).SMARCA4 and NKX2-1 exhibited CFN/CCCN interactions with theRNA binding proteins DDX5, DHX9, HNRNPAB, and lysine acetyl-transferase NCOA2 (Fig. 8B). These links from DDX5 to NCOA2,NKX2-1, and SMARCA4 were preserved in a highly curated network

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

focused on direct binding interactions (Fig. 8C). This is consistent witha mechanism to control NKX2-1 expression through long noncodingRNAs (54). The acetyltransferase EP300, themethyltransferase PRMT1,the kinases PKN2, CHEK2, and YES1, and the bromodomain-containing kinase BAZ1A also had cluster-filtered interactions with thisgroup (Fig. 8B), indicating that the interplay of phosphorylation, acet-ylation, andmethylation is likely to play a role in controlling expressionand activity of SMARCA4 and NKX2-1.

In sum, we detected a large number of proteins that were modifiedbymore than one type of PTM; in this study, we detectedmore than 700proteins that were phosphorylated, acetylated, and methylated (Fig. 9Aand fig. S15A). Correlation was poor (R2 = 0.03368) comparing relativeabundance of proteins detected by their PTMs in our data to total pro-tein abundance estimates for human proteins in paxDB (fig. S15B) (55).This suggests that the amount of detectable PTMs was governed largelyby signaling events rather than by total protein amounts. Elucidation ofclusters of positively correlatedPTMs,when combinedwithPPI informa-tion, identified cell signaling pathways that are active in lung cancer cell

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HNRNPAB

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Fig. 8. Pathways to SMARCA4 andNKX2-1. (A) Gene expression data from 29NSCLC cell lines from the CCLE (49) plotted on a blue-red scale (key) (50). NKX2-1 and SMARCA4(highlighted) are among themost dysregulated genes in lung cancer. (B) CFN and CCCNpath from EP300 to NKX2-1 and SMARCA4, where node size and color (refer to the key inFig. 2) indicate total ratio data for all experiments where lung cancer cell lines were compared to normal lung tissue. (C) Shortest paths from EGFR andMET to transcription factorsin a CFNderived from the PPI data setwithhighly curatedmolecular interactionswith a focus on direct interactions for which there is strong evidence (20, 85). Note that DDX5 andNCOA2 bind to NKX2-1 and SMARCA4 as in (B). Node size is CFN betweenness, and node color is normalized betweenness defined as CFN betweenness divided by the between-ness from all PPI data sets before filtering.

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lines. In addition, our observations suggest that proteins that function assignal integrating hubs may have one or more exclusive OR (XOR)switches governed by a subset of antagonistic relationships among phos-phorylation, acetylation, andmethylation sites (Fig. 9B). Because differentPTMs govern interactions among proteins with PTM-specific binding

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

domains (Fig. 9B), proteins modified by more than one PTM typemay thus function as hubs for signal integration or pathway controlswitches. Identification of these cell signaling hubs, and the enzymes thatmodify them, provides insight into the complex signal transductionmechanisms that regulate lung cancer cell lines.

DISCUSSIONThe data generated for this study presented a unique opportunity tosimultaneously examine, on a large scale, proteins modified by tyrosineand serine/threonine phosphorylation, lysine acetylation, and lysineand arginine methylation (Fig. 1B). This allowed definition of relation-ships betweenkinases, phosphatases, and enzymes known to affect otherPTMs, including acetyltransferases, deacetylases, methyltransferases,and demethylases. Our computational data analysis approach was tointegrate two different kinds of information: clustering based on sta-tistical relationships among various PTMs, and PPI data from publicdatabases, to outline signal transduction pathways (Fig. 1A). Westarted with PPI networks retrieved from Pathway Commons, String,GeneMANIA (15, 16), BioPlex (12), and the kinase-substrate datafrom PhosphoSitePlus (13, 14), and then filtered interactions basedon PTM clustering. Clustering methods using t-SNE were previouslyused for analyzing lung cancer phosphoproteomic data (23), andthe CFN approach we utilized here was previously used on phospho-proteomic data fromneuroblastoma cell lines (10).We further refinedthis approach with an additional step (PMD) to break up large clus-ters, as described inMaterials andMethods and in the SupplementaryMaterials. We have shown that the CFN derived from these dataeffectively removes biases in PPI networks where well-studied pro-teins have more links (fig. S6) and that the number of PTMs does notoverly bias node betweenness (fig. S7), so that the two kinds ofinformation were well balanced for construction of a CFN.

