Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration.
Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration.
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DOI：
10.1038/ncb1868
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发表时间：
2009-05
影响因子：
21.3
通讯作者：
Ginsberg, Mark H.
中科院分区：
文献类型：
--
作者：
Huang, Cai;Rajfur, Zenon;Yousefi, Nima;Chen, Zaozao;Jacobson, Ken;Ginsberg, Mark H.
细胞迁移是一个动态过程，需要对整合素激活以及粘着斑组装 - 拆卸进行时空调节。踝蛋白是一种肌动蛋白和β整合素尾部结合蛋白，对整合素激活和粘着斑形成至关重要。钙蛋白酶介导的踝蛋白切割在粘着斑周转中起关键作用；然而，踝蛋白头部（TH）结构域作为两种切割产物之一，刺激整合素激活，定位于粘着斑，并维持细胞边缘突起，这表明粘着斑拆卸需要在踝蛋白水解下游有额外的步骤。在此我们表明，TH比全长踝蛋白更紧密地结合Smurf1（一种参与细胞极性和迁移的E3泛素连接酶），并且这种相互作用导致TH泛素化和降解。TH是细胞周期蛋白依赖性激酶5（Cdk5，一种细胞迁移和癌症转移的调节因子）的底物。Cdk5在丝氨酸425位点磷酸化TH，抑制其与Smurf1的结合，从而阻止TH泛素化和降解。表达talS425A（其抵抗Cdk5磷酸化，从而增加其对Smurf1介导的泛素化的敏感性）导致广泛的粘着斑周转并抑制细胞迁移。因此，由钙蛋白酶切割踝蛋白产生的TH通过Smurf1介导的泛素化而降解；此外，Cdk5的磷酸化调节Smurf1与TH的结合，并以此方式控制TH周转和粘着稳定性，最终控制细胞迁移。
Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly-disassembly. Talin, an actin and β integrin tail-binding protein, is essential for integrin activation and focal adhesion formation. Calpain-mediated cleavage of talin plays a key role in focal adhesion turnover; however, the talin head (TH) domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions, and maintains cell edge protrusions, suggesting that additional steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that TH binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration, more tightly than full length talin and that this interaction leads to TH ubiquitination and degradation. TH was a substrate for Cdk5, a regulator of cell migration and cancer metastasis. Cdk5 phosphorylated TH at Ser425, inhibiting its binding to Smurf1, thus preventing TH ubiquitination and degradation. Expression of talS425A, which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitination, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, TH produced by calpain cleavage of talin, is degraded via Smurf1-mediated ubiquitination; moreover, phosphorylation by Cdk5 regulates Smurf1 binding to TH and, in this way, controls TH turnover and adhesion stability and, ultimately, cell migration.
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影响因子：
7.8
作者：
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作者：
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影响因子：
11.2
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影响因子：
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作者：
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