The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

Laura S Harrington; Greg M Findlay; Alexander Gray; Tatiana Tolkacheva; Simon Wigfield; Heike Rebholz; Jill Barnett; Nick R Leslie; Susan Cheng; Peter R Shepherd; Ivan Gout; C Peter Downes; Richard F Lamb

doi:10.1083/jcb.200403069

The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

Laura S Harrington, Greg M Findlay, Alexander Gray, Tatiana Tolkacheva, Simon Wigfield, Heike Rebholz, Jill Barnett, Nick R Leslie, Susan Cheng, Peter R Shepherd, Ivan Gout, C Peter Downes, Richard F Lamb

Research output: Contribution to journal › Article › peer-review

964 Citations (Scopus)

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.

Original language	English
Pages (from-to)	213-223
Number of pages	11
Journal	Journal of Cell Biology
Volume	166
Issue number	2
DOIs	https://doi.org/10.1083/jcb.200403069
Publication status	Published - 19 Jul 2004

Keywords

Animals
Cell Survival
Chemotaxis
Fibroblasts
Insulin
Insulin Receptor Substrate Proteins
Insulin-Like Growth Factor I
Intracellular Signaling Peptides and Proteins
Mice
Phosphatidylinositol 3-Kinases
Phosphoproteins
Phosphorylation
Proteins
Repressor Proteins
Ribosomal Protein S6 Kinases
Signal Transduction
Tumor Suppressor Proteins

Access to Document

10.1083/jcb.200403069

Cite this

@article{4dfc896c6b414723a96d970b74255f5c,

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.",

keywords = "Animals, Cell Survival, Chemotaxis, Fibroblasts, Insulin, Insulin Receptor Substrate Proteins, Insulin-Like Growth Factor I, Intracellular Signaling Peptides and Proteins, Mice, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Proteins, Repressor Proteins, Ribosomal Protein S6 Kinases, Signal Transduction, Tumor Suppressor Proteins",

author = "Harrington, {Laura S} and Findlay, {Greg M} and Alexander Gray and Tatiana Tolkacheva and Simon Wigfield and Heike Rebholz and Jill Barnett and Leslie, {Nick R} and Susan Cheng and Shepherd, {Peter R} and Ivan Gout and Downes, {C Peter} and Lamb, {Richard F}",

note = "Copyright The Rockerfeller University Press",

year = "2004",

month = jul,

day = "19",

doi = "10.1083/jcb.200403069",

language = "English",

volume = "166",

pages = "213--223",

journal = "Journal of Cell Biology",

issn = "0021-9525",

publisher = "Rockefeller University Press",

number = "2",

}

TY - JOUR

T1 - The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

AU - Harrington, Laura S

AU - Findlay, Greg M

AU - Gray, Alexander

AU - Tolkacheva, Tatiana

AU - Wigfield, Simon

AU - Rebholz, Heike

AU - Barnett, Jill

AU - Leslie, Nick R

AU - Cheng, Susan

AU - Shepherd, Peter R

AU - Gout, Ivan

AU - Downes, C Peter

AU - Lamb, Richard F

N1 - Copyright The Rockerfeller University Press

PY - 2004/7/19

Y1 - 2004/7/19

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Survival

KW - Chemotaxis

KW - Fibroblasts

KW - Insulin

KW - Insulin Receptor Substrate Proteins

KW - Insulin-Like Growth Factor I

KW - Intracellular Signaling Peptides and Proteins

KW - Mice

KW - Phosphatidylinositol 3-Kinases

KW - Phosphoproteins

KW - Phosphorylation

KW - Proteins

KW - Repressor Proteins

KW - Ribosomal Protein S6 Kinases

KW - Signal Transduction

KW - Tumor Suppressor Proteins

U2 - 10.1083/jcb.200403069

DO - 10.1083/jcb.200403069

M3 - Article

C2 - 15249583

SN - 0021-9525

VL - 166

SP - 213

EP - 223

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 2

ER -

The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

Abstract

Keywords

Access to Document

Fingerprint

Cite this