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G-mediated activation of protein kinase D exhibits subunit specificity and requires G-responsive phospholipase C isoforms

Lau, WW;Chan, AS;Poon, LS;Zhu, J;Wong, YH;

Protein kinase D (PKD) constitutes a novel family of serine/threonine protein kinases implicated in fundamental biological activities including cell proliferation, survival, migration, and immune responses. Activation of PKD in these cellular activities has been linked to many extracellular signals acting through antigen receptor engagement, receptor tyrosine kinases, as well as G protein-coupled receptors. In the latter case, it is generally believed that the G subunits of the Gq family are highly effective in mediating PKD activation, whereas little is known with regard to the ability of G dimers and other G subunits to stimulate PKD. It has been suggested that the interaction between G and the PH domain of PKD, or the G-induced PLC/PKC activity is critical for the induction of PKD activation. However, the relative contribution of these two apparently independent events to G-mediated PKD activation has yet to be addressed.,In this report, we demonstrate that among various members in the four G protein families, only the G subunits of the Gq family effectively activate all the three PKD isoforms (PKD1/2/3), while G subunits of other G protein families (Gs, Gi, and G12) are ineffective. Though the G subunits of Gi family are unable to stimulate PKD, receptors linked to Gi proteins are capable of triggering PKD activation in cell lines endogenously expressing (HeLa cells and Jurkat T-cells) or exogenously transfected with (HEK293 cells) G-sensitive PLC2/3 isoforms. This indicates that the Gi-mediated PKD activation is dependent on the released G dimers upon stimulation. Further investigation on individual G combinations (i.e. G1 with G1-13) revealed that, even if they can stimulate the PLC activity in a comparable manner, only those G1 dimers with 2, 3, 4, 5, 7, and 10 can serve as effective activators of PKD. We also demonstrated that Gi-mediated PKD activation is essential for the SDF-1-induced chemotaxis on Jurkat T-cells.,Our current report illustrates that G dimers from the Gi proteins may activate PKD in a PLC2/3-dependent manner, and the specific identities of G components within G dimers may determine this stimulatory action.