Gab-1-mediated IGF-1 signaling in IRS-1-deficient 3T3 fibroblasts

The insulin receptor substrate (IRS) family of proteins mediate a variety o f intracellular signaling events by serving as signaling platforms downstre am of several receptor tyrosine kinases including the insulin and insulin-l ike growth factor-1 (IGF-1) receptors. Recently, several new members of thi s family have been identified including IRS-3, IRS-4, and growth factor rec eptor-binding protein a-associated binder-1 (Gab-l). 3T3 cell lines derived from IRS-l-deficient embryos exhibit a 70-80% reduction in IGF-l-stimulate d S-phase entry and a parallel decrease in the induction of the immediate-e arly genes c-fos and egr-1 but unaltered activation of the mitogen-activate d protein kinases extracellular signal-regulated kinase-l and extracellular signal-regulated kinase-2. Reconstitution of IRS-1 expression in IRS-1-def icient fibroblasts by retroviral mediated gene transduction is capable of r estoring these defects. Overexpression of Gab-l in IRS-l-deficient fibrobla sts also results in the restoration of egr-1 induction to levels similar to those achieved by IRS-1 reconstitution and markedly increases IGF-l-stimul ated S-phase progression. Gab-l is capable of regulating these biological e nd points despite the absence of IGF-1 stimulated tyrosine phosphorylation. These data provide evidence that Gab-l may serve as a unique signaling int ermediate in insulin/IGF-1 signaling for induction of early gene expression and stimulation of mitogenesis without direct tyrosine phosphorylation.