Role of EGF receptor and Pyk2 in endothelin-1-induced ERK activation in rat cardiomyocytes

Hiroaki Kodama, Keiichi Fukuda, Toshiyuki Takahashi, Motoaki Sano, Takahiro Kato, Satoko Tahara, Daihiko Hakuno, Toshihiko Sato, Tomohiro Manabe, Fusako Konishi, Satoshi Ogawa

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

G protein-coupled receptor (GPCR)-evoked signal transduction pathways leading to the activation of extracellular signal-regulated kinases (ERK) are quite different among cell types. In cardiomyocytes, much attention has been focused on the activation of protein kinase C (PKC) or mobilization of intracellular Ca2+ ([Ca2+]i), however, the contributions of tyrosine kinases are controversial. In the present study, we characterized the signaling pathways involving tyrosine kinases, Pyk2 and epidermal growth factor receptor (EGFR), and their contribution to ERK activation in cultured cardiomyocytes. We initially investigated the potential involvement of [Ca2+]i and PKC on the activation of these kinases in endothelin-stimulated cardiomyocytes. Interestingly, activation of Pyk2 was abrogated by chelating [Ca2+]i or by downregulation of PKC, whereas transactivation of EGFR was solely dependent on PKC. By using a compound that selectively interferes with EGFR (AG1478), c-Src (PP1), or disrupts actin cytoskeleton (cytochalasin D), we demonstrated that cytochalasin D completely inhibited the activation of Pyk2, but not that of EGFR, whereas AG1478 did not inhibit the activation of Pyk2, indicating that transactivation of EGFR and signaling pathways involving Pyk2 were distinct pathways. Furthermore, activation of ERK and Shc, and c-fos gene expression were significantly inhibited by AG1478 but not by cytochalasin D or PP1. Overexpression of deletion mutant of EGFR attenuated the activation of ERK. These facts demonstrated the existence of two distinct tyrosine kinase pathways requiring Pyk2 or EGFR downstream from GPCR in cardiomyocytes. EGFR was Ca2+-independently activated and predominantly contributed to Shc/ERK/c-fos activation, while Pyk2 or c-Src contributed less to it.

Original languageEnglish
Pages (from-to)139-150
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume34
Issue number2
DOIs
Publication statusPublished - 2002 Feb 1

Keywords

  • Cardiac hypertrophy
  • Endothelin-1
  • Epidermal growth factor receptor
  • Extracellular signal regulated kinase
  • Pyk2
  • Signal transduction
  • c-Src

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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