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TSC1-2肿瘤抑制因子通过调节IRS蛋白来控制胰岛素-PI3K信号通路。

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

作者信息

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

机构信息

Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, England, UK.

出版信息

J Cell Biol. 2004 Jul 19;166(2):213-23. doi: 10.1083/jcb.200403069. Epub 2004 Jul 12.

DOI:10.1083/jcb.200403069
PMID:15249583
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2172316/
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.

摘要

胰岛素样生长因子通过激活磷酸肌醇3 - 羟基激酶（PI3K）引发多种反应。结节性硬化复合物（TSC1 - 2）通过负向调节一种蛋白激酶p70S6K（S6K1）来抑制细胞生长，而p70S6K的激活通常需要PI3K信号。在此，我们表明TSC1 - 2是胰岛素向PI3K信号传导所必需的。TSC1 - 2通过抑制S6K的活性来维持胰岛素向PI3K的信号传导，当S6K被激活时，它会通过抑制IRS - 1基因表达和直接磷酸化IRS - 1来使胰岛素受体底物（IRS）功能失活。我们的结果表明，由TSC1 - 2功能障碍引起的肿瘤恶性潜能较低，这可能是由于TSC突变细胞无法激活PI3K及其下游效应器所致。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/9c5ec81ddb9b/200403069f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/5b7310c35d71/200403069f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/3b978eb1dd4a/200403069f3ac.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/c202141652b0/200403069f4ad.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/365e41abaae7/200403069f5ad.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/a60cfd4f6ddc/200403069f6ad.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/d9146c4f5529/200403069f7ab.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/9c5ec81ddb9b/200403069f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/5b7310c35d71/200403069f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/1a4b8b47f45a/200403069f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/3b978eb1dd4a/200403069f3ac.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/c202141652b0/200403069f4ad.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/365e41abaae7/200403069f5ad.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/a60cfd4f6ddc/200403069f6ad.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/d9146c4f5529/200403069f7ab.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f2f/2172316/9c5ec81ddb9b/200403069f8.jpg

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