Regulation of calcium-sensitive tyrosine kinase Pyk2 by angiotensin II in endothelial cells - Roles of Yes tyrosine kinase and tyrosine phosphatase SHP-2

Calcium-sensitive tyrosine kinase Pyk2 has been implicated in the regulatio n of ion channels, cellular adhesion, and mitogenic and hypertrophic reacti ons. In this study, we have investigated the regulation of Pyk2 by angioten sin II (Ang II) in pulmonary vein endothelial cells. We found that the Ang II-induced tyrosine phosphorylation of Pyk2, which requires the activity of Src family kinase, was specifically regulated by the Src family kinase mem ber, Yes kinase, Moreover, we identified for the first time the constitutiv e association of Pyk2 with an Src homology 2 (SH2) domain-containing tyrosi ne phosphatase SHP-2. SHP-2 interacts with Pyk2 through a region other than its SH2 domains. Pyk2 can be dephosphorylated in vitro in SHP-2 immunoprec ipitates and in intact cells expressing an NH, terminus-truncated form of S HP-2, which lacks the two SH2 domains but has an enhanced phosphatase activ ity. Ang II activates the endogenous SHP-2, Finally, the SHP-2-mediated dep hosphorylation of Pyk2 correlates with the negative effect of SHP-2 on the Ang II-induced activation of extracellular signal-regulated kinase and c-Ju n NH2-terminal kinase. Thus, the balance of Pyk2 tyrosine phosphorylation i n response to Ang II is controlled by Yes kinase and by a tyrosine phosphat ase SHP-2 in endothelial cells.