The cell signaling pathways within the CFN were based on knownPPIs and clustering of PTMs in lung cancer cell lines, so for interactionsbetween any two proteins to be retained in the CFN, they must be in-cluded in the same PTM cluster. Starting with drug targets (the proteinsthat bind to and are directly affected by drugs), we examined links,shortest paths in the CFN, to proteins whose PTMs were changed bydrug treatment (Figs. 2 and 3). This effectively outlined signaling path-ways in lung cancer cell lines betweendrug targets anddownstreampro-teins whose PTMs were affected by the drug.

The hypothesis that certain PTMs may have a mutually opposing,antagonistic relationship to one another was first suggested in ourresults by drug treatments that caused protein acetylation to increaseand phosphorylation to concomitantly decrease (Figs. 2 and 3). Thelinks between the acetyltransferase EP300 and heat shock proteins in-cluding HSP90s, suggested that the HSP90 inhibitor geldanamycinaffects the balance between the phosphorylation and acetylation of en-docytic and cytoskeletal proteins. This in turn perturbs endocytosis andcytoskeletal dynamics, which influences membrane trafficking and ac-tivity of selected RTKs and other proteins involved in signal trans-duction (Fig. 6). These results are consistent with previous workshowing that geldanamycin affects membrane traffic and cytoskeletaldynamics to regulate activity and intracellular localization of manysignaling proteins (43–45). EP300 had many CFN links to enzymesthat regulate other PTMs, including kinases, phosphatases, and methyl-transferases (Fig. 4 and figs. S11 and S12). EP300 has been previouslyreported to function in cytosol to regulate autophagy (56, 57). Ourdata suggest that EP300 (and possibly other acetyltransferases) may

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Fig. 9. Dual PTMsmay function as dueling PTMs. (A) Venn diagram showing theoverlap among proteins modified by more than one type of PTM. A similar Venndiagram in which tyrosine and serine/threonine phosphorylation are separated isshown in fig. S15A. (B) Schematic of the findings. Proteins in molecular signalingpathways modified by more than one PTM have different sets of interacting pro-teins (5, 6). PTM-driven interactions occur through recognition of specifically mod-ified amino acid residues by protein domains listed under the PTM type in thefigure. Acetylated (Ac) proteins interact with bromodomain and BET (bromodo-main and extraterminal domain) proteins (green); methylated proteins interactwith proteins containing tudor domains if methylated on arginine (RMe); orchromo, PWWP (’Pro-Trp-Trp-Pro’), and MBT (malignant brain tumor) domains ifmethylated on lysine (KMe) (purple). Phosphorylated proteins interact with sev-eral protein families (red): tyrosine phosphorylated proteins (pY) interact with SH2(Src homology domain 2) and PTB (phosphotyrosine binding) domains; serine/threonine phosphorylated proteins (pS/T) interact with a variety of proteins in-cluding 14-3-3 protein family members and proteins containing the domainsWW (domain with 2 conserved Trp residues), FHA (forkhead-associated domain),WD40 (WD or b-transducin repeats), and LRR (leucine-rich repeats). Our data sug-gest that where inverse correlations exist between different PTMs, these mayfunction as exclusive “OR” (XOR) switches to direct alternative cellular outcomes.This principle applies to phosphorylation versus acetylation; phosphorylation ver-sus methylation; and methylation versus acetylation.

