title: The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins.
abstract: 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.
authors.affiliation: Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, England, UK.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Harrington
authors.forename: Greg M
authors.initials: GM
authors.lastname: Findlay
authors.forename: Alex
authors.initials: A
authors.lastname: Gray
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tolkacheva
authors.forename: Simon
authors.initials: S
authors.lastname: Wigfield
authors.forename: Heike
authors.initials: H
authors.lastname: Rebholz
authors.forename: Jill
authors.initials: J
authors.lastname: Barnett
authors.forename: Nick R
authors.initials: NR
authors.lastname: Leslie
authors.forename: Susan
authors.initials: S
authors.lastname: Cheng
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
authors.forename: Ivan
authors.initials: I
authors.lastname: Gout
authors.forename: C Peter
authors.initials: CP
authors.lastname: Downes
authors.forename: Richard F
authors.initials: RF
authors.lastname: Lamb
mesh_terms: 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*
chemical_list: 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