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

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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 (CasΔSD), 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 CasΔSD, 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.

Original languageEnglish
Pages (from-to)1372-1379
Number of pages8
JournalHypertension
Volume41
Issue number6
DOIs
Publication statusPublished - 2003 Jun 1

Keywords

  • Cardiac hypertrophy
  • Endothelin-1
  • Focal adhesion
  • Kinase
  • Phosphorylation

ASJC Scopus subject areas

  • Internal Medicine

Fingerprint Dive into the research topics of 'Selective involvement of p130Cas/Crk/Pyk2/c-Src in endothelin-1-induced JNK activation'. Together they form a unique fingerprint.

  • Cite this

    Kodama, H., Fukuda, K., Takahashi, E., Tahara, S., Tomita, Y., Ieda, M., Kimura, K., Owada, K. M., Vuori, K., & Ogawa, S. (2003). Selective involvement of p130Cas/Crk/Pyk2/c-Src in endothelin-1-induced JNK activation. Hypertension, 41(6), 1372-1379. https://doi.org/10.1161/01.HYP.0000069698.11814.F4