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play a role in regulating other membrane traffic and cytoskeletal me-chanisms. Consistent with this notion, HDAC6 acetyltransferase regu-lates the acetylation status of microtubules and modulates EGFRtrafficking (58). That geldanamycin affects the balance of differentPTMs sheds new light on the elusive mechanisms of action of thisclass of drug, which is important to understand because HSP90 in-hibitors are an emerging therapy for lung cancer (59–61).

Further support for an antagonistic relationship between certainphosphorylation and acetylation sites was provided by examining neg-ative correlations between PTMswithin the same protein and visualizingthem as edges (Fig. 5, A and B). In addition, cluster-filtered interac-tions existed between kinase signaling pathways and bromodomain-containing proteins that bind to acetylated lysine moieties (Fig. 5E).These interactions were most frequent among proteins with negativecorrelations between phosphorylation and acetylation sites on the sameprotein (Fig. 5F). Negative correlations within proteins were also iden-tified for acetylation versusmethylation sites (Fig. 7, A and B) and phos-phorylation versus methylation sites (Fig. 7, C and D). These dataelucidated a family of different PTMs that potentially function as mul-tiple XOR switches in signaling pathways (Fig. 9B).

Our data are consistent with the notion that different PTMs onthe same protein integratemultiple signals to generate combinatorialoutputs (62). These interconnected, functionally associated mechanismscoevolved across eukaryotes (2, 63) and are associated with oncogenesis(40). Our study indicates that acetylation and methylation, togetherwith phosphorylation, increase the interactome of hubs in the signaltransduction network by conditionally altering the sets of interactingproteins with particular protein domains (Fig. 9) (64, 65). Proteins inthe networkmay be classified as proteins that attach (writers), recognize(readers), and remove (erasers) PTMs (2). The readers of acetylationcontain bromo and BET domains (5). Readers of methylation are pro-teins that have the tudor domain for arginine methylation, andchromo, MBD, and PWWP domains for lysine methylation (66). It isnoteworthy that bromodomain-containing proteins include kinases(BAZ1A, TRIM33, BRD2, and BRD4), acetyltransferases (EP300and CREBBP), and methyltransferases (ASH1L and KMT2A; Fig. 5E).This emphasizes the interconnected nature of mechanisms involving dif-ferent PTMs.

Signaling pathways outlined using CFNs involve a large number ofmodified RNA binding, cytoskeletal, and membrane traffic proteins.The number of RNA binding and cytoskeletal proteins in these net-worksmakes sense in light of the number of mechanisms involved withRNA transport, sequestration, and regulatory RNA molecules (67–71).Cells evolved mechanisms to control protein expression by transcrip-tion, translation, and transport of RNA to different intracellular loca-tions. Two RNA binding proteins were the most highly modifiedproteins in the data (AHNAK and SRRM2; fig. S7). Several such highlymodified RNA binding proteins are dysregulated in cancer and movefrom cytoplasm to nucleus in response to phosphorylation (72). Ourdata suggest that methylation and acetylation also likely play a role inthis process.

Signal transduction involvesmore than the threePTMs studied here,for example, generation of secondmessengers and covalent attachmentof carbohydrates, lipids, or ubiquitin family proteins, which cause addi-tional changes in activity, intracellular location, and binding partners(62–64). Accurate models of signal transduction should attempt to in-tegrate data about these processes for a complete picture. For example,METubiquitination and internalization are regulatedbyphosphorylationat Tyr1003, the c-CBL E3 ubiquitin ligase binding site (73). This PTM on

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

MET clustered with phosphorylation of EGFR at Tyr869 and Tyr1197

but not at Tyr1045, EGFR’s c-CBL binding site (Fig. 5, C and D) (74).It would also be useful to correlate gene expression patterns with

PTMs. This remains challenging, however, because the correlation be-tween protein and mRNA levels is poor, as shown for example duringXenopus embryogenesis, where large cells allow direct comparisons(75), although many differences may be resolved using a simple modelfor expression kinetics (76). PTMs in cells are evenmore highly variableand dynamic than protein levels. For example, very different phos-phorylation patterns in the anaphase-promoting complex and mitoticspindle checkpoint proteins are observed in response to antimitotic drugs(77), and PTMs showmuchmoremarked changes thanmRNAor pro-tein during developmental progression (76). PTMs aremore likely to beuseful to inform us about cell signaling pathways than transcription be-cause they are closer to signaling events, at least those that are upstreamof transcription (25, 76).

