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10.1074/jbc.M114.622274

http://scihub22266oqcxt.onion/10.1074/jbc.M114.622274
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suck abstract from ncbi


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pmid25825495
      J+Biol+Chem 2015 ; 290 (22 ): 13763-78
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  • Recruitment of Matrix Metalloproteinase-9 (MMP-9) to the Fibroblast Cell Surface by Lysyl Hydroxylase 3 (LH3) Triggers Transforming Growth Factor-? (TGF-?) Activation and Fibroblast Differentiation #MMPMID25825495
  • Dayer C ; Stamenkovic I
  • J Biol Chem 2015[May]; 290 (22 ): 13763-78 PMID25825495 show ga
  • Solid tumor growth triggers a wound healing response. Similar to wound healing, fibroblasts in the tumor stroma differentiate into myofibroblasts (also referred to as cancer-associated fibroblasts) primarily, but not exclusively, in response to transforming growth factor-? (TGF-?). Myofibroblasts in turn enhance tumor progression by remodeling the stroma. Among proteases implicated in stroma remodeling, matrix metalloproteinases (MMPs), including MMP-9, play a prominent role. Recent evidence indicates that MMP-9 recruitment to the tumor cell surface enhances tumor growth and invasion. In the present work, we addressed the potential relevance of MMP-9 recruitment to and activity at the surface of fibroblasts. We show that recruitment of MMP-9 to the fibroblast cell surface occurs through its fibronectin-like (FN) domain and that the molecule responsible for the recruitment is lysyl hydroxylase 3 (LH3). Functional assays suggest that both pro- and active MMP-9 trigger ?-smooth muscle actin expression in cultured fibroblasts, reflecting myofibroblast differentiation, possibly as a result of TGF-? activation. Moreover, the recombinant FN domain inhibited both MMP-9-induced TGF-? activation and ?-smooth muscle actin expression by displacing MMP-9 from the fibroblast cell surface. Together our results uncover LH3 as a new docking receptor of MMP-9 on the fibroblast cell surface and demonstrate that the MMP-9 FN domain is essential for the interaction. They also show that the recombinant FN domain inhibits MMP-9-induced TGF-? activation and fibroblast differentiation, providing a potentially attractive therapeutic reagent toward attenuating tumor progression where MMP-9 activity is strongly implicated.
  • |Animals [MESH]
  • |CHO Cells [MESH]
  • |Cell Differentiation [MESH]
  • |Cell Line, Tumor [MESH]
  • |Cell Membrane/metabolism [MESH]
  • |Cell Separation [MESH]
  • |Cricetinae [MESH]
  • |Cricetulus [MESH]
  • |Fibroblasts/*metabolism [MESH]
  • |Flow Cytometry [MESH]
  • |HEK293 Cells [MESH]
  • |Humans [MESH]
  • |Liver/metabolism [MESH]
  • |Matrix Metalloproteinase 9/*metabolism [MESH]
  • |Microscopy, Fluorescence [MESH]
  • |Myofibroblasts/cytology [MESH]
  • |Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase/*metabolism [MESH]
  • |Recombinant Proteins/metabolism [MESH]
  • |Transforming Growth Factor beta/*metabolism [MESH]


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