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

作者：Laura Harrington, Greg M. Findlay, Alex Gray, Т. А. Толкачева, Simon Wigfield, Heike Rebholz, Jill Barnett, Nicholas R. Leslie, Susan Cheng, Peter R. Shepherd, Ivan Gout, C. Peter Downes, Richard F. Lamb · 发表于：The Journal of Cell Biology · 年份：2004 · DOI：10.1083/jcb.200403069 · 被引用次数：1120 · 研究领域：Tuberous Sclerosis Complex Research、PI3K/AKT/mTOR signaling in cancer、Polyamine Metabolism and Applications

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.