Our study integrating three different PTMs contains a large amountof information that outlines signaling pathwayswhen clustering is com-bined with known PPIs. These data elucidated clusters of highly cor-related PTMs among groups of proteins [Figs. 5B (yellow CCCNedges) and 6, B andD]. This means that if one or a few of these PTMsare detected, then other members of the clique are likely to be found,which is useful for determining signatures of pathway activation or dis-ease state. There aremore synergistic relationships, as well as dueling orantagonistic relationships, among different PTMs in lung cancersignaling pathways than can be presented from our data; therefore,we have created a browser-accessible interface as a resource for furtherexploration by other investigators (https://cynetworkbrowser.umt.edu/).Networks are also available on the NDEx repository (https://doi.org/10.18119/N9F59Z) and in data file S1. The data will be useful for pre-diction of pathways of drug resistance (78), and side effects fromdrugsthat target writers, readers, and erasers of acetylation andmethylation(4–9).

MATERIALS AND METHODSModification-specific antibody immunoprecipitation andmass spectrometryPTMs of 45 lung cancer cell lines, 12 derived from SCLC and 33 fromNSCLC, were compared to normal lung tissue (pooled from anonymouspatients) using an established protocol (26, 27). In addition, several celllines were treatedwith crizotinib, gefitinib, geldanamycin, or imatinib at1 mM for 1 to 24 hours. In all, 15 six-plex TMT experiments were per-formed. Briefly, cells were washed and harvested in phosphate-bufferedsaline, and cell pellets were frozen in liquid nitrogen. Cells were lysed ina 10:1 (v/w) volume of lysis buffer [4% SDS, 100 mM NaCl, 20 mMHepes (pH 8.5), 5 mM dithiothreitol, 2.5 mM sodium pyrophosphate,1 mM b-glycerophosphate, 1 mM Na3VO4, and leupeptin (1 mg/ml)],and proteins were reduced at 60°C for 45 min. Proteins were thenalkylated by the addition of 10 mM iodoacetamide (Sigma-Aldrich)for 15 min at room temperature in the dark, and methanol/chloroformwas precipitated. Protein pellets were resuspended in urea lysis buffer[8 M urea, 20 mM Hepes (pH 8.0), 1 mM sodium orthovanadate, 2.5mM sodium pyrophosphate, and 1 mM b-glycerolphosphate] and so-nicated. Insolublematerial was removed by centrifugation at 10,000g for5 min, and the supernatant was diluted fourfold in 20 mM Hepes (pH8.5) and 1 mMCaCl2 for Lys-C digestion overnight at 37°C, then dilut-ed twofold followed by trypsin digestion for 4 to 6 hours at 37°C.Samples were then acidified to pH 2 to 3 with formic acid, and peptides

