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.
Yu
Q
Q
Molecular Pathology Unit, Massachusetts General Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02129 USA.
Stamenkovic
I
I
D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology; D018960:Hyaluronan Receptors / Q000502:physiology; D006868:Hydrolysis; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008805:Mice, Inbred A; D008817:Mice, Mutant Strains; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D016212:Transforming Growth Factor beta; D010447:Peptide Hydrolases; D020780:Matrix Metalloproteinase 9