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?v?6 Integrin Is Required for TGF?1-Mediated Matrix Metalloproteinase2 Expression #MMPMID25558779
Dutta A; Li J; Fedele C; Sayeed A; Singh A; Violette SM; Manes TD; Languino LR
Biochem J 2015[Mar]; 466 (3): 525-36 PMID25558779show ga
TGF?1 activity depends on a complex signaling cascade that controls expression of several genes. Among others, TGF?1 regulates expression of matrix metalloproteinases (MMPs) through activation of Smads. Here, we demonstrate for the first time that the ?v?6 integrin interacts with TGF? receptor II (T?RII) through the ?6 cytoplasmic domain and promotes Smad3 activation in prostate cancer cells. Another related ?v integrin, ?v?5, as well as the ?v?6/3 integrin, which contains a chimeric form of ?6 with a ?3 cytoplasmic domain, do not associate with T?RII and fail to show similar responses. We provide evidence that ?v?6 is required for upregulation of MMP2 by TGF?1 through a Smad3-mediated transcriptional program in prostate cancer cells. The functional relevance of these results is underscored by the finding that ?v?6 modulates cell migration in a MMP2-dependent manner on an ?v?6 specific ligand, latency associated peptide (LAP)-TGF?. Overall, these mechanistic studies establish that expression of a single integrin, ?v?6, is sufficient to promote activation of Smad3, regulation of MMP2 levels, and consequent catalytic activity, as well as cell migration. Our study describes a new TGF?1/?v?6/MMP2 signaling pathway that, given TGF?1 pro-metastatic activity, may have profound implications for prostate cancer therapy.
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Biochem+J 2015 ; 466 (3): 525-36
