Recruitment of Matrix Metalloproteinase-9 (MMP-9) to the fibroblast cell surface by Lysyl Hydroxylase-3 (LH3) triggers TGF-{beta} activation and fibroblast differentiation [Cell Biology]

March 30th, 2015 by Dayer, C., Stamenkovic, I.

ABSTRACT 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 (CAFs), primarily, but not exclusively, in response to transforming growth factor-beta (TGF-β). 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 α-smooth muscle actin (α-SMA) expression in cultured fibroblasts, which reflects myofibroblast differentiation, possibly as a result of TGF-β activation. Moreover, the recombinant FN domain inhibits both MMP-9-induced TGF-β activation and α-SMA 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-β activation and fibroblast differentiation, providing a potentially attractive therapeutic reagent toward attenuating tumor progression where MMP-9 activity is strongly implicated.
  • Posted in Journal of Biological Chemistry, Publications
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