A role for PYK2 in regulation of ERK1/2 MAP kinases and PI 3-kinase by ANG II in vascular smooth muscle

Abstract

Abnormal vascular smooth muscle cell (VSMC) growth plays a key role in the pathogenesis of hypertension and atherosclerosis. Angiotensin II (ANG II) elicits a hypertrophic growth response characterized by an increase in protein synthesis without cell proliferation. The present study investigated the role of the nonreceptor tyrosine kinase PYK2 in the regulation of ANG II-induced signaling pathways that mediate VSMC growth. Using coimmunoprecipitation analysis, the role of PYK2 as an upstream regulator of both extracellular signal-related kinase (ERK) 1/2 mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI 3-kinase) pathways was examined in cultured rat aortic VSMC. ANG II (100 nM) promoted the formation of a complex between PYK2 and the ERK1/2 regulators Shc and Grb2. ANG II caused a rapid and Ca(2+)-dependent tyrosine phosphorylation of the adapter molecule p130Cas, which coimmunoprecipitated both PYK2 and PI 3-kinase in ANG II-treated VSMC. Complex formation between PI 3-kinase and p130Cas and PYK2 was associated with a rapid phosphorylation of the ribosomal p70(S6) kinase in a Ca(2+)- and tyrosine kinase-dependent manner. These data suggest that PYK2 is an important regulator of multiple signaling pathways involved in ANG II-induced VSMC growth.

Soluble Fractalkine Prevents Monocyte Chemoattractant Protein-1-Induced Monocyte Migration via Inhibition of Stress-Activated Protein Kinase 2/p38 and Matrix Metalloproteinase Activities

“…Several reports have shown that activation of Pyk2 was necessary for the activation of ERKs and/or SAPKs in different cell lines and in response to various stimuli (47)(48)(49)(50)(51)(52). Thus, it was of interest to determine whether the inhibition by s-FKN of MCP-1-induced p38/SAPK2 activity, which leads to the abrogation of MCP-1-induced chemotaxis of MonoMac6 cells, was associated with an inhibition of Pyk2 activity.…”

Essential role of Pyk2 and Src kinase activation in neuropeptide-induced proliferation of small cell lung cancer cells

“…In this context, Ca 2 þ -dependent proline-rich tyrosine kinase Pyk2 has been identified as an intermediate in [Ca 2 þ ] i -mediated ERK activation in a variety of different cells (Lev et al, 1995;Rocic et al, 2001). Pyk2 is closely related to focal adhesion kinase (FAK) and highly expressed in the central nervous system, cells derived from hematopoietic lineages as well as in liver, renal epithelial and vascular smooth muscle cells (Schlaepfer et al, 1999).…”

ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca2+, PKC, and Rho kinase

“…Pyk2 lacks Src homology 2 and 3 (SH2 and SH3) domains but contains sequences capable of binding to SH2 and SH3 domains of other proteins, including Src family kinases, the adaptor protein Grb2 (14,26), and the focal adhesion proteins paxillin (17,19,22,28,46) and p130CAS (43). In particular, tyrosine-402 (Tyr-402) has been identified as the key site for Pyk2 autophosphorylation and activation (14), with other tyrosine sites contributing to subsequent transphosphorylation and enhanced kinase activity (27,50).…”