Ca(2+)-sensitive tyrosine kinase Pyk2/CAK beta-dependent signaling is essential for G-protein-coupled receptor agonist-induced hypertrophy.
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.
Hirotani
Shinichi
S
Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, Box A8, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Higuchi
Yoshiharu
Y
Nishida
Kazuhiko
K
Nakayama
Hiroyuki
H
Yamaguchi
Osamu
O
Hikoso
Shungo
S
Takeda
Toshihiro
T
Kashiwase
Kazunori
K
Watanabe
Tetsuya
T
Asahi
Michio
M
Taniike
Masayuki
M
Tsujimoto
Ikuko
I
Matsumura
Yasushi
Y
Sasaki
Terukatsu
T
Hori
Masatsugu
M
Otsu
Kinya
K
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D051418:Focal Adhesion Kinase 2; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D019332:Endothelin-1; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D010656:Phenylephrine; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat; D020830:rac1 GTP-Binding Protein; D002118:Calcium