RECEPTOR-TYROSINE-KINASE-MEDIATED AND G-BETA-GAMMA-MEDIATED MAP KINASE ACTIVATION BY A COMMON SIGNALING PATHWAY

MITOGEN-ACTIVATED protein (MAP) kinases mediate the phosphorylation and activation of nuclear transcription factors that regulate cell growth(1). MAP kinase activation may result from stimulation of either tyrosine-kinase (RTK) receptors, which possess intrinsic tyrosine kinase activity, or G-protein-coupled receptors (GPCR)(2-4). RTK-mediated mitogenic signalling involves a series of SH2- and SH3-dependent protein-protein interactions between tyrosine-phosphorylated receptor, Shc, Grb2 and Sos, resulting in Ras-dependent MAP kinase activation(5-7). The beta gamma subunits of heterotrimeric G proteins (G beta gamma) also mediate Ras-dependent MAP kinase activations(8-10) by an as-yet unknown mechanism. Here we demonstrate that activation of MAP kinase by G(i)-coupled receptors is preceded by the G beta gamma-mediated tyrosine phosphorylation of Shc, leading to an increased functional association between Shc, Grb2 and Sos. Moreover, disruption of the Shc-Grb2-Sos complex blocks G beta gamma-mediated MAP kinase activation, indicating that G beta gamma does not mediate MAP kinase activation by a direct interaction with Sos. These results indicate that G beta gamma-mediated MAP kinase activation is initiated by a tyrosine phosphorylation event and proceeds by a pathway common to both GPCRs and RTKs.