title: Ca(2+)-sensitive tyrosine kinase Pyk2/CAK beta-dependent signaling is essential for G-protein-coupled receptor agonist-induced hypertrophy.
abstract: 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.
authors.affiliation: Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, Box A8, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirotani
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Shungo
authors.initials: S
authors.lastname: Hikoso
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kashiwase
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Michio
authors.initials: M
authors.lastname: Asahi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Taniike
authors.forename: Ikuko
authors.initials: I
authors.lastname: Tsujimoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Terukatsu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
mesh_terms: 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
chemical_list: 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