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J. Biol. Chem., Vol. 281, Issue 28, 19781-19792, July 14, 2006

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Role of Protein-tyrosine Phosphatase SHP₂ in Focal Adhesion Kinase Down-regulation during Neutrophil Cathepsin G-induced Cardiomyocytes Anoikis^*

Khadija Rafiq, Mikhail A. Kolpakov, Malika Abdelfettah, Daniel N. Streblow, Aviv Hassid^¶, Louis J. Dell'Italia^||, and Abdelkarim Sabri¹

From the Cardiovascular Research Center, Department of Anatomy and Cell Biology, Temple University, Philadelphia, Pennsylvania 19140, the Oregon Health and Science University, Portland, Oregon 97201, the ^¶University of Tennessee, Memphis, Tennessee 38163, and the ^||University of Alabama at Birmingham, Birmingham, Alabama 35294

Inflammatory cells and their proteases contribute to tissue reparation at site of inflammation. Although beneficial at early stages, excessive inflammatory reaction leads to cell death and tissue damage. Cathepsin G (Cat.G), a neutrophil-derived serine protease, has been shown to induce neonatal rat cardiomyocyte detachment and apoptosis by anoikis through caspase-3 dependent pathway. However the early mechanisms that trigger Cat.G-induced caspase-3 activation are not known. This study identifies focal adhesion kinase (FAK) tyrosine dephosphorylation as an early mechanism that regulates Cat.G-induced anoikis in cardiomyocytes. Both FAK tyrosine phosphorylation at Tyr-397 and kinase activity decrease rapidly upon Cat.G treatment and was associated with a decrease of FAK association with adapter and cytoskeletal proteins, p130^Cas and paxillin, respectively. FAK-decreased tyrosine phosphorylation is required for Cat.G-induced myocyte anoikis as concurrent expression of phosphorylation-deficient FAK mutated at Tyr-397 or pretreatment with a protein-tyrosine phosphatase (PTP) inhibitor, pervanadate, blocks Cat.G-induced FAK tyrosine dephosphorylation, caspase-3 activation and DNA fragmentation. Analysis of PTPs activation shows that Cat.G treatment induces an increase of SHP₂ and PTEN phosphorylation; however, only SHP₂ forms a complex with FAK in response to Cat.G. Expression of dominant negative SHP₂ mutant markedly attenuates FAK tyrosine dephosphorylation induced by Cat.G and protects myocytes to undergo apoptosis. In contrast, increased SHP₂ expression exacerbates Cat.G-induced FAK tyrosine dephosphorylation and myocyte apoptosis. Taken together, these results show that Cat.G induces SHP₂ activation that leads to FAK tyrosine dephosphorylation and promotes cardiomyocyte anoikis.

Received for publication, December 7, 2005 , and in revised form, May 8, 2006.

^* This work was supported by National Institutes of Health Grants HL76799 (to A. S.) and HL63886 and HL72902 (to A. H.) and by American Heart Association Grant 0430301N (to A. S.). 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.

¹ To whom correspondence should be addressed: Cardiovascular Research Center, Temple University, MRB 801, 3420 N. Broad St., Philadelphia, PA 19140. Tel.: 215-707-4915; Fax: 215-707-5737; E-mail: sabri{at}temple.edu.

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