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(Hypertension. 2003;41:1372.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Selective Involvement of p130Cas/Crk/Pyk2/c-Src in Endothelin-1-Induced JNK Activation

Hiroaki Kodama; Keiichi Fukuda; Eiichi Takahashi; Satoko Tahara; Yuichi Tomita; Masaki Ieda; Kensuke Kimura; Koji M. Owada; Kristiina Vuori; Satoshi Ogawa

From the Cardiopulmonary Division, Department of Internal Medicine (H.K., K.F., E.T., S.T., Y.T., M.I., K.K., S.O.), and the Institute for Advanced Cardiac Therapeutics (K.F.), School of Medicine, Keio University, Tokyo, Japan; the Institute of Molecular and Cellular Biology for Pharmaceutical Sciences, Kyoto Pharmaceutical University (K.M.O.), Kyoto, Japan; and the La Jolla Cancer Research Center, Burnham Institute (K.V.), La Jolla, Calif.

Correspondence to Keiichi Fukuda, MD, PhD, Cardiopulmonary Division, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail kfukuda{at}sc.itc.keio.ac.jp

Both integrin-based focal adhesion complexes and receptor tyrosine kinases have been proposed as scaffolds on which the G protein-coupled receptor (GPCR)-induced signaling complex might assemble. We have recently reported that Ca²⁺-sensitive tyrosine kinase, Pyk2, and epidermal growth factor receptor (EGFR) act as independently regulated scaffolds in cardiomyocytes. In this report, we investigated the activation and regulation of p130Cas, Crk, Pyk2, and c-Src by a well-known hypertrophic agonist, endothelin-1 (ET), and determined their contributions to the activation of c-Jun NH₂-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in cardiomyocytes. Like Pyk2, ET-induced tyrosine phosphorylation of p130Cas was significantly inhibited by either chelating intracellular Ca²⁺ ([Ca²⁺]_i) or a protein kinase C inhibitor, calphostin C. This activation of p130Cas was also abrogated by the tetrapeptide RGDS, which disrupts integrin heterodimerization; cytochalasin D, which depolymerizes the actin cytoskeleton; or a selective Src family kinase inhibitor, PP2, but not by an EGFR inhibitor, AG1478. We also observed ET-induced temporal associations of Pyk2 with active c-Src, followed by p130Cas with Pyk2, c-Src, and Crk. Overexpression of a dominant-negative mutant of p130Cas (CasSD), Crk (CrkSH2m), Pyk2 (PKM), or C-terminal Src kinase (Csk), but not of a deletion mutant of EGFR (533delEGFR), attenuated ET-induced JNK activation. Similarly, an ET-induced increase in c-jun promoter luciferase activity was inhibited by overexpression of CasSD, CrkSH2m, PKM, or Csk. In contrast, ET-induced ERK activation and c-fos gene expression were predominantly regulated by EGFR. Collectively, the focal adhesion-dependent p130Cas/Crk/Pyk2/c-Src-mediated pathway is selectively involved in ET-induced JNK activation in cardiomyocytes.

Key Words: endothelin-1 • cardiac hypertrophy • kinase • focal adhesion • phosphorylation

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