Berrier Allison L, Martinez Robert, Bokoch Gary M, LaFlamme Susan E
The Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208, USA.
J Cell Sci. 2002 Nov 15;115(Pt 22):4285-91. doi: 10.1242/jcs.00109.
Rac1 is a small Rho family GTPase that regulates changes in cell morphology associated with cell spreading and migration. Integrin-mediated adhesion is known to activate Rac1 and to regulate the interaction of Rac1 with downstream effectors. Currently, it is not clear how integrins signal Rac1 activation following cell adhesion. Integrin beta cytoplasmic domains (beta-tails) are known to be required for integrin-mediated cell spreading, and isolated beta tails expressed as tac-beta tail chimeras can inhibit cell spreading indicating that protein interactions with beta tails can regulate this process. Our recent studies demonstrated that the expression of constitutively activated Rac1 can restore cell spreading inhibited by tac beta tail chimeras, suggesting a role for Rac1 in the regulation of cell spreading by beta tails. Hence, we examined the role of beta tails in integrin activation of Rac1. By using recombinant wild-type and mutant integrin heterodimers, we demonstrate that integrin beta tails are required for adhesion to increase Rac1-GTP loading. We demonstrate that clustering tac-beta tail chimeras, on the surface of cells in suspension, activates Rac1. Thus, beta tails are not only required, but also sufficient for integrin-triggered Rac1 activation. Our findings indicate that integrin beta-tails are an important link between integrin engagement and Rac1 signaling, and that protein interactions initiated at beta tails are sufficient for integrins to regulate Rac1 activity.
Rac1是一种小的Rho家族GTP酶，可调节与细胞铺展和迁移相关的细胞形态变化。已知整合素介导的黏附可激活Rac1，并调节Rac1与下游效应器的相互作用。目前，尚不清楚细胞黏附后整合素如何信号传导激活Rac1。已知整合素β细胞质结构域（β尾）是整合素介导的细胞铺展所必需的，以tac-β尾嵌合体形式表达的分离β尾可抑制细胞铺展，这表明与β尾的蛋白质相互作用可调节这一过程。我们最近的研究表明，组成型激活的Rac1的表达可恢复被tac-β尾嵌合体抑制的细胞铺展，提示Rac1在β尾调节细胞铺展中起作用。因此，我们研究了β尾在整合素激活Rac1中的作用。通过使用重组野生型和突变型整合素异二聚体，我们证明整合素β尾是黏附增加Rac1-GTP负载所必需的。我们证明在悬浮细胞表面聚集tac-β尾嵌合体可激活Rac1。因此，β尾不仅是必需的，而且对于整合素触发的Rac1激活也是足够的。我们的发现表明，整合素β尾是整合素结合与Rac1信号传导之间的重要联系，并且在β尾起始的蛋白质相互作用足以使整合素调节Rac1活性。
