| First Author | Wei X | Year | 2017 |
| Journal | J Cell Biol | Volume | 216 |
| Issue | 5 | Pages | 1455-1471 |
| PubMed ID | 28408404 | Mgi Jnum | J:246266 |
| Mgi Id | MGI:5920390 | Doi | 10.1083/jcb.201609073 |
| Citation | Wei X, et al. (2017) Smurf1 inhibits integrin activation by controlling Kindlin-2 ubiquitination and degradation. J Cell Biol 216(5):1455-1471 |
| abstractText | Integrin activation is an indispensable step for various integrin-mediated biological functions. Kindlin-2 is known to coactivate integrins with Talin; however, molecules that restrict integrin activation are elusive. Here, we demonstrate that the E3 ubiquitin ligase Smurf1 controls the amount of Kindlin-2 protein in cells and hinders integrin activation. Smurf1 interacts with and promotes Kindlin-2 ubiquitination and degradation. Smurf1 selectively mediates degradation of Kindlin-2 but not Talin, leading to inhibition of alphaIIbbeta3 integrin activation in Chinese hamster ovary cells and beta1 integrin activation in fibroblasts. Enhanced activation of beta1 integrin was found in Smurf1-knockout mouse embryonic fibroblasts, which correlates with an increase in Kindlin-2 protein levels. Similarly, a reciprocal relationship between Smurf1 and Kindlin-2 protein levels is found in tissues from colon cancer patients, suggesting that Smurf1 mediates Kindlin-2 degradation in vivo. Collectively, we demonstrate that Smurf1 acts as a brake for integrin activation by controlling Kindlin-2 protein levels, a new mechanism that permits precise modulation of integrin-mediated cellular functions. |
