Activation of pyk2/related focal adhesion tyrosine kinase and focal adhesion kinase in cardiac remodeling.

Abstract	Cellular remodeling during progression of dilation involves focal adhesion contact reorganization. However, the signaling mechanisms and structural consequences leading to impaired cardiomyocyte adhesion are poorly defined. These events were studied in tropomodulin-overexpressing transgenic mice that develop dilated cardiomyopathy associated with chronic elevation of intracellular calcium. Analysis of tropomodulin-overexpressing transgenic hearts by immunoblot and confocal microscopy revealed activation and redistribution of signaling molecules known to regulate adhesion. Calcium-dependent pyk2/related focal adhesion tyrosine kinase (RAFTK) showed changes in expression and phosphorylation state, similar to changes observed for a related downstream target molecule of pyk2/RAFTK termed focal adhesion kinase. Paxillin, the target substrate molecule for focal adhesion kinase phosphorylation, was redistributed in tropomodulin-overexpressing transgenic hearts with enhanced paxillin phosphorylation and cleavage. Certain aspects of the in vivo signaling phenotype including increased paxillin phosphorylation could be recapitulated in vitro using neonatal rat cardiomyocytes infected with recombinant adenovirus to overexpress tropomodulin. In addition, increasing intracellular calcium levels with ionomycin induced pyk2/RAFTK phosphorylation, and adenovirally mediated expression of wild-type pyk2/RAFTK resulted in increased phospho-pyk2/RAFTK levels and concomitant paxillin phosphorylation. Collectively, these results delineate a cardiomyocyte signaling pathway associated with dilation that has potential relevance for cardiac remodeling, focal adhesion reorganization, and loss of contractility.
Authors	Jaime Melendez, Sara Welch, Erik Schaefer, Christine S Moravec, Shalom Avraham, Hava Avraham, Mark A Sussman
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 47 Pg. 45203-10 (Nov 22 2002) ISSN: 0021-9258 [Print] United States
PMID	12228222 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Carrier Proteins Cytoskeletal Proteins Microfilament Proteins Paxillin Phosphoproteins Pxn protein, mouse Pxn protein, rat Tmod1 protein, mouse Tmod1 protein, rat Tropomodulin Protein-Tyrosine Kinases Focal Adhesion Kinase 1 Focal Adhesion Kinase 2 Focal Adhesion Protein-Tyrosine Kinases Ptk2 protein, mouse Ptk2 protein, rat Ptk2b protein, mouse Ptk2b protein, rat Calcium
Topics	Animals Animals, Newborn Calcium (metabolism) Carrier Proteins (genetics, metabolism) Cell Adhesion (physiology) Cells, Cultured Cytoskeletal Proteins (metabolism) Cytoskeleton (metabolism) Enzyme Activation Focal Adhesion Kinase 1 Focal Adhesion Kinase 2 Focal Adhesion Protein-Tyrosine Kinases Focal Adhesions (metabolism) Heart (physiology) Immunohistochemistry Mice Mice, Transgenic Microfilament Proteins (genetics, metabolism) Myocytes, Cardiac (cytology, metabolism) Paxillin Phosphoproteins (metabolism) Phosphorylation Protein Transport (physiology) Protein-Tyrosine Kinases (metabolism) Rats Rats, Sprague-Dawley Signal Transduction (physiology) Tropomodulin Ventricular Remodeling

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!