Tumor Biophysics Laboratory, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007 Salamanca, Spain.
Tumour-Stroma Signalling Laboratory, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007 Salamanca, Spain.
Genes (Basel). 2021 May 27;12(6):819. doi: 10.3390/genes12060819.
Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway and the PI3K/AKT pathways, respectively. However, the myriad proteins close to the plasma membrane that activate or inhibit Ras make it a major regulator of many apparently unrelated pathways. On the other hand, Rho is weakly oncogenic by itself, but it critically regulates microfilament dynamics; that is, actin polymerization, disassembly and contraction. Polymerization is driven mainly by the Arp2/3 complex and formins, whereas contraction depends on myosin mini-filament assembly and activity. These two pathways intersect at numerous points: from Ras-dependent triggering of Rho activators, some of which act through PI3K, to mechanical feedback driven by actomyosin action. Here, we describe the main points of connection between the Ras and Rho pathways as they coordinately drive oncogenic transformation. We emphasize the biochemical crosstalk that drives actomyosin contraction driven by Ras in a Rho-dependent manner. We also describe possible routes of mechanical feedback through which myosin II activation may control Ras/Rho activation.
Ras 和 Rho 蛋白是 GTP 调节的分子开关，可控制真核细胞中的多种信号通路。Ras 是最早被鉴定的致癌基因之一，似乎在许多人类癌症中发生了突变。它主要通过 MAPK 通路和 PI3K/AKT 通路分别促进增殖和存活。然而，靠近质膜的大量激活或抑制 Ras 的蛋白质使其成为许多看似不相关通路的主要调节剂。另一方面，Rho 本身的致癌性较弱，但它对微丝动力学（即肌动蛋白聚合、解聚和收缩）具有关键调节作用。聚合主要由 Arp2/3 复合物和formin 驱动，而收缩取决于肌球蛋白微丝组装和活性。这两条通路在许多点相交：从 Ras 依赖性触发 Rho 激活剂开始，其中一些通过 PI3K 起作用，到由肌动球蛋白作用驱动的机械反馈。在这里，我们描述了 Ras 和 Rho 通路之间协调驱动致癌转化的主要连接点。我们强调了 Ras 以 Rho 依赖性方式驱动肌球蛋白收缩的生化串扰。我们还描述了可能的机械反馈途径，通过该途径肌球蛋白 II 的激活可能控制 Ras/Rho 的激活。
