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Smurf1通过控制Kindlin-2的泛素化和降解来抑制整合素激活。

Smurf1 inhibits integrin activation by controlling Kindlin-2 ubiquitination and degradation.

作者信息

Wei Xiaofan, Wang Xiang, Zhan Jun, Chen Yuhan, Fang Weigang, Zhang Lingqiang, Zhang Hongquan

机构信息

Department of Human Anatomy, Histology, and Embryology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China.

State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.

出版信息

J Cell Biol. 2017 May 1;216(5):1455-1471. doi: 10.1083/jcb.201609073. Epub 2017 Apr 13.

DOI:10.1083/jcb.201609073
PMID:28408404
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5412569/
Abstract

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 αIIbβ3 integrin activation in Chinese hamster ovary cells and β1 integrin activation in fibroblasts. Enhanced activation of β1 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.

摘要

整合素激活是各种整合素介导的生物学功能中不可或缺的一步。已知Kindlin-2与Talin共同激活整合素；然而，限制整合素激活的分子尚不清楚。在此，我们证明E3泛素连接酶Smurf1控制细胞中Kindlin-2蛋白的量并阻碍整合素激活。Smurf1与Kindlin-2相互作用并促进其泛素化和降解。Smurf1选择性地介导Kindlin-2而非Talin的降解，导致中国仓鼠卵巢细胞中αIIbβ3整合素激活以及成纤维细胞中β1整合素激活受到抑制。在Smurf1基因敲除的小鼠胚胎成纤维细胞中发现β1整合素的激活增强，这与Kindlin-2蛋白水平的增加相关。同样，在结肠癌患者的组织中发现Smurf1和Kindlin-2蛋白水平之间存在反向关系，表明Smurf1在体内介导Kindlin-2的降解。总体而言，我们证明Smurf1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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/588a0c98902a/JCB_201609073_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/d10611e5d496/JCB_201609073_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/41a4b6d02dc4/JCB_201609073_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/5e84404e8a53/JCB_201609073_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/e7267219c977/JCB_201609073_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/db2b46350446/JCB_201609073_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/dc309831156a/JCB_201609073_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/387b176998e5/JCB_201609073_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/588a0c98902a/JCB_201609073_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/d10611e5d496/JCB_201609073_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/41a4b6d02dc4/JCB_201609073_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/5e84404e8a53/JCB_201609073_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/e7267219c977/JCB_201609073_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/db2b46350446/JCB_201609073_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/dc309831156a/JCB_201609073_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/387b176998e5/JCB_201609073_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3665/5412569/588a0c98902a/JCB_201609073_Fig8.jpg

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