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Printed in the USA on recycled paper (25% post-consumer waste fiber) using vegetable inks and processed chlorine free. © 2015 Cell Signaling Technology, Inc. Cell Signaling Technology® and CST™ are trademarks of Cell Signaling Technology, Inc.
CST Signaling PaThway DiagramS for
Development and Differentiation
www.cellsignal.com/developmentpws14PSTREFMDEVE0262ENG_00
Please see our website for all pathway diagram backgrounds.
Direct Stimulatory Modification
Direct Inhibitory Modification
Multistep Stimulatory Modification
Multistep Inhibitory Modification
Tentative Stimulatory Modification
Tentative Inhibitory Modification
Separation of Subunits or Cleavage Products
Joining of Subunits
Translocation
Transcriptional Stimulatory Modification
Transcriptional Inhibitory Modification
Kinase
Phosphatase
Transcription Factor
Caspase
Receptor
Enzyme
pro-apoptotic
pro-survival
GAP/GEF
GTPase
G-protein
Acetylase
Deacetylase
Ribosomal subunit
Angiopoietin 1
Angiopoietin 2
bFGF
Ephrin
PDGF
SLIT
VEGF
4E-BP1
Ets2
HIF-1α
HIF-1α
HIF-1α
HIF-1α HIF-1β
HIF-1β
PHDs
CBP/p300
MMPs
MMPs
PDGFR
Tie2VEGFR2
FGFR
Integrins Integrins
Neuropilin
Stat3Target Genes
Target GenesHRE
Normoxia
Hypoxia
Precursor Endothelial Cell
Platelet
Tip Cell
PericyteEndothelial
Cell
BasementMembrane
Tumor Associated Macrophage (TAM)
• Growth Factors• Cytokines• ECM Proteases
elF4E1
Erk1/2Akt
OH
OH
NucleusTumor CellTumor Cell
Tie2
EPH
ROBO1/2
ROBO3
• Growth Factors• Cytokines• ECM Proteases
Angiogenesis Signaling in Tumor Neovascularization© 2008–2015 Cell Signaling Technology, Inc.
NICD
NucleusCytoplasm
Frizzled
Gαq/o
Erk1/2
Nanog
NICD
Sox2Oct-4
TCFs
Erk1/2
Ras/Raf
Gene Expression
Pluripotency and Self RenewalhESC markers:
Gene Expression Gene Expression
Akt
Smad2/3
Smad2/3
Smad2/3Smad2/3
Smad2/3β-catenin
β-catenin
β-catenin Smad4
Smad4
Smad1/5/9
Smad1/5/9
Smad1/5/9
Smad1/5/9
Smad4
Smad1/5/9
PI3K
IGF-IRFGFR
TGF-β/Activin/NodalBMP
MEK1/2
PP2A
LRP
Wnt
SARA
AxinAPC
GSK-3
γ−Secretase
Polycomb
Oct-4 Sox2 NanogSSEA3/4 TRA-1-60 TRA-1-81
DifferentiationEndoderm MesodermEctoderm Primordial Germ Cells
Notch
ESC Pluripotency Differentiation© 2009–2015 Cell Signaling Technology, Inc.
ZO-2
AMOT
AMOT
AMOT
WBP2
β-TrCP
FRMDMerlin
KIBRA
SAV114-3-3 MARK4α-catenin
p73 RUNX
Mst1/2
SIK1-3
CK1
Rho
LKB1
LATS1/2MOB1 F-actin
ITCH
VGL4
Ajuba
YAP/TAZ
YAP/TAZ
YAP
14-3-3
YAP
TEAD1-4TEAD1-4 Smad
RASSFTAOK-1-3
PP2A
PP1
ASPP2
Merlin
Gα12/13
Gαq/11
Gαi/o
Gαs
FAT4 ?
??
CD
44
Crb
Transcription
Nucleus
Cytoplasm
Adhe
rens
Jun
ctio
nTi
ght J
unct
ion
GPCR Signaling Mechanical Signaling
YAP/TAZ
YAP/TAZ YAP/TAZYAP/TAZYAP/TAZ
Hippo Signaling© 2010–2015 Cell Signaling Technology, Inc.
