Smurf1 inhibits integrin activation by controlling Kindlin-2 ubiquitination and degradation.
Smurf1 inhibits integrin activation by controlling Kindlin-2 ubiquitination and degradation.
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Smurf1 通过控制 Kindlin-2 泛素化和降解来抑制整合素激活
DOI：
10.1083/jcb.201609073
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发表时间：
2017-05-01
期刊：
影响因子：
--
通讯作者：
Zhang H
中科院分区：
文献类型：
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作者：
Wei X;Wang X;Zhan J;Chen Y;Fang W;Zhang L;Zhang H
整合素活化是整合素介导的各种生物学功能的不可或缺的步骤。Kindlin-2已知与Talin共活化整联蛋白;然而，限制整联蛋白活化的分子是难以捉摸的。在这里，我们证明了E3泛素连接酶Smurf 1控制细胞中Kindlin-2蛋白的量，并阻碍整合素活化。Smurf 1与Kindlin-2相互作用并促进Kindlin-2泛素化和降解。Smurf 1选择性介导Kindlin-2而非Talin的降解，导致抑制中国仓鼠卵巢细胞中IIb 3整合素活化和成纤维细胞中1整合素活化。在Smurf 1基因敲除小鼠胚胎成纤维细胞中发现1整合素的激活增强，这与Kindlin-2蛋白水平的增加相关。类似地，在结肠癌患者的组织中发现Smurf 1和Kindlin-2蛋白水平之间的相互关系，表明Smurf 1介导体内Kindlin-2降解。总的来说，我们证明了Smurf 1通过控制Kindlin-2蛋白水平作为整合素激活的制动器，这是一种允许精确调节整合素介导的细胞功能的新机制。
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 &agr;IIb&bgr;3 integrin activation in Chinese hamster ovary cells and &bgr;1 integrin activation in fibroblasts. Enhanced activation of &bgr;1 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.