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- Title
Tyrosine phosphatase SHP-2 regulates IL-1 signaling in fibroblasts through focal adhesions.
- Authors
Herrera Abreu, Maria Teresa; Qin Wang; Vachon, Eric; Suzuki, Tomoko; Chung-Wai Chow; Yingchun Wang; Ouyang Hong; Villar, Jesús; McCulloch, Christopher A. G.; Downey, Gregory P.
- Abstract
Interleukin-1β (IL-1β) mediates destruction of matrix collagens in diverse inflammatory diseases including arthritis, periodontitis, and pulmonary fibrosis by activating fibroblasts, cells that interact with matrix proteins through integrin-based adhesions. In vitro, IL-1β signaling is modulated by focal adhesions, supramolecular protein complexes that are enriched with tyrosine kinases and phosphatases. We assessed the importance of tyrosine phosphatases in regulating cell–matrix interactions and IL-1β signaling. In human gingival fibroblasts plated on fibronectin, IL-1β enhanced the maturation of focal adhesions as defined by morphology and enrichment with paxillin and α-actinin. IL-1β also induced activation of ERK and recruitment of phospho-ERK to focal complexes/adhesions. Treatment with the potent tyrosine phosphatase inhibitor pervanadate, in the absence of IL-1β, recapitulated many of these responses indicating the importance of tyrosine phosphatases. Immunoblotting of collagen bead-associated complexes revealed that the tyrosine phosphatase, SHP-2, was also enriched in focal complexes/adhesions. Depletion of SHP-2 by siRNA or by homologous recombination markedly altered IL-1β-induced ERK activation and maturation of focal adhesions. IL-1β-induced tyrosine phosphorylation of SHP-2 on residue Y542 promoted focal adhesion maturation. Association of Gab1 with SHP-2 in focal adhesions correlated temporally with activation of ERK and was abrogated in cells expressing mutant (Y542F) SHP-2. We conclude that IL-1β mediated maturation of focal adhesions is dependent on tyrosine phosphorylation of SHP-2 at Y542, leading to recruitment of Gab1, a process that may influence the downstream activation of ERK. J. Cell. Physiol. 207: 132–143, 2006. © 2005 Wiley-Liss, Inc.
- Subjects
INTERLEUKIN-1; COLLAGEN; ARTHRITIS; PERIODONTITIS; CELLS; AMINO acids
- Publication
Journal of Cellular Physiology, 2006, Vol 207, Issue 1, p132
- ISSN
0021-9541
- Publication type
Article
- DOI
10.1002/jcp.20544