Role of protein tyrosine phosphatase SHP2 in focal adhesion kinase downregulation during neutrophil cathepsin G-induced cardiomyocytes anoikis

doi:10.1074/jbc.M513040200

HOME

HELP

FEEDBACK

SUBSCRIPTIONS

Role of protein tyrosine phosphatase SHP₂ in focal adhesion kinase downregulation 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 Sabri

Anatomy & Cell Biology, Temple University, Philadelphia, PA 19140

Corresponding Author: sabri{at}temple.edu

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, p130Cas 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.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

T. M. Marin, C. F.M.Z. Clemente, A. M. Santos, P. K. Picardi, V. D.B. Pascoal, I. Lopes-Cendes, M. J.A. Saad, and K. G. Franchini
Shp2 Negatively Regulates Growth in Cardiomyocytes by Controlling Focal Adhesion Kinase/Src and mTOR Pathways
Circ. Res., October 10, 2008; 103(8): 813 - 824.
[Abstract] [Full Text] [PDF]

A. Sabri, K. Rafiq, R. Seqqat, M. A. Kolpakov, R. Dillon, and L. J. Dell'italia
Sympathetic Activation Causes Focal Adhesion Signaling Alteration in Early Compensated Volume Overload Attributable to Isolated Mitral Regurgitation in the Dog
Circ. Res., May 9, 2008; 102(9): 1127 - 1136.
[Abstract] [Full Text] [PDF]

K. Rafiq, M. Hanscom, K. Valerie, S. F. Steinberg, and A. Sabri
Novel Mode for Neutrophil Protease Cathepsin G Mediated Signaling: Membrane Shedding of Epidermal Growth Factor Is Required for Cardiomyocyte Anoikis
Circ. Res., January 4, 2008; 102(1): 32 - 41.
[Abstract] [Full Text] [PDF]

H.-B. Guo, M. Randolph, and M. Pierce
Inhibition of a Specific N-Glycosylation Activity Results in Attenuation of Breast Carcinoma Cell Invasiveness-related Phenotypes: INHIBITION OF EPIDERMAL GROWTH FACTOR-INDUCED DEPHOSPHORYLATION OF FOCAL ADHESION KINASE
J. Biol. Chem., July 27, 2007; 282(30): 22150 - 22162.
[Abstract] [Full Text] [PDF]