Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases.
Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases.
复制标题
整合素通过依赖Rho GTPases的机制来使线粒体功能进行信号转导。
DOI：
10.1083/jcb.200111028
复制
发表时间：
2002-07-22
影响因子：
7.8
通讯作者：
Werb, Zena
中科院分区：
文献类型：
--
作者：
Werner, Erica;Werb, Zena
我们在此显示，小GT3 Rac的瞬时激活，随后活性氧（ROS）升高，这是导致NFκB激活和胶原酶-1（CL-1）/基质金属蛋白酶-1在整合素介导的细胞形状改变后产生的信号转导级联反应中的必要早期步骤。我们的证据表明，这构成了一个新的机制，小GTP酶介导的ROS生产。活化的RhoA还诱导ROS产生并上调CL-1表达。阻止肌动蛋白细胞骨架重组的Rac突变体（L37）阻止了整合素诱导的CL-1表达，而在体外废除Rac与中性粒细胞NADPH膜氧化酶结合的突变（H26和N130）则没有。相反，ROS是由整合素诱导的线粒体功能变化产生的，这些变化被Bcl-2抑制，并涉及瞬时膜电位损失。显示线粒体膜电位的这种短暂降低的细胞已经致力于CL-1表达。这些结果揭示了一种新的信号转导机制，由整合素参与触发，其中整体线粒体代谢反应导致基因表达而不是凋亡。
We show here the transient activation of the small GTPase Rac, followed by a rise in reactive oxygen species (ROS), as necessary early steps in a signal transduction cascade that lead to NFκB activation and collagenase-1 (CL-1)/matrix metalloproteinase-1 production after integrin-mediated cell shape changes. We show evidence indicating that this constitutes a new mechanism for ROS production mediated by small GTPases. Activated RhoA also induced ROS production and up-regulated CL-1 expression. A Rac mutant (L37) that prevents reorganization of the actin cytoskeleton prevented integrin-induced CL-1 expression, whereas mutations that abrogate Rac binding to the neutrophil NADPH membrane oxidase in vitro (H26 and N130) did not. Instead, ROS were produced by integrin-induced changes in mitochondrial function, which were inhibited by Bcl-2 and involved transient membrane potential loss. The cells showing this transient decrease in mitochondrial membrane potential were already committed to CL-1 expression. These results unveil a new molecular mechanism of signal transduction triggered by integrin engagement where a global mitochondrial metabolic response leads to gene expression rather than apoptosis.