Document Detail

Selective involvement of p130Cas/Crk/Pyk2/c-Src in endothelin-1-induced JNK activation.
MedLine Citation:
PMID:  12719447     Owner:  NLM     Status:  MEDLINE    
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 (CasDeltaSD), 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 CasDeltaSD, 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.
Hiroaki Kodama; Keiichi Fukuda; Eiichi Takahashi; Satoko Tahara; Yuichi Tomita; Masaki Ieda; Kensuke Kimura; Koji M Owada; Kristiina Vuori; Satoshi Ogawa
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Publication Detail:
Type:  Journal Article     Date:  2003-04-28
Journal Detail:
Title:  Hypertension     Volume:  41     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2003 Jun 
Date Detail:
Created Date:  2003-06-06     Completed Date:  2003-06-27     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1372-9     Citation Subset:  IM    
Cardiopulmonary Division, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
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MeSH Terms
Calcium / physiology
Cells, Cultured
Crk-Associated Substrate Protein
Endothelin-1 / pharmacology*
Enzyme Activation
Focal Adhesion Kinase 2
Focal Adhesions / metabolism
JNK Mitogen-Activated Protein Kinases
MAP Kinase Signaling System*
Mitogen-Activated Protein Kinases / metabolism*
Myocytes, Cardiac / drug effects,  enzymology*,  metabolism
Phosphoproteins / genetics,  physiology
Protein Kinase C / physiology
Protein-Tyrosine Kinases / genetics,  physiology
Proto-Oncogene Proteins / genetics,  physiology
Proto-Oncogene Proteins c-crk
Proto-Oncogene Proteins pp60(c-src) / physiology
Rats, Wistar
Retinoblastoma-Like Protein p130
Transcriptional Activation
Tyrosine / metabolism
Reg. No./Substance:
0/Bcar1 protein, rat; 0/Crk protein, rat; 0/Crk-Associated Substrate Protein; 0/Endothelin-1; 0/Phosphoproteins; 0/Proteins; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-crk; 0/Retinoblastoma-Like Protein p130; 55520-40-6/Tyrosine; 7440-70-2/Calcium; EC Adhesion Kinase 2; EC Kinases; EC tyrosine-protein kinase; EC Proteins pp60(c-src); EC protein, rat; EC Kinase C; EC Mitogen-Activated Protein Kinases; EC Protein Kinases

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