title: 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.affiliation: Department of Medicine, University of Toronto, Toronto General Hospital Research Institute of the University Health Network, Ontario, Canada.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Herrera Abreu
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Eric
authors.initials: E
authors.lastname: Vachon
authors.forename: Tomoko
authors.initials: T
authors.lastname: Suzuki
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Chow
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wang
authors.forename: Ouyang
authors.initials: O
authors.lastname: Hong
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
authors.forename: Christopher A G
authors.initials: CA
authors.lastname: McCulloch
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
mesh_terms: D000185:Actinin / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000494:pharmacology; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D005353:Fibronectins; C098587:GAB1 protein, human; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D051419:Paxillin; D034741:RNA, Small Interfering; C076715:pervanadate; D000185:Actinin; D014638:Vanadates; D014443:Tyrosine; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse