Article: article from journal or magazin.
Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis.
Genes and Development
We have uncovered a novel functional relationship between the hyaluronan receptor CD44, the matrix metalloproteinase-9 (MMP-9) and the multifunctional cytokine TGF-beta in the control of tumor-associated tissue remodeling. CD44 provides a cell surface docking receptor for proteolytically active MMP-9 and we show here that localization of MMP-9 to cell surface is required for its ability to promote tumor invasion and angiogenesis. Our observations also indicate that MMP-9, as well as MMP-2, proteolytically cleaves latent TGF-beta, providing a novel and potentially important mechanism for TGF-beta activation. In addition, we show that MMP-9 localization to the surface of normal keratinocytes is CD44 dependent and can activate latent TGF-beta. These observations suggest that coordinated CD44, MMP-9, and TGF-beta function may provide a physiological mechanism of tissue remodeling that can be adopted by malignant cells to promote tumor growth and invasion.
Animals, Antigens, CD44/physiology, Cell Membrane/enzymology, Culture Media, Conditioned/pharmacology, Endothelium, Vascular/enzymology, Endothelium, Vascular/pathology, Hydrolysis, Keratinocytes/enzymology, Keratinocytes/metabolism, Male, Mammary Neoplasms, Experimental/blood supply, Mammary Neoplasms, Experimental/enzymology, Matrix Metalloproteinase 9/metabolism, Mice, Mice, Inbred A, Mice, Mutant Strains, Neoplasm Invasiveness, Neovascularization, Pathologic/enzymology, Neovascularization, Pathologic/metabolism, Peptide Hydrolases/metabolism, Protein Isoforms/metabolism, Transforming Growth Factor beta/metabolism, Tumor Cells, Cultured
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