Tyrosine phosphatase SHP-2 regulates IL-1 signaling in fibroblasts through focal adhesions.

Abstract

Interleukin-1beta (IL-1beta) 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-1beta 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-1beta signaling. In human gingival fibroblasts plated on fibronectin, IL-1beta enhanced the maturation of focal adhesions as defined by morphology and enrichment with paxillin and alpha-actinin. IL-1beta 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-1beta, 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-1beta-induced ERK activation and maturation of focal adhesions. IL-1beta-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-1beta 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.

• Authors: Maria Teresa Herrera Abreu, Qin Wang, Eric Vachon, Tomoko Suzuki, Chung-Wai Chow, Yingchun Wang, Ouyang Hong, Jesús Villar, Christopher A G McCulloch, Gregory P Downey
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 207 Issue 1 Pg. 132-43 (Apr 2006) ISSN: 0021-9541 [Print] United States
• PMID: 16250012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Enzyme Inhibitors
• Fibronectins
• GAB1 protein, human
• Interleukin-1
• Intracellular Signaling Peptides and Proteins
• Paxillin
• RNA, Small Interfering
• pervanadate
• Actinin
• Vanadates
• Tyrosine
• Collagen
• Extracellular Signal-Regulated MAP Kinases
• PTPN11 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Protein Tyrosine Phosphatases
• Ptpn11 protein, mouse

Topics

• Actinin (metabolism)
• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Cell Line
• Cells, Cultured
• Collagen (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibroblasts (drug effects, metabolism)
• Fibronectins (pharmacology)
• Focal Adhesions (drug effects, metabolism)
• Humans
• Interleukin-1 (pharmacology)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, genetics, metabolism)
• Mice
• Mutation
• Paxillin (metabolism)
• Phosphorylation (drug effects)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Protein Tyrosine Phosphatases (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (genetics)
• Signal Transduction (physiology)
• Transfection
• Tyrosine (metabolism)
• Vanadates (pharmacology)