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were purified on a Waters Sep-Pak column and dried in a speed-vac.Peptides were purified on a Waters Sep-Pak column and quantifiedusing a micro-BCA assay (Thermo). Mass tag (six-plex TMT reagents;Thermo) were cross-linked to peptides in 30% acetonitrile/200 mMHepes (pH 8.5) for 1 hour at room temperature, and the reaction wasstopped by the addition of 0.3% (v/v) hydroxyamine. Combinedsamples were then sequentially immunoprecipitated with cocktails ofmodification-specific antibodies from Cell Signaling Technology inthe following order: anti-phosphotyrosine (P-Tyr-1000, #8954); anti-phosphoserine/threonine (AGC/PSD family Kinase Substrate Antibody;CST in-house antibody validated for peptide immunoprecipitation)(phospho-Akt substrate, #9614; Phospho-AMPKSubstrateMotif, #5759;Phospho-ATM/ATR Substrate, #9607 and #6966); anti-acetyllysine[acetylated-Lysine, #9814 (79)]; anti-methyllysine [Mono-MethylLysine, #14679 (80)]; and anti-methylarginine [Mono-Methyl Argi-nine, #8015 (80)] (see Fig. 1B). After anti-phosphotyrosine and anti-phosphoserine/threonine immunoprecipitation, phosphopeptideswere further purified on a TiO2 column [Thermo Fisher Scientific (81)].Samples were thenmixed in equimolar ratios, and the ratios were checkedand samples run on an Orbitrap Q Exactive MS (Thermo Fisher).Identification of peptides and quantification of mass tags were ob-tained from the MS2 spectrum after fragmentation by tandem massspectrometry analysis, as described (28, 80). Peptides with false discov-ery rate (FDR) <1% were selected for further analysis. Modificationsites with site localization scores of less than A-score 13 were ex-cluded from analysis (82).The data were filtered to include singlemodification sites present in three or more experiments for the finalanalysis. For display of results in heat maps, treatment/control ratioswere calculated as fold change (treatment/control if treatment > con-trol; −1/treatment/control if treatment < control).

Final clustering for CFNsA detailed discussion of data analysis considerations and networkdevelopment is provided in text S1. TMT ratio data were used to cal-culate pairwise-complete Euclidean distance and Spearman and hybridSpearman-Euclidean dissimilarity (SED) (10, 23). Clusters were identi-fied using t-SNE, as discussed below. Clusters containing more than 80modifications were subjected to PMD with dimensionality reduced tothe number of experiments that contained modifications in the cluster,and t-SNE was then performed on these PMD embeddings. Clusterswere examined manually, and those that were sparsely populated withdata (meaning that containedmodificationsmostly fromone experiment)were discarded. An adjacency matrix was constructed by pairing co-clusteredmodifications to each other. To construct CCCNs, the adjacencymatrixwas used to filter Spearman correlations at various values, as shownin fig. S9, excluding values that were not between coclustered modifica-tions. Spearman correlation values were used to represent network edgeweights in modification site CCCNs. This protein modification CCCNwas used to construct a protein CCCN by merging all coclustered cor-relation edges into the gene names of modified proteins. The final geneCCCN represents the sum of modification correlations among all pro-teins (genes) that clustered together, whosemodifications were detectedin two or more experiments and whose Spearman correlation is greaterthan the absolute value of minimum densities shown in fig. S9B.

Pairwise-complete Euclidean distance andSpearman correlationPairwise-complete Euclidean distance and Spearman correlation wereperformed in R using previously described methods (10, 23). Embed-

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

dingswere created fromEuclidean distance; Spearmandissimilaritywasdefined as 1 − abs(cor); and hybrid SED was defined as the mean ofnormalized Euclidean and Spearman dissimilarity as 1 − cor.

Matrix decompositionMatrix decomposition was performed using the methods described byWitten et al. (83) using the R package PMA (Penalized MultivariateAnalysis). Parameter selection for PMD via cross-validation was firstperformed using the tuning function PMD.cv. The function PMD,which applies an L1 penalty on the columns and rows, was used to obtaina matrix of 90 factors (equivalent in size to the original data) and 15factors (the number of TMT runs). The original data were not centeredfor these calculations. Alternatively, the data were further standardizedsuch that each column has zero mean and unit variance (normalized,centered, or nc). Groups with greater than three sites were evaluated.

t-SNE embeddingst-SNE embeddings were created using Rtsne, the Barnes-Hut imple-mentation of t-SNE. The pairwise-complete method produced clustersthat weremore readily distinguished (fig. S1), with othermethods tend-ing to crowd many sites into one or two very large clusters. This wasmitigated in twoways, by reducing the perplexity in t-SNE and reducingvector length for inclusion of neighbors in clusters (the “too long” value)in the minimum spanning tree length to define clusters. These param-eters were optimized as much as possible to avoid one large cluster andalso many single-site clusters. The typical settings with Rtsne weredimensions = 3, perplexity = 15, and q = 0.25, and the initial principalcomponents analysis step turned off.

