Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis.
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.
Mesh Terms:
Animals, Antigens, CD44, Cell Membrane, Culture Media, Conditioned, Endothelium, Vascular, Hydrolysis, Keratinocytes, Male, Mammary Neoplasms, Experimental, Matrix Metalloproteinase 9, Mice, Mice, Inbred A, Mice, Mutant Strains, Neoplasm Invasiveness, Neovascularization, Pathologic, Peptide Hydrolases, Protein Isoforms, Transforming Growth Factor beta, Tumor Cells, Cultured
Animals, Antigens, CD44, Cell Membrane, Culture Media, Conditioned, Endothelium, Vascular, Hydrolysis, Keratinocytes, Male, Mammary Neoplasms, Experimental, Matrix Metalloproteinase 9, Mice, Mice, Inbred A, Mice, Mutant Strains, Neoplasm Invasiveness, Neovascularization, Pathologic, Peptide Hydrolases, Protein Isoforms, Transforming Growth Factor beta, Tumor Cells, Cultured
Genes Dev.
Date: Jan. 15, 2000
PubMed ID: 10652271
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