Journal
EMBO JOURNAL
Volume 25, Issue 17, Pages 3934-3942Publisher
WILEY
DOI: 10.1038/sj.emboj.7601281
Keywords
apoptosis; cell survival signaling; epithelial cell polarization; integrin; tetraspanin
Categories
Funding
- NCI NIH HHS [CA89113, P30 CA022453, P30CA22453, R01 CA089113] Funding Source: Medline
- NIEHS NIH HHS [P30 ES006639, P30 ES06639] Funding Source: Medline
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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 beta 1, and their co-localizations on the cell surface of human breast epithelial MCF10A cells. TIMP-1 expression correlated with the level of active integrin beta 1 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 over-expression 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 beta 1, and consequently reversed TIMP-1-mediated integrin beta 1 activation, cell survival signaling and apoptosis inhibition. CD63 downregulation also restored polarization and apoptosis of TIMP-1 over-expressing 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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