TOR ( target of rapamycin) signaling

Apr 4, 2005

serine/threonine protein kinasePI-3K-kinase related kinase (PIKK)superfamily

Central role of TOR in cell growth and proliferation (disruption of gene encoding TOR results in lethality in all species)

TOR: integrator of nutrient and growth factor Coordinator of cell growth and proliferation

Nutrients and Growth factor TOR

Transcription, translation and ribosome biogenesis

Cell growth (in crease in proliferating or non-proliferating cell mass and size via macromolecular biosynthesis)

Cell proliferation (increase in cell number)

Coupled, allowing cells to proliferate continuously while maintaining their size

maintain individual cells, organs and whole organisms a characteristic size(Dysregulation of TOR signaling result in pathological changes in organ size, and diseases such as

cancer, heart hypertrophy, muscular atrophy)

caAkt: Constitutively active Akt

kdAkt: Kinase deficient Akt

Myostatin肌抑素

Discovery of rapamycin and identification of TOR Structure of TOR protein TOR signaling Upstream Downstream TOR-binding proteins TOR function TOR and diseases Future directions

Discovery of rapamycin and identification of TOR

1970s, rapamycin purification from Streptomyces hygroscopicus in Easter Island, antifungal activity

inhibit mammalian cell, especially immune system (B and T) cell proliferation as well as against solid tumors, potential immunosuppressant and anticancer drug

1989, FKBP12 (FK506-binding protein of 12 kDa, isomerase, protein folding) in Saccharomyces cerevisiae, direct receptor of rapamycin

1991, Genetic screens for mutations that rendered for S. cerevisiae resistant to the growth inhibitory effect of rapamycin identified two target of rapamycin proteins: TOR1 and TOR2

1994-1995, identification and cloning mTOR (mammalian target of rapamycin) from human rat and mouse. also named FRAP (FKBP-12-rapamycin-associated protein), RAFT (rapamycin and FKBP12 target), RAPT (rapamycin target) and SEP (sirolimus effector protein)

1999, TOR inhibitor rapamycin was approved as an immunosuppressant (inhibit kidney transplant rejection) and cardiology drug (restenosis after angioplasty 血管形成术后再狭窄 ) by FDA

rapamycin analogs CCI-779 and RAD001 are currently being tested in phase III clinical trials

An example of investigative power of “Chemical genetics” (use drugs or bioactive compounds as probes for dissection of signaling pathways)

Structure of TOR protein

Large (290 kDa) evolutionarily conserved (40-60% identical among mammals, flies, worms and yeast)member of PIKK superfamily (MEC1, TEL1, RAD3, MEI41, DNA-PK, ATM, ATR and TRRAP)

HEAT repeats (Huntingtin, EF3, A subunit of PP2A and TOR motifs): 20 tandemly helical repeated, protein- protein interactionFAT (FRAP-ATM-TRRAP) and FATC (FAT C-terminus): modulation of catalytic kinase activityFRB (FKPP12-rapamycin binding domain)Kinase domainRepressor domain: auto-inhibitory domain

Structure of mTOR protein

TOR signaling (in mammalian cells)

TOR upstream signaling

Growth factor/RTKIRS: insulin receptor substratePI-3K/Akt/PKBPTEN: phosphatase and tensin homologue deleted on chromosome ten (mutated in multiple advanced cancers, MMAC), a lipid phosphatasePDK1: phosphoinositide-dependent protein kinase1TSC1: tuberous sclerosis( 结节性脑硬化 ) complex 1(hamartin 错构瘤蛋白 );TSC2 : tuberin 马玲薯球蛋白

TOR upstream signaling

Rheb: small GTPase, TSC2 function as Rheb- GAP, shifting to Rheb-GDP;Rheb-GEF shifting to Rheb-GTP?AMPK:AMP-dependent protein kinaseLKB1: key regulator of AMPK activity, mutated in Peutz-Jeghers SyndromeRaptor: regulatory associated protein of mTORGL(mammalian)or LST8 (yeast)

TOR downstream pathway

S6K: p70 S6 kinaseS6 protein: 40S ribosomal protein, drive 5’ TOP (terminal oligopyrimidine tract) mRNA translation4EBP1: eIF4E binding proteineIF4E: eukaryotic translation initiation factor 4E recognizes the 5’ end cap of mRNA, increase key growth-promoting proteins, cyclin D1, c-Myccdks: cyclin-dependent kinasepRb: protein retinoblastoma ( 眼癌 )PP2A: protein phosphatase 2A

TOR-binding proteins in yeastTORC1: AVO1, AVO2, AVO3, TOR2, LST8 controls actin organization, not a rapamycin targetTORC2: TOR1, TOR2, KOG1, LST8

TOR-binding proteins in mammalian cellraptor: regulatory associated protein of mTORGL: mammalian LST8,

Raptor: regulatory associated protein of mTOR

TOR functionBrain development learning and memory formationapoptosis

TOR inhibit autophagy

TOR and apoptosis

TOR and apoptosis

TOR and diseases

cancer heart hypertrophymuscular atrophyHamartoma syndromesInherited human dieases

TOR and Cancers

mTOR and Hamartoma syndromes

Tor andInherited human dieases

Future directions

TOR deficiency in C. elegans doubles lifespan, whether TOR controls lifespan in mammals ?How TOR senses and is activated by the presence of nutrients such as amino acid?Downstream targets and cellular processes that are regulated by TORRole of TOR in apoptosis?Understanding TOR signaling in neurons and muscle cells lead to new therapy for muscular wasting and memory impairmentTOR-binding proteins, gel filtration 2M