Random clustersRandom clusters were generated by sampling the total number of sitesor genes from the data using a probability vector to obtain the averagenumber of genes and sites similar to real clusters from all embeddings.The probability of random coclustering of different modification sitesfrom the same protein was weighted to the number of modificationsites per protein; that is, proteins with many modification sites inthe data were more likely to cocluster in random clusters. The av-erage %NA of random clusters was equal to that in the entire dataset (fig. S2C).

Internal evaluationsIndex is defined as

Index ¼ ½ð1þ realsamplesÞ � ð1þ clearsitesÞ=ð1þ percent NAÞ�=no:sites

where intensity = total signal− (total signal × percentNA/100); clearsites =no: sites− sites culled by slope; realsamples = no: samples− (no: samples ×percent single site samples × 100); and no. sites = number ofmodificationsites in the cluster. This formula is modified from that previously defined(23): “single site samples” is the number of cases where a sample in thecluster contains only one site, and “single sample sites” represents thenumber of caseswhere a site in the cluster is represented in only one sam-ple. The “culled by slope” function sorts sites and samples from largestto smallest within each cluster and measures the slope of the regressionline for each site in all the samples. If the slope is negative, then the sitefollows the general pattern in the cluster. If the slope is positive, then thesite is more highly expressed in different samples than the rest of thegroup and is culled.

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External evaluationThe Pathway Commons data set was extracted from publicly availableresources (20). Interactions were filtered to include only “in-complex-with,” “controls-phosphorylation-of,” “controls-state-change-of,”“controls-expression-of,” and “controls-transport-of.”The gene namesof modified proteins were used to retrieve interactions among proteinswithin all clusters, and the number of edges was quantified.

PPI edgesPPI edges were retrieved from Pathway Commons, as described above,and from STRING, GeneMANIA (using the website or the Cytoscapeplugin) (15, 16), BioPlex (12), and the kinase-substrate data fromPhosphoSitePlus (13, 14). Text mining, colocalization, and coexpres-sion edges were excluded to focus on interactions that are likely partof cell signaling pathways. We found it most useful to limit interactionsto those defined by direct physical interactions from curated pathways.For example, genetic interactionsmay be direct or indirect, so they wereexcluded in some cases to focus on direct physical interactions (84). ACFNwas constructed from a PPI data set with highly curatedmolecularinteractions with a focus on direct interactions for which there is strongevidence (Fig. 8C) (20, 85).

Network analysesFor the CCCN, we used clustering to filter correlations between all sites.The resulting protein CCCN was used to create a CFN of PPI interac-tions that were filtered on the basis of clustering by excluding all inter-actions save those from proteins with coclustered modifications. Toidentify pathways that are likely to be active in lung cancer cell lines, shortestpaths were determined using the R package igraph (igraph.org). Acomposite of all the shortest paths was assembled for Figs. 2 (A and B)and 3D. Centrality was identified by node degree and betweenness andcalculatedusing igraph functions.Networkswere also graphed to showpro-tein modifications with correlation edges from the CCCN. In the CCCNgraphs, correlationedgesdepictPTMsthat coclusterwithedges representingSpearman correlations greater than the threshold of |0.543|, as defined in fig.S9. In addition, for Figs. 5B and 7 (B andD), negative correlations less than−0.5 are shown between different modifications within the same protein.

Website constructionTo enable exploration of the networks in detail by other investiga-tors, we developed a website for interactive visualization (https://cynetworkbrowser.umt.edu/). Our novel infrastructure allows a webclient (browser) to interface to a server-based instance of Cytoscape.Networks and their underpinning data are stored on the server as R datafiles, and each web session corresponds to an instance of Cytoscape onthe server. The web client presents a graph rendered by the Javascriptlibrary cytoscape.js.Actions on the site initiate queries to thePython serv-er, which in turn uses theR-to-python interface (rpy2) to call the relevantR function. R communicates with the server-based instance of Cytoscapevia the RCy3 library (bioconductor.org) (86). The cyREST interface (87)returns updated graph information to the client, in the form of JSONdata, by connecting Cytoscape to a Python Flask-WSGI server.

