Signal Transduction TIMP-1 via TWIST1 Induces EMT Phenotypes in Human Breast Epithelial Cells
نویسندگان
چکیده
Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates intracellular signaling networks for inhibition of apoptosis. Tetraspanin (CD63), a cell surface binding partner for TIMP-1, was previously shown to regulate integrin-mediated survival pathways in the human breast epithelial cell line MCF10A. In the current study, we show that TIMP-1 expression induces phenotypic changes in cell morphology, cell adhesion, cytoskeletal remodeling, and motility, indicative of an epithelial–mesenchymal transition (EMT). This is evidenced by loss of the epithelial cell adhesion molecule E-cadherin with an increase in the mesenchymal markers vimentin, Ncadherin, and fibronectin. Signaling through TIMP-1, but not TIMP-2, induces the expression of TWIST1, an important EMT transcription factor known to suppress E-cadherin transcription, in a CD63-dependent manner. RNAi-mediated knockdown of TWIST1 rescued E-cadherin expression in TIMP-1–overexpressing cells, demonstrating a functional significance of TWIST1 in TIMP-1–mediated EMT. Furthermore, analysis of TIMP-1 structuralmutants reveals that TIMP-1 interactions withCD63 that activate cell survival signaling andEMTdonot require the matrix metalloproteinase (MMP)–inhibitory domain of TIMP-1. Taken together, these data demonstrate that TIMP-1 binding to CD63 activates intracellular signal transduction pathways, resulting in EMT-like changes in breast epithelial cells, independent of its MMP-inhibitory function. Implications: TIMP-10s function as an endogenous inhibitor of MMP or as a "cytokine-like" signaling molecule may be a critical determinant for tumor cell behavior. Mol Cancer Res; 1–10. 2014 AACR.
منابع مشابه
TIMP-1 via TWIST1 induces EMT phenotypes in human breast epithelial cells.
UNLABELLED Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates intracellular signaling networks for inhibition of apoptosis. Tetraspanin (CD63), a cell surface binding partner for TIMP-1, was previously shown to regulate integrin-mediated survival pathways in the human breast epithelial cell line MCF10A. In the current study, we show that TIMP-1 expression induces phenotypic changes in c...
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