Linkage of G Protein-Coupled Receptors to the MAPK Signaling Pathway Through PI 3-Kinase γ

The tyrosine kinase class of receptors induces mitogen-activated protein 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) stimulate MAPK through G$_{\beta\gamma}$ subunits, but the subsequent intervening molecules are still poorly defined. Overexpression of phosphoinositide 3-kinase γ (PI3Kγ) in COS-7 cells activated MAPK in a G$_{\beta\gamma}$-dependent fashion, and expression of a catalytically inactive mutant of PI3Kγ abolished the stimulation of MAPK by G$_{\beta\gamma}$ or in response to stimulation of muscarinic (m2) G protein-coupled receptors. Signaling from PI3Kγ to MAPK appears to require a tyrosine kinase, Shc, Grb2, Sos, Ras, and Raf. These findings indicate that PI3Kγ mediates G$_{\beta\gamma}$-dependent regulation of the MAPK signaling pathway.