Cell fractionationH3122 cells were treated with 1 nM geldanamycin for 15 hours or nottreated, and thenmechanically permeabilized using a Balch homogenizer(10, 46, 47). Permeabilized cells were centrifuged at 1000g for 10min, andthe organelles in the supernatant were applied to velocity sedimentationgradients, as described previously (10, 46). Four fractions were collected

Grimes et al., Sci. Signal. 11, eaaq1087 (2018) 22 May 2018

from organelle gradients, as shown in Fig. 9A. Lysosomes are found infraction 1, and endosomes in fractions 2 and 3 (10, 46). The 1000g pellets(cell ghosts) were solubilized for 1.5 hours on ice in 1%Triton X-100 andsubjected to floatation equilibrium gradients, as described, except that the10,000g centrifugation step was omitted (10, 47). Four fractions fromthe floatation equilibrium gradients were collected: Fraction 1 is fromthe bottomof the gradient, fraction 2 contains the lipid rafts as previouslycharacterized, and fractions 3 and 4 contain additional floating mem-branes at the top of the gradient, as shown in Fig. 9A. Samples were pre-pared for TMT mass spectrometry as described above, except withoutimmunoprecipitation with modification-specific antibodies, so totalprotein amounts weremeasured; 10mass tag labels were used (ThermoTMTplex); and samples were analyzed on an Orbitrap Fusion Lumos(Thermo Fisher Scientific). The iBAQ method was used to normalizesignals, where a protein’s total intensity is divided by the number oftryptic peptides between 6 and 30 amino acids in length (88). Westernblots with lysates from H3122 and H3255 cells were then performed toverify results from select proteins in duplicate experiments. Antibodiesto b-actin (#4970), phospho-CTTN Tyr421 (#4569), CTTN (#3503),phospho-ERK1/2 Thr202/Tyr204 (#4370), CCT2 (#3561), CLTC(#4796), CRKL (#3182), LASP1 (#8636), and YWHAZ (#7413) werefrom Cell Signaling Technology; antibody to ERK1/2 (sc-93) was fromSanta Cruz Biotechnology. All antibodies were incubated at 1:1000 (ex-cept phospho-ERK1/2, 1:2000) overnight at 4°C according to the man-ufacturers’ protocol. Duplicate blots were used to probe phospho- andnon–phospho-CTTN and ERK1/2. Western blot chemiluminescentsignals were obtained on a Fuji LAS-3000 and quantified using ImageGauge software. The amount of each protein in each fraction as a percentin the whole cell was then calculated by dividing Western blot or massspectrometry signals by the total in all fractions (10, 47). Ratioswere thencalculated to compare geldanamycin-treated to control samples.

SUPPLEMENTARY MATERIALSwww.sciencesignaling.org/cgi/content/full/11/531/eaaq1087/DC1Text S1. Data analysis considerations and network development.Fig. S1. Example t-SNE embeddings.Fig. S2. Initial evaluation of clusters derived from t-SNE embeddings.Fig. S3. Correlation between replicates.Fig. S4. Number of edges per gene in clusters.Fig. S5. Correlation between degree and betweenness.Fig. S6. CFN betweenness is not biased by overrepresentation in PPI databases.Fig. S7. The number of posttranslational modifications per protein weakly correlates with CFNbetweenness.Fig. S8. The effect of applying PTM correlation threshold on CFNs.Fig. S9. Network density as a function of PTM correlation threshold defines a minimum forconstruction of a PTM CCCN.Fig. S10. Relative network density of drug-affected proteins.Fig. S11. EP300 interactions with PTM-modifying enzymes.Fig. S12. Combined EP300 CCCN and CFN.Fig. S13. Comparison of tyrosine phosphorylation, serine/threonine phosphorylation, and acetylation.Fig. S14. Western blot data from cell fractionation experiments.Fig. S15. Separation of tyrosine and serine/threonine phosphorylation and relative abundancecompared to paxDB.Table S1. Proteins with PTMs that have negative correlations.Table S2. Amount of proteins in cell fractions.Data file S1. Cytoscape file: Complete cocluster correlation network.References (89–91)

