Gab-1-mediated IGF-1 signaling in IRS-1-deficient 3T3 fibroblasts.
The insulin receptor substrate (IRS) family of proteins mediate a variety of intracellular signaling events by serving as signaling platforms downstream of several receptor tyrosine kinases including the insulin and insulin-like growth factor-1 (IGF-1) receptors. Recently, several new members of this family have been identified including IRS-3, IRS-4, and growth factor receptor-binding protein 2-associated binder-1 (Gab-1). 3T3 cell lines derived from IRS-1-deficient embryos exhibit a 70-80% reduction in IGF-1-stimulated S-phase entry and a parallel decrease in the induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases extracellular signal-regulated kinase-1 and extracellular signal-regulated kinase-2. Reconstitution of IRS-1 expression in IRS-1-deficient fibroblasts by retroviral mediated gene transduction is capable of restoring these defects. Overexpression of Gab-1 in IRS-1-deficient fibroblasts also results in the restoration of egr-1 induction to levels similar to those achieved by IRS-1 reconstitution and markedly increases IGF-1-stimulated S-phase progression. Gab-1 is capable of regulating these biological end points despite the absence of IGF-1 stimulated tyrosine phosphorylation. These data provide evidence that Gab-1 may serve as a unique signaling intermediate in insulin/IGF-1 signaling for induction of early gene expression and stimulation of mitogenesis without direct tyrosine phosphorylation.
Winnay
J N
JN
Division of Cellular and Molecular Physiology, Joslin Diabetes Center and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Brüning
J C
JC
Burks
D J
DJ
Kahn
C R
CR
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002455:Cell Division; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D005822:Genetic Vectors; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D019000:Phosphotyrosine / Q000032:analysis; D011994:Recombinant Proteins / Q000378:metabolism; D012190:Retroviridae; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; C490897:Gab1 protein, mouse; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases