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      Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein.

      The EMBO Journal

      Antigens, CD, metabolism, physiology, Antigens, CD29, Antigens, CD63, Apoptosis, Cell Adhesion, Cell Line, Cell Membrane, Cell Polarity, Cell Survival, Down-Regulation, Epithelial Cells, cytology, Gene Library, Humans, Mammary Glands, Human, Membrane Proteins, Platelet Membrane Glycoproteins, Protein Binding, Signal Transduction, Tissue Inhibitor of Metalloproteinase-1, Two-Hybrid System Techniques

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          This study identified CD63, a member of the tetraspanin family, as a TIMP-1 interacting protein by yeast two-hybrid screening. Immunoprecipitation and confocal microscopic analysis confirmed CD63 interactions with TIMP-1, integrin beta1, and their co-localizations on the cell surface of human breast epithelial MCF10A cells. TIMP-1 expression correlated with the level of active integrin beta1 on the cell surface independent of cell adhesion. While MCF10A cells within a three-dimensional (3D) matrigel matrix form polarized acinar-like structures, TIMP-1 overexpression disrupted breast epithelial cell polarization and inhibited caspase-mediated apoptosis in centrally located cells, necessary for the formation and maintenance of the hollow acinar-like structures. Small hairpin RNA (shRNA)-mediated CD63 downregulation effectively reduced TIMP-1 binding to the cell surface, TIMP-1 co-localization with integrin beta1, and consequently reversed TIMP-1-mediated integrin beta1 activation, cell survival signaling and apoptosis inhibition. CD63 downregulation also restored polarization and apoptosis of TIMP-1 overexpressing MCF10A cells within a 3D-matrigel matrix. Taken together, the present study identified CD63 as a cell surface binding partner for TIMP-1, regulating cell survival and polarization via TIMP-1 modulation of tetraspanin/integrin signaling complex.

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