Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain.
Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, Campus Unamuno, Salamanca, Spain
Mol Cell Biol. 2014 Sep 15;34(18):3388-406. doi: 10.1128/MCB.00347-14. Epub 2014 Jun 30.
Rac1 regulates lamellipodium formation, myosin II-dependent contractility, and focal adhesions during cell migration. While the spatiotemporal assembly of those processes is well characterized, the signaling mechanisms involved remain obscure. We report here that the cytoskeleton-related Coronin1A and -1B proteins control a myosin II inactivation-dependent step that dictates the intracellular dynamics and cytoskeletal output of active Rac1. This step is signaling-branch specific, since it affects the functional competence of active Rac1 only when forming complexes with downstream ArhGEF7 and Pak proteins in actomyosin-rich structures. The pathway is used by default unless Rac1 is actively rerouted away from the structures by upstream activators and signals from other Rho GTPases. These results indicate that Coronin1 proteins are at the center of a regulatory hub that coordinates Rac1 activation, effector exchange, and the F-actin organization state during cell signaling. Targeting this route could be useful to hamper migration of cancer cells harboring oncogenic RAC1 mutations.
Rac1 调节细胞迁移过程中的片状伪足形成、肌球蛋白 II 依赖性收缩和黏附斑。虽然这些过程的时空组装已经得到很好的描述，但涉及的信号机制仍不清楚。我们在这里报告，细胞骨架相关的 Coronin1A 和 Coronin1B 蛋白控制肌球蛋白 II 失活依赖性步骤，该步骤决定了活性 Rac1 的细胞内动力学和细胞骨架输出。该步骤是信号分支特异性的，因为只有当它与下游的 ArhGEF7 和 Pak 蛋白在富含肌动球蛋白的结构中形成复合物时，它才会影响活性 Rac1 的功能能力。除非 Rac1 被上游激活剂和其他 Rho GTPase 的信号主动重新路由离开这些结构，否则该途径是默认使用的。这些结果表明，Coronin1 蛋白是一个调节中心的核心，该中心在细胞信号传导过程中协调 Rac1 的激活、效应物交换和 F-actin 组织状态。靶向该途径可能有助于阻止携带致癌性 RAC1 突变的癌细胞的迁移。
