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Ca(2+)-sensitive tyrosine kinase Pyk2/CAK beta-dependent signaling is essential for G-protein-coupled receptor agonist-induced hypertrophy.

Authors: Hirotani, S  Higuchi, Y  Nishida, K  Nakayama, H  Yamaguchi, O  Hikoso, S  Takeda, T  Kashiwase, K  Watanabe, T  Asahi, M  Taniike, M  Tsujimoto, I  Matsumura, Y  Sasaki, T  Hori, M  Otsu, K 
Citation: Hirotani S, etal., J Mol Cell Cardiol. 2004 Jun;36(6):799-807.
Pubmed: (View Article at PubMed) PMID:15158121
DOI: Full-text: DOI:10.1016/j.yjmcc.2004.03.002

G-protein-coupled receptor agonists including endothelin-1 (ET-1) and phenylephrine (PE) induce hypertrophy in neonatal ventricular cardiomyocytes. Others and we previously reported that Rac1 signaling pathway plays an important role in this agonist-induced cardiomyocyte hypertrophy. In this study reported here, we found that a Ca(2+)-sensitive non-receptor tyrosine kinase, proline-rich tyrosine kinase 2 (Pyk2)/cell adhesion kinase beta (CAKbeta), is involved in ET-1- and PE-induced cardiomyocyte hypertrophy medicated through Rac1 activation. ET-1, PE or the Ca(2+) inophore, ionomycin, stimulated a rapid increase in tyrosine phosphorylation of Pyk2. The tyrosine phosphorylation of Pyk2 was suppressed by the Ca(2+) chelator, BAPTA. ET-1- or PE-induced increases in [(3)H]-leucine incorporation and expression of atrial natriuretic factor and the enhancement of sarcomere organization. Infection of cardiomyocytes with an adenovirus expressing a mutant Pyk2 which lacked its kinase domain or its ability to bind to c-Src, eliminated ET-1- and PE-induced hypertrophic responses. Inhibition of Pyk2 activation also suppressed Rac1 activation and reactive oxygen species (ROS) production. These findings suggest that the signal transduction pathway leading to hypertrophy involves Ca(2+)-induced Pyk2 activation followed by Rac1-dependent ROS production.

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CRRD Object Information
CRRD ID: 1642626
Created: 2007-10-04
Species: All species
Last Modified: 2007-10-04
Status: ACTIVE



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