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TOR ( target of rapamycin)
signaling
Apr 4, 2005
serine/threonine protein
kinase
PI-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)
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)
TOR: integrator of nutrient and growth factor
Coordinator of cell growth and proliferation
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
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, proteinprotein interaction
FAT (FRAP-ATM-TRRAP) and FATC (FAT C-terminus):
modulation of catalytic kinase activity
FRB (FKPP12-rapamycin binding domain)
Kinase domain
Repressor domain: auto-inhibitory domain
 Structure of mTOR protein
 TOR signaling (in mammalian cells)
TOR upstream signaling
Growth factor/RTK
IRS: insulin receptor substrate
PI-3K/Akt/PKB
PTEN: phosphatase and tensin homologue
deleted on chromosome ten (mutated in multiple
advanced cancers, MMAC), a lipid phosphatase
PDK1: phosphoinositide-dependent protein
kinase1
TSC1: 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 RhebGAP, shifting to Rheb-GDP;Rheb-GEF shifting
to Rheb-GTP?
AMPK:AMP-dependent protein kinase
LKB1: key regulator of AMPK activity, mutated
in Peutz-Jeghers Syndrome
Raptor: regulatory associated protein of mTOR
GbL(mammalian)or LST8 (yeast)
TOR downstream pathway
S6K: p70 S6 kinase
S6 protein: 40S ribosomal protein, drive 5’
TOP (terminal oligopyrimidine tract) mRNA
translation
4EBP1: eIF4E binding protein
eIF4E: eukaryotic translation initiation factor 4E
recognizes the 5’ end cap of mRNA, increase key
growth-promoting proteins, cyclin D1, c-Myc
cdks: cyclin-dependent kinase
pRb: protein retinoblastoma (眼癌)
PP2A: protein phosphatase 2A
 TOR-binding proteins in yeast
TORC1: AVO1, AVO2, AVO3, TOR2, LST8 controls actin
organization, not a rapamycin target
TORC2: TOR1, TOR2, KOG1, LST8
 TOR-binding proteins in mammalian cell
raptor: regulatory associated protein of mTOR
GbL: mammalian LST8,
 Raptor:
regulatory
associated
protein of
mTOR
TOR
function
Brain
development
learning and
memory
formation
apoptosis
 TOR
inhibit
autophagy
 TOR
and
apoptosis
 TOR
and
apoptosis
TOR and diseases
 cancer
 heart hypertrophy
muscular atrophy
Hamartoma syndromes
Inherited human dieases
TOR
and
Cancers
mTOR and Hamartoma syndromes
Tor and
Inherit
ed
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 TOR
Role of TOR in apoptosis?
Understanding TOR signaling in neurons and
muscle cells lead to new therapy for muscular
wasting and memory impairment
TOR-binding proteins, gel filtration 2M