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

TLDR

Insulin-like growth factors activate PI3K signaling, while the TSC1‑2 complex normally suppresses cell growth by inhibiting the PI3K‑dependent kinase p70S6K. TSC1‑2 preserves insulin‑PI3K signaling by restraining S6K activity, thereby preventing S6K‑mediated repression of IRS‑1 transcription and phosphorylation of IRS‑1. Loss of TSC1‑2 abolishes insulin‑PI3K signaling, and the resulting failure to activate PI3K and downstream effectors explains the low malignant potential of tumors with TSC1‑2 dysfunction.

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.