LINKAGE OF G-PROTEIN-COUPLED RECEPTORS TO THE MAPK SIGNALING PATHWAY THROUGH PI 3-KINASE-GAMMA

The tyrosine kinase class of receptors induces mitogen-activated prote in kinase (MAPK) activation through the sequential interaction of the signaling proteins Grb2, Sos, Ras, Raf, and MEK. Receptors coupled to heterotrimeric guanine triphosphate-binding protein (G protein) stimul ate MAPK through G(beta gamma) subunits, but the subsequent intervenin g molecules are still poorly defined. Overexpression of phosphoinositi de 3-kinase gamma (PI3K gamma) in COS-7 cells activated MAPK in a G(be ta gamma)-dependent fashion, and expression of a catalytically inactiv e mutant of PI3K gamma abolished the stimulation of MAPK by G(beta gam ma) or in response to stimulation of muscarinic (m2) G protein-coupled receptors. Signaling from PI3K gamma to MAPK appears to require a tyr osine kinase, Shc, Grb2, Sos, Ras, and Raf. These findings indicate th at PI3K gamma mediates G(beta gamma)-dependent regulation of the MAPK signaling pathway.