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

Laura S. Harrington; Greg M. Findlay; Alex 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
, Alex 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

MRC PPU

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

992 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

6K
Nsulin
PI3K
RS proteins
TSC1-2

ASJC Scopus subject areas

Cell Biology

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10.1083/jcb.200403069

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@article{31490066780047b4a87248e110af2800,

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 = "6K, Nsulin, PI3K, RS proteins, TSC1-2",

author = "Harrington, \{Laura S.\} and Findlay, \{Greg M.\} and Alex 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.\}",

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",

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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, Alex

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.

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 - 6K

KW - Nsulin

KW - PI3K

KW - RS proteins

KW - TSC1-2

UR - https://www.scopus.com/pages/publications/3342958797

U2 - 10.1083/jcb.200403069

DO - 10.1083/jcb.200403069

M3 - Article

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AN - SCOPUS:3342958797

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

ASJC Scopus subject areas

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