Unique regulation of c-Jun N-terminal kinase by PYK2/CAK-beta in angiotensin II-stimulated vascular smooth muscle cells

Activation of tyrosine kinases is believed to play a central role in angiot ensin II (AngII) signaling. Here, we have investigated whether a tyrosine k inase, PYK2, is functionally involved in AngII-induced c-Jun N-terminal kin ase (JNK) activation in vascular smooth muscle cells (VSMCs). Adenovirus ex pressing PYK2 kinase-inactive mutant K457A or a tyrosine phosphorylation si te mutant Y402F was transfected in VSMCs. AngII-induced JNK phosphorylation was markedly enhanced by K457A, whereas it was suppressed by Y402F. Protei n synthesis induced by AngII was also enhanced by K457A and inhibited by Y4 02F. In this regard, K457A suppressed PYK2 kinase activation by AngII, wher eas it enhanced AngII-induced PYK2 Tyr(402) phosphorylation. By contrast, Y 402F inhibited PYK2 Tyr(402) phosphorylation, whereas it markedly enhanced AngII-induced PYK2 kinase activation. Thus, we conclude that PYK2 kinase ac tivity negatively regulates JNK activation and protein synthesis, whereas T yr(402) phosphorylation positively regulates these events in AngII-stimulat ed VSMCs, suggesting a unique role of PYK2 in mediating vascular remodeling . (C) 2001 Academic Press.