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Acknowledgments: M.G. and M.C. dedicate this paper to the memory of E. Herbert. Wethank S. Beausoleil for data wrangling and discussions, A. Guo for antibody information,N. Fernandez for the gene expression clustergrammer visualization, and J. Syrenne forcomments on the manuscript. Experimental data were obtained at Cell Signaling Technology.Funding: This work was supported by the NIH grants BD2K LINCS Data Coordination andIntegration Center (grant number U54HL127624) and Knowledge Management Center for theIlluminating the Druggable Genome project (grant number U24CA224260). Authorcontributions: M.G. performed the data analysis and cell fractionation experiments andwrote the manuscript; J.G., W.C., and T.W. constructed the website; B.H., T.L., L.F., andK.R. performed the experiments; K.R., T.L., and M.C. designed the experiments; B.Z., E.S., N.R.C.,A.L., P.H., and A.M. contributed to data curation and analysis; M.C. funded the experiments;and A.M. edited the manuscript and managed the funding for data analysis. Competinginterests: M.C. is the founder and CEO of Cell Signaling Technology and Bluefin Biomedicine.All the other authors declare that they have no competing interests. Data and materialsavailability: There are patents on the generation of the motif antibodies and PTMscan technology used in this study (“Production of Motif-Specific and Context-IndependentAntibodies Using Peptide Libraries as Antigens,” U.S. Pat. No. 9085609 and USPat. No. 9738711). Data are available at https://www.phosphosite.org/Supplemental_Files/,and networks may be explored at https://cynetworkbrowser.umt.edu/ and https://doi.org/10.18119/N9F59Z. All other data needed to evaluate the conclusions in the paper are presentin the paper and/or the Supplementary Materials.

Submitted 2 October 2017Accepted 4 May 2018Published 22 May 201810.1126/scisignal.aaq1087

Citation: M. Grimes, B. Hall, L. Foltz, T. Levy, K. Rikova, J. Gaiser, W. Cook, E. Smirnova,T. Wheeler, N. R. Clark, A. Lachmann, B. Zhang, P. Hornbeck, A. Ma’ayan, M. Comb,Integration of protein phosphorylation, acetylation, and methylation data sets to outlinelung cancer signaling networks. Sci. Signal. 11, eaaq1087 (2018).

16 of 16

cancer signaling networksIntegration of protein phosphorylation, acetylation, and methylation data sets to outline lung

Travis Wheeler, Neil R. Clark, Alexander Lachmann, Bin Zhang, Peter Hornbeck, Avi Ma'ayan and Michael CombMark Grimes, Benjamin Hall, Lauren Foltz, Tyler Levy, Klarisa Rikova, Jeremiah Gaiser, William Cook, Ekaterina Smirnova,

DOI: 10.1126/scisignal.aaq1087 (531), eaaq1087.11Sci. Signal. 

more extensive PTM networks than was previously appreciated.networks may inform new drug development for lung cancer patients and exemplify how cell signaling is regulated by far far beyond its target; and that RNA binding proteins appear to be critical effectors of many signaling paths. Theseincreased, acetylation decreased; that the drug geldanamycin broadly alters the PTM landscape and, thus, has effects explored various regulatory patterns. The authors found that many PTMs are exclusive, in that as phosphorylationphosphoproteomic, acetylomic, and methylomic data from lung cancer cells versus those in normal lung tissue and

. integrated genomic, proteomic,et alare the inputs of other posttranslational modifications (PTMs). Grimes informed much of our current knowledge of cell signaling networks and facilitated drug development. Less appreciated

Various ''omics'' analyses of cells provide insight into cellular health and behavior. Phosphoproteomic analysis hasMultiomics analysis of lung cancer

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