G(BETA-GAMMA) SUBUNITS MEDIATE MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION BY THE TYROSINE KINASE INSULIN-LIKE GROWTH-FACTOR-1 RECEPTOR

The receptors for insulin-like growth factor 1 (IGF1) and insulin are related heterotetrameric proteins which, like the epidermal growth fac tor (EGF) receptor, possess intrinsic ligand-stimulated tyrosine prote in kinase activity, In Rat 1 fibroblasts, stimulation of mitogen-activ ated protein (MAP) kinase via the IGF1 receptor and the G(i)-coupled r eceptor for lysophosphatidic acid (LPA), but not via the EGF receptor, is sensitive both to pertussis toxin treatment and to cellular expres sion of a specific G(beta gamma) subunit-binding peptide, The IGF1, LP A, and EGF receptor-mediated signals are all sensitive to inhibitors o f tyrosine protein kinases, require p21(ras) activation, and are indep endent of protein kinase C. These data suggest that some tyrosine kina se growth factor receptors (e.g. IGF1 receptor) and classical G protei n-coupled receptors (e.g. LPA receptor) employ a similar mechanism for mitogenic signaling that involves both tyrosine phosphorylation and G (beta gamma) subunits derived from pertussis toxin-sensitive G protein s.