| First Author | Mise N | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 37 | Pages | 31393-405 |
| PubMed ID | 22778267 | Mgi Jnum | J:315058 |
| Mgi Id | MGI:6829816 | Doi | 10.1074/jbc.M112.357624 |
| Citation | Mise N, et al. (2012) Zyxin is a transforming growth factor-beta (TGF-beta)/Smad3 target gene that regulates lung cancer cell motility via integrin alpha5beta1. J Biol Chem 287(37):31393-405 |
| abstractText | Although TGF-beta acts as a tumor suppressor in normal tissues and in early carcinogenesis, these tumor suppressor effects are lost in advanced malignancies. Single cell migration and epithelial-mesenchymal transition (EMT), both of which are regulated by TGF-beta, are critical steps in mediating cancer progression. Here, we sought to identify novel direct targets of TGF-beta signaling in lung cancer cells and have indentified the zyxin gene as a target of Smad3-mediated TGF-beta1 signaling. Zyxin concentrates at focal adhesions and along the actin cytoskeleton; as such, we hypothesized that cytoskeletal organization, motility, and EMT in response to TGF-beta1 might be regulated by zyxin expression. We show that TGF-beta1 treatment of lung cancer cells caused rapid phospho-Smad3-dependent expression of zyxin. Zyxin expression was critical for the formation and integrity of cell adherens junctions. Silencing of zyxin decreased expression of the focal adhesion protein vasodilator-activated phospho-protein (VASP), although the formation and morphology of focal adhesions remained unchanged. Zyxin-depleted cells displayed significantly increased integrin alpha5beta1 levels, accompanied by enhanced adhesion to fibronectin and acquisition of a mesenchymal phenotype in response to TGF-beta1. Zyxin silencing led to elevated integrin alpha5beta1-dependent single cell motility. Importantly, these features are mirrored in the K-ras-driven mouse model of lung cancer. Here, lung tumors revealed decreased levels of both zyxin and phospho-Smad3 when compared with normal tissues. Our data thus demonstrate that zyxin is a novel functional target and effector of TGF-beta signaling in lung cancer. By regulating cell-cell junctions, integrin alpha5beta1 expression, and cell-extracellular matrix adhesion, zyxin may regulate cancer cell motility and EMT during lung cancer development and progression. |
