title: Importance of protein-tyrosine phosphatase-alpha catalytic domains for interactions with SHP-2 and interleukin-1-induced matrix metalloproteinase-3 expression.
abstract: Interleukin-1 (IL-1) induces extracellular matrix degradation as a result of increased expression of matrix metalloproteinases (MMPs). We examined adhesion-restricted signaling pathways that enable IL-1-induced MMP release in human gingival and murine fibroblasts. Of the seven MMPs and three tissue inhibitors of MMPs screened, IL-1 enhanced release only of MMP3 when cells formed focal adhesions. Inhibition of protein-tyrosine phosphatases (PTPs), which are enriched in focal adhesions, blocked IL-1-induced MMP3 release. Accordingly, in contrast to wild-type cells, fibroblasts null for PTPalpha did not exhibit IL-1-induced MMP3 release. IL-1 treatment enhanced the recruitment of SHP-2 and PTPalpha to focal adhesions and the association of PTPalpha with SHP-2. Pulldown assays confirmed a direct interaction between PTPalpha and SHP-2, which was dependent on the intact, membrane-proximal phosphatase domain of PTPalpha. Interactions between SHP-2 and PTPalpha, recruitment of SHP-2 to focal adhesions, IL-1-induced ERK activation, and MMP3 expression were all blocked by point mutations in the phosphatase domains of PTPalpha. These data indicate that IL-1-induced signaling through focal adhesions leading to MMP3 release and interactions between SHP-2 and PTPalpha are dependent on the integrity of the catalytic domains of PTPalpha.
authors.affiliation: Matrix Dynamics Group, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Dhaarmini
authors.initials: D
authors.lastname: Rajshankar
authors.forename: Carol
authors.initials: C
authors.lastname: Laschinger
authors.forename: Ilana
authors.initials: I
authors.lastname: Talior-Volodarsky
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D051381:Rats; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D007375:Interleukin-1; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D019278:Matrix Metalloproteinase 3
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