This grant seeks to better understand the regulatory mechanisms of G protein regulation of nonreceptor tyrosine kinases, which comprise two major groups of cellular proteins playing important roles in signal transduction. Our laboratory has genetically demonstrated that Gq- and Gi-coupled receptors activate mitogen-activated protein kinase pathways requiring nonreceptor tyrosine kinases. Gs-coupled receptors initiate a tyrosine kinase-dependent, but cAMP-PKA independent, apoptotic pathway in thymocytes. To provide a biochemical mechanism for the dependence of G protein signals on tyrosine kinases in these physiological processes, we have shown biochemically that: 1) purified Gaq subunits can directly stimulate the kinase activity of Bruton's tyrosine kinase (Btk); 2) purified Ga12 subunits can directly stimulate the kinase activity of Btk, and a Ras-GAP (GTPase-activating-protein) through a conserved PHJBM domain present on both Btk and Ras-GAP; 3) purified Gas and Gai subunits can directly stimulate the kinase activity of another tyrosine kinase, Src. We plan to characterize these regulatory mechanisms by which G proteins regulate these tyrosine kinases in order to better understand G protein signaling and the biological functions of G proteins.
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