Smad2/3TRAF4/6
USP4/11/15
PP2A
ROCK
PI3K
Akt
mTOR
CBP
Smad4
Smad7
Smad1/5/9Smad1/5/9
Smad4Smad2/3Smad2/3
Smad6/7
Smad2/3
RasSOS
Erk1/2
Smad1/5/9
Smad1/5/9
Smad4
Smad4Smad2/3
Smad2/3CBPSmad4
Smad1/5/9Smad1/5/9
JNK
TAK1
p38 NF-κB
JNKp38TAK1
TGF-β Ligands:TGF-βs, Activins, Nodals BMP Ligands:
BMP-2, -4, -7, MIS
Par6
SARA
RhoA
Smurf2
Smad7
TMEPAIRac/Cdc42
PKC
mDia PAK
MLC LIMK
Cofilin
c-Abl
Smurf1
Smurf1
TF TF
LIMK
Cofilin
p70 S6K
GRB2Shc
4E-BP1/2
Smurf2
Type I ReceptorType II Receptor
Type I ReceptorType II Receptor
Actin PolymerizationStress Fibers
Transcription Factors:AP-1 bZIP homeodomainRUNX Sp1 nuclear receptorsFox IRF-7 bHLH
Corepressors:c-Ski/SnoN Evi1HDAC4/5 TGIFTob (BMP only) SIP1
Coactivators:CBP/p300 SMIFMSG1 ARC105
Cell AdhesionActin Polymerization
Stress Fibers
NucleusCytoplasm
TGF-β Signaling© 2003–2015 Cell Signaling Technology, Inc.
WTXTAB1
TAB2
SFRP SFRPWIFPorc
WLS
WntDKKs
R-spondins
Frizzled Frizzled
APC
β-TrCP
Groucho
ICATChibby
LEF1/TCF1
Dvl
Dvl
Naked
RNF43ZNRF3
LGR5/6
PAR-1
LRP5
/6
Axin
Axin
PP2A
TCF3
Brg1Pygo BCL9
α-catenin
p120
LRP5
/6
Groucho
FoxO
Snail1TAZ
FoxO
Skp
β-catenin
β-catenin
β-catenin
CYLDTankyrase
HDAC
CBP
β-catenin
NLK
NLK
Rac1
GSK-3
GSK-3
β-catenin
TAK1
ub
Cadherin
CK1
CK1
ub
β-catenin
HDAC
β-catenin
ub
OFF
Hesx1
Target Genes: Myc, Cyclin D1, TCF-1, PPAR-δ, MMP-7, Axin-2, CD44, etc.
ON-StateOFF-State
NucleusCytoplasm
Migration
Adhesion
ProteasomalDegradation
Pit1
Wnt/β-Catenin Signaling© 2003–2015 Cell Signaling Technology, Inc.
ub
ub
ubub
ub
NEDD4
Neur or Mib
ADAM/TACE
Epsin
NICD
TM
InactiveLigand
ActiveLigand
γ-SecretaseComplex
Deltex
α-AdaptinNUMB
FBX7
SHARP
HDACKDM5A KDM5A
CtBP1 CIR
SMRTSKIPCSL
SKIPCSLMAML
HAT
Notch Target GenesHES FamilyMycp21Cyclin D3
NicastrinPresenilin
APH-1PEN-2
Inactive Active
S1 Cleavage
S2 Cleavage
S3 Cleavage
SignalReceiving
Cell
ExtracellularSpace
SignalSending
Cell
Furin
O-Fut
Golgi
Fringe
ER
NotchNotch
DeltaJagged Delta
Jagged
Nucleus
Ligand-receptor Internalization
Endosome
Endosome
LigandRepositioning
Recycling
LysosomalDegradation
UbiquitinDegradation
ActivatedReceptor
Cytoplasm
Notch Signaling© 2006–2015 Cell Signaling Technology, Inc.
SUFU
GLI 1/2/3
SUFU
GLI 1/2/3
SUFU
PKA
CK1
GSK-3β
β−TrCP
GLI 1/2/3
GLI 3-R
GLI 1/2/3GLI 1/2-Act
GLI 1/2-ActCyclin D, Cyclin E,Myc, GLI1, PTCH1,PTCH2, Hhip1
HhN
HhN
Hh
Skn
DISP1
ER/Golgi
Hh Secreting Cell
PTCH1
PTCH2
Nucleus
no transcription oftarget genes
Nucleus CytoplasmCytoplasm
Activator
Repressor
SMO
SMOProteasome
PrimaryCilium
PrimaryCilium
CDON/BOC
Shh
KCTD11
β-Arrestin
Dhh
Ihh
MammalianLigands:
Hhip1 GAS1
PTCH1
CDON/BOC MicrotubulesMicrotubules
GLI 3-R
KIF7KIF7
SCUBE2
GLI 1/2 Degradation
HhNGαi
Off-State On-State
Hedgehog Signaling© 2006–2015 Cell Signaling Technology, Inc.