The heterotrimeric G(q) protein-coupled angiotensin II receptor activates p21(ras) via the tyrosine kinase-Shc-Grb2-Sos pathway in cardiac myocytes

p21(ras) plays an important role in cell proliferation, transformation and differentiation. Recently, the requirement of p21(ras) has been suggested for cellular responses induced by stimulation of heterotrimeric G protein-coupled receptors. However, it remains to be determined how agonists for G protein-coupled receptors activate p21(ras) in metazoans. We show here that stimulation of the G(q) protein-coupled angiotensin II (Ang II) receptor causes activation of p21(ras) in cardiac myocytes. The p21(ras) activation by Ang II is mediated by an increase in the guanine nucleotide exchange activity, but not by an inhibition of the GTPase-activating protein. Ang II causes rapid tyrosine phosphorylation of Shc and its association with Grb2 and mSos-1, a guanine nucleotide exchange factor of p21(ras). This leads to translocation of mSos-1 to the membrane fraction. Shc associates with the SH3 domain of Fyn whose tyrosine kinase activity is activated by Ang II with a similar time course as that of tyrosine phosphorylation of Shc Ang II-induced increase in the guanine nucleotide exchange activity was inhibited by a peptide ligand specific to the SH3 domain of the Src family tyrosine kinases. These results suggest that an agonist for a pertussis toxin-insensitive G protein-coupled receptor may initiate the crosstalk with non-receptor-type tyrosine kinases, thereby activating p21(ras) using a similar mechanism as receptor tyrosine kinase-induced p21(ras) activation.