Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase
Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase
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DOI：
10.4049/jimmunol.179.4.2397
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Matsuda, Tadashi
中科院分区：
文献类型：
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作者：
Sekine, Yuichi;Tsuji, Satoshi;Matsuda, Tadashi
信号转导接合蛋白-2(STAP-2)是最近发现的一种接合蛋白，在其C-末端含有Pleckstrin同源和Src同源2结构域以及YXXQ基序。我们以前的研究表明，STAP-2与STAT3和STAT5结合，并调节它们的信号通路。在本研究中，我们发现PMA治疗后STAP-2缺陷的脾细胞或T细胞与纤维连接蛋白的粘附性增强，并且STAP-2缺陷的T细胞含有增加的粘着斑激酶(FAK)的蛋白含量。此外，STAP-2的过表达导致Jurkat T细胞FAK蛋白含量显著降低，整合素通过降解FAK介导T细胞与纤维连接蛋白的黏附。关于这种作用的机制，我们发现STAP-2与FAK结合并促进其降解，蛋白酶体抑制剂阻断FAK的降解，STAP-2招募内源性E3泛素连接酶Cb1到FAK。这些结果揭示了一种新的调控机制，即通过STAP-2直接与FAK相互作用并降解FAK，从而调节整合素介导的T细胞信号转导。
Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin homology- and Src homology 2-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies demonstrated that STAP-2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, we find that STAP-2-deficient splenocytes or T cells exhibit enhanced cell adhesion to fibronectin after PMA treatment, and that STAP-2-deficient T cells contain the increased protein contents of focal adhesion kinase (FAK). Furthermore, overexpression of STAP-2 induces a dramatic decrease in the protein contents of FAK and integrin-mediated T cell adhesion to fibronectin in Jurkat T cells via the degradation of FAK. Regarding the mechanism for this effect, we found that STAP-2 associates with FAK and enhances its degradation, proteasome inhibitors block FAK degradation, and STAP-2 recruits an endogenous E3 ubiquitin ligase, Cbl, to FAK. These results reveal a novel regulation mechanism for integrin-mediated signaling in T cells via STAP-2, which directly interacts with and degrades FAK.