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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.

Pubmed ID: 10652271

Authors

  • Yu Q
  • Stamenkovic I

Journal

Genes & development

Publication Data

January 15, 2000

Associated Grants

  • Agency: NCI NIH HHS, Id: CA09216
  • Agency: NCI NIH HHS, Id: CA55375
  • Agency: NIGMS NIH HHS, Id: GM48614

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