The platelet-derived growth factor receptor stimulation of p42/p44 mitogen-activated protein kinase in airway smooth muscle involves a G-protein-mediated tyrosine phosphorylation of Gab1

Using cultured airway smooth muscle cells, we showed previously that the pl atelet-derived growth factor (PDGF) receptor uses the G-protein, G(i), to s timulate Grb-2-associated phosphoinositide 3-kinase (PI3K) activity. We als o showed that this was an intermediate step in the activation of p42/p44 mi togen-activated protein kinase (p42/p44 MAPK) by PDGF. We now present two l ines of evidence that provide further support for this model. First, we rep ort that PDGF stimulates the G(i)-mediated tyrosine phosphorylation of the Grb-2 adaptor protein, Gab1. This phosphorylation appears to be necessary f or association of PI3K1a with the Gab1-Grb-2 complex. Second, PI3K appears to promote the subsequent association of dynamin II (which is involved in c lathrin-mediated endocytic processing) with the complex. Furthermore, inhib itors of PI3K and clathrin-mediated endocytosis reduced the PDGF-dependent activation of p42/p44 MAPK, suggesting a role for PI3K in the endocytic sig naling process leading to stimulation of p42/p44 MAPK. Together, these resu lts begin to define a common signaling model for certain growth factor rece ptors (e.g., PDGF, insulin, insulin-like growth factor-1, and fibroblast gr owth factor) which use G(i) to transmit signals to p42/p44 MAPK.