Laura S. Harrington 1 , Greg M. Findlay 1 , Alex Gray 2 , Tatiana Tolkacheva 1 , Simon Wigfield 1 , Heike Rebholz 3 , Jill Barnett 2 , Nick R. Leslie 2 , Susan Cheng 4 , Peter R. Shepherd 4 , Ivan Gout 3 , C. Peter Downes 2 , Richard F. Lamb 1
19 July 2004
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.