Evidence that β3 integrin-induced Rac activation involves the calpain-dependent formation of integrin clusters that are distinct from the focal complexes and focal adhesions that form as Rac and RhoA become active
Evidence that β3 integrin-induced Rac activation involves the calpain-dependent formation of integrin clusters that are distinct from the focal complexes and focal adhesions that form as Rac and RhoA become active
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DOI：
10.1083/jcb.151.3.685
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发表时间：
2000-10-30
影响因子：
7.8
通讯作者：
Fox, JEB
中科院分区：
文献类型：
--
作者：
Bialkowska, K;Kulkarni, S;Fox, JEB
整合素与细胞外基质的相互作用导致信号传递、细胞骨架重组和细胞行为的改变。虽然已知许多信号传导分子在Rac诱导的局灶性复合物或Rho诱导的局灶性粘连内被激活，但整合素介导的粘连导致Rac和Rho激活的方式尚不清楚。在本研究中，我们确定了Rac激活上游形成的整合素簇。这些簇含有Rac结合蛋白，并且似乎参与Rac活化。整联蛋白簇含有钙蛋白酶和钙蛋白酶切割的β 3整联蛋白，而一旦Rac和Rho被激活就形成的局灶性复合物和局灶性粘连则没有。此外，整联蛋白簇的形成依赖于钙蛋白酶。相比之下，虽然Rac和Rho-GTP酶依赖于钙蛋白酶的激活，形成局灶性复合物和局灶性粘连的组成性活性的Rac或Rho，分别发生，即使钙蛋白酶抑制剂存在。总之，这些数据与整合素诱导的Rac活化需要形成整合素簇的模型一致。簇以钙蛋白酶依赖性方式形成，包含钙蛋白酶、钙蛋白酶切割的整联蛋白和Rac结合蛋白。一旦Rac被激活，其他整合素信号传导复合物通过钙蛋白酶非依赖性机制形成。
Interaction of integrins with the extracellular matrix leads to transmission of signals, cytoskeletal reorganizations, and changes in cell behavior. While many signaling molecules are known to be activated within Rac-induced focal complexes or Rho-induced focal adhesions, the way in which integrin-mediated adhesion leads to activation of Rac and Rho is not known. In the present study, we identified clusters of integrin that formed upstream of Rac activation. These clusters contained a Rac-binding protein(s) and appeared to be involved in Rac activation. The integrin clusters contained calpain and calpain-cleaved beta3 integrin, while the focal complexes and focal adhesions that formed once Rac and Rho were activated did not. Moreover, the integrin clusters were dependent on calpain for their formation. In contrast, while Rac- and Rho-GTPases were dependent on calpain for their activation, formation of focal complexes and focal adhesions by constitutively active Rac or Rho, respectively, occurred even when calpain inhibitors were present. Taken together, these data are consistent with a model in which integrin-induced Rac activation requires the formation of integrin clusters. The clusters form in a calpain-dependent manner, contain calpain, calpain-cleaved integrin, and a Rac binding protein(s). Once Rac is activated, other integrin signaling complexes are formed by a calpain-independent mechanism(s).