αvβ6 integrin is required for TGFβ1-mediated matrix metalloproteinase2 expression

Transforming growth factor (TGF) beta 1 activity depends on a complex signalling cascade that controls expression of several genes. Among others, TGF beta 1 regulates expression of matrix metalloproteinases (MMPs) through activation of Smads. In the present study, we demonstrate for the first time that the alpha v beta 6 integrin interacts with TGF beta receptor II (T beta RII) through the beta 6 cytoplasmic domain and promotes Smad3 activation in prostate cancer (PrCa) cells. Another related alpha v integrin, alpha v beta 5, as well as the alpha v beta 6/3 integrin, which contains a chimeric form of beta 6 with a beta 3 cytoplasmic domain, do not associate with T beta RII and fail to show similar responses. We provide evidence that alpha v beta 6 is required for up-regulation of MMP2 by TGF beta 1 through a Smad3-mediated transcriptional programme in PrCa cells. The functional relevance of these results is underscored by the finding that alpha v beta 6 modulates cell migration in an MMP2-dependent manner on an alpha v beta 6-specific ligand, latency-associated peptide (LAP)-TGF beta. Overall, these mechanistic studies establish that expression of a single integrin, alpha v beta 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 beta 1-alpha v beta 6-MMP2 signalling pathway that, given TGF beta 1 pro-metastatic activity, may have profound implications for PrCa therapy.