title: Differential effects of Pyk2 and FAK on the hypertrophic response of cardiac myocytes.
abstract: The related cytoplasmic non-receptor tyrosine kinases Pyk2 (proline-rich tyrosine kinase 2) and FAK (focal adhesion kinase) have been implicated in phenylephrine-induced G-protein-coupled receptor-mediated signaling mechanisms leading to cardiomyocyte hypertrophy. We report that, in phenylephrine-stimulated neonatal rat ventricular myocytes (NRVM), Pyk2 augments expression of the hypertrophic marker atrial natriuretic factor (ANF) but reduces cytoskeletal organization and cell spreading. In contrast, FAK attenuates ANF production but does not alter cytoskeletal organization and cell spreading. Pyk2 and FAK exhibit differential localization in both unstimulated and phenylephrine-stimulated myocytes. Pyk2 catalytic activity is required for Pyk2 to augment ANF secretion but is not necessary to reduce cell spreading. Pyk2 autophosphorylation is required but not sufficient for Pyk2 to augment ANF secretion. Expression of the Pyk2 FERM domain as an autonomous fragment inhibits phenylephrine-mediated ANF secretion and reduces cell spreading. In addition, expression of the Pyk2 FERM domain inhibits the ability of Pyk2 to augment ANF secretion; this is correlated with reduced Pyk2 autophosphorylation. These data indicate that Pyk2 and FAK have different roles and occupy different positions in signaling pathways leading to the development of cardiomyocyte hypertrophy.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, 85259, USA.
authors.forename: Emmanuel B
authors.initials: EB
authors.lastname: Menashi
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Loftus
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000819:agonists / Q000096:biosynthesis; D024722:Cardiac Myosins / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000187:drug effects / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection
chemical_list: D002316:Cardiotonic Agents; D018994:Myosin Light Chains; C107184:myosin light chain 2; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496052:Ptk2 protein, rat; D024722:Cardiac Myosins