The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins.
Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.
Harrington
Laura S
LS
Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, England, UK.
Findlay
Greg M
GM
Gray
Alex
A
Tolkacheva
Tatiana
T
Wigfield
Simon
S
Rebholz
Heike
H
Barnett
Jill
J
Leslie
Nick R
NR
Cheng
Susan
S
Shepherd
Peter R
PR
Gout
Ivan
I
Downes
C Peter
CP
Lamb
Richard F
RF
D000818:Animals; D002470:Cell Survival; D002633:Chemotaxis; D005347:Fibroblasts / Q000166:cytology; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D011506:Proteins; D012097:Repressor Proteins; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D019893:Ribosomal Protein S6 Kinases