期刊
JOURNAL OF CELL BIOLOGY
卷 216, 期 5, 页码 1455-1471出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201609073
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资金
- Chinese Ministry of Science and Technology [2016YFC1302103, 2015CB553906, 2013CB910501]
- National Natural Science Foundation of China [81230051, 81472734, 31170711, 81300563, 81670626]
- Natural Science Foundation of Beijing Municipality [7120002, 7171005]
- Ministry of Education of China
- Peking University [BMU20120314, BMU20130364]
- Leading Academic Discipline Project of the Beijing Education Bureau
- Peking-Tsinghua Center for Life Sciences
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 aIIb beta 3 integrin activation in Chinese hamster ovary cells and beta 1 integrin activation in fibroblasts. Enhanced activation of beta 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.
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