The abl-related gene tyrosine kinase acts through p190RhoGAP to inhibit actomyosin Contractility and regulate focal adhesion dynamics upon adhesion to fibronectin
The abl-related gene tyrosine kinase acts through p190RhoGAP to inhibit actomyosin Contractility and regulate focal adhesion dynamics upon adhesion to fibronectin
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DOI：
10.1091/mbc.e07-01-0075
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发表时间：
2007-10-01
影响因子：
3.3
通讯作者：
Koleske, Anthony J.
中科院分区：
文献类型：
--
作者：
Peacock, Justin G.;Miller, Ann L.;Koleske, Anthony J.
在迁移的细胞中，肌动蛋白聚合促进前缘的突出，而肌动球蛋白收缩性促进净细胞体移位。虽然他们促进F-肌动蛋白依赖性突起的细胞周边后，粘附到纤连蛋白（FN），抗体1家族激酶抑制FN上的细胞迁移。我们提供的证据表明，抗体1相关基因（精氨酸/抗体12）激酶抑制成纤维细胞迁移衰减肌动球蛋白收缩和调节局灶性粘附动力学。arg（-/-）成纤维细胞以比野生型（wt）细胞更快的平均速度迁移，而这些细胞中的Arg再表达减慢迁移。令人惊讶的是，更快迁移的arg（-/-）成纤维细胞具有更突出的F-肌动蛋白应力纤维和粘着斑，并且相对于wt细胞表现出增加的肌动球蛋白收缩性。有趣的是，精氨酸需要不同的功能域来抑制局灶性粘连和肌动球蛋白收缩性。激酶结构域的精氨酸N-末端的一半可以通过RhoA抑制剂p190 RhoGAP减弱应力纤维的形成和细胞收缩性。然而，精氨酸需要其激酶活性和其细胞因子结合C-末端的一半，以充分抑制局灶性粘连。虽然局灶性粘附在arg（-/-）细胞的后缘中不能有效地翻转，但arg（-/-）细胞的收缩性增加将粘附从基底上撕裂，从而允许在这些细胞中观察到更快的迁移。总之，我们的数据强烈表明，精氨酸抑制细胞迁移，限制肌动球蛋白收缩性和调节其耦合基板通过局灶性粘连。
in migrating cells, actin polymerization promotes protrusion of the leading edge, whereas actomyosin contractility powers net cell body translocation. Although they promote F-actin-dependent protrusions of the cell periphery upon adhesion to fibronectin (FN), Ab1 family kinases inhibit cell migration on FN. We provide evidence here that the Ab1-related gene (Arg/Ab12) kinase inhibits fibroblast migration by attenuating actomyosin contractility and regulating focal adhesion dynamics. arg(-/-) fibroblasts migrate at faster average speeds than wild-type (wt) cells, whereas Arg re-expression in these cells slows migration. Surprisingly, the faster migrating arg(-/-) fibroblasts have more prominent F-actin stress fibers and focal adhesions and exhibit increased actomyosin contractility relative to wt cells. Interestingly, Arg requires distinct functional domains to inhibit focal adhesions and actomyosin contractility. The kinase domain-containing Arg N-terminal half can act through the RhoA inhibitor p190RhoGAP to attenuate stress fiber formation and cell contractility. However, Arg requires both its kinase activity and its cytoskeleton-binding C-terminal half to fully inhibit focal adhesions. Although focal adhesions do not turn over efficiently in the trailing edge of arg(-/-) cells, the increased contractility of arg(-/-) cells tears the adhesions from the substrate, allowing for the faster migration observed in these cells. Together, our data strongly suggest that Arg inhibits cell migration by restricting actomyosin contractility and regulating its coupling to the substrate through focal adhesions.