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J. Biol. Chem., Vol. 279, Issue 51, 53516-53523, December 17, 2004

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Cardiomyocyte Apoptosis Triggered by RAFTK/pyk2 via Src Kinase Is Antagonized by Paxillin^*

Jaime Melendez, Christopher Turner, Hava Avraham¶, Susan F. Steinberg||, Erik Schaefer**, and Mark A. Sussman

From the The Children's Hospital Research Foundation, Division of Molecular Cardiovascular Biology, Cincinnati, Ohio 45229, State University of New York, Health Science Center, Syracuse, New York 13210, ^¶Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, ^||Columbia University, Department of Pharmacology, New York, New York 10032, ^**Biosource International, Hopkinton, Massachusetts 01748, and San Diego State University Heart Institute and Department of Biology, San Diego, California 92182

Altered cellular adhesion and apoptotic signaling in cardiac remodeling requires coordinated regulation of multiple constituent proteins that comprise cytoskeletal focal adhesions. One such protein activated by cardiac remodeling is related adhesion focal tyrosine kinase (RAFTK, also known as pyk2). Adenoviral-mediated expression of RAFTK in neonatal rat cardiomyocytes involves concurrent increases in phosphorylation of Src, c-Jun N-terminal kinase, and p38 leading to characteristic apoptotic changes including cleavage of poly(ADP-ribose) polymerase, caspase-3 activation, and increased DNA laddering. DNA laddering was decreased by mutation of the Tyr⁴⁰² Src-binding site in RAFTK, suggesting a central role for Src activity in apoptotic cell death that was confirmed by adenoviral-mediated Src expression. Multiple apoptotic signaling cascades are recruited by RAFTK as demonstrated by prevention of apoptosis using caspase-3 inhibitor IV (caspase-3 specific inhibitor), PP2 (Src-specific kinase inhibitor), or Csk (cellular negative regulator for Src), as well as dominant negative constructs for p38 or MKP-1. These RAFTK-mediated phenotypic characteristics are prevented by concurrent expression of wild-type or a phosphorylation-deficient paxillin mutated at Tyr³¹ and Tyr¹¹⁸. Wild-type or mutant paxillin protein accumulation in the cytoplasm has no overt effect upon cell structure, but paxillin accumulation prevents losses of myofibril organization as well as focal adhesion kinase, vinculin, and paxillin protein levels mediated by RAFTK. Apoptotic signaling cascade inhibition by paxillin indicates interruption of signaling proximal to but downstream of RAFTK activity. Chronic RAFTK activation in cardiac remodeling may represent a maladaptive reactive response that can be modulated by paxillin, opening up novel possibilities for inhibition of cardiomyocyte apoptosis and structural degeneration in heart failure.

Received for publication, July 27, 2004 , and in revised form, August 11, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: SDSU Heart Institute and Dept. of Biology, San Diego State University, 5500 Campanile Dr., San Diego, CA 92182. Tel.: 619-594-2983; Fax: 619-594-0712; E-mail: sussman{at}heart.sdsu.edu.

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