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- Title
The TSC1-2 tumor suppressor controls insulin-Pl3k signaling via regulation of IRS proteins.
- Authors
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.
- Abstract
Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3 K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires P13K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to P13K. TSC1-2 maintains insulin signaling to P13K by restraining the activity of S6K, which when activated mactiyates insulin receptor substrate (IRS) function, via repression of IRS-i 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 P13K and its downstream effectors.
- Subjects
INSULIN; TUBEROUS sclerosis; GENE expression; PHOSPHORYLATION; SOMATOMEDIN; CELL growth
- Publication
Journal of Cell Biology, 2004, Vol 166, Issue 2, p213
- ISSN
0021-9525
- Publication type
Article
- DOI
10.1083/jcb.200403069