G Protein Signaling Adaptable G Protein

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

The main members of the mitogen-activated protein kinase (MAPK) family, extracellular signal–regulated kinases (ERKs) 1 and 2, c-Jun N-terminal kinase, and p38, are well characterized and regulate such cellular responses as proliferation and differentiation. In contrast, less is known about the regulation of the more recent additions to the MAPK family, such as ERK5, which is activated by various growth factor receptors, cytokine receptors, and G_q-coupled G protein–coupled receptors (GPCRs). In response to epidermal growth factor, activation of ERK5 requires the MAPK kinase MEK5 and the atypical protein kinase C isoform PKC; however, how ERK5 is activated by GPCRs is unclear. García-Hoz et al. found that stimulation of m1 muscarinic acetylcholine receptors led to the phosphorylation and activation of ERK5 in NIH 3T3 cells, which was independent of Src family kinases, EGF receptors, and phospholipase C–β (PLC-β), an effector of G_q that leads to the activation of ERK1/2. Stimulation of another G_q-coupled GPCR led to the activation of ERK5 in wild-type, but not in PKC-deficient, mouse embryonic fibroblasts, and coimmunoprecipitation studies showed that G_q physically associated with PKC. Immunoprecipitated complexes of tagged G_q and PKC proteins contained MEK5. MEK5 and PKC contain PB1 domains through which they can interact; however, a PB1 domain–deficient mutant of MEK5 was found in immunoprecipitated complexes of G_q and PKC. In addition to suggesting roles for MEK5 and PKC as effectors of G_q, this study also suggests that G_q acts as a scaffold protein that independently binds to MEK5 and PKC to mediate the activation of ERK5.

C. García-Hoz, G. Sánchez-Fernández, M. T. Díaz-Meco, J. Moscat, F. Mayor, C. Ribas, G_q acts as an adaptor protein in protein kinase C (PKC)-mediated ERK5 activation by G protein-coupled receptors (GPCR). J. Biol. Chem. 285, 13480–13489 (2010). [Abstract] [Full Text]