mTORC1通过激活Rho-ROCK信号调节胞质分裂
mTORC1 regulates cytokinesis through activation of Rho-ROCK signaling
摘要：
了解细胞协调其大小与分裂能力的机制长期以来一直吸引着生物学家的兴趣。雷帕霉素靶蛋白（TOR）通路越来越被认为是细胞大小的主要调节因子，但TOR活性如何与细胞周期偶联的知之甚少。在这里，我们确定mTOR复合物1（mTORC 1）通过激活Rho GTP酶-Rho激酶（ROCK）信号级联促进胞质分裂。mTORC 1信号转导的过度激活通过耗尽其任何负调节因子：TSC 1、TSC 2、PTEN或DEPTOR，以雷帕霉素敏感的方式诱导多倍体。mTORC 1过度活化介导的多倍化通过长时间但最终失败的脱落尝试发生，然后再融合。与ROCK 2过表达的作用类似，这些mTORC 1驱动的异常胞质分裂事件伴随着Rho-GTP负荷增加、广泛的质膜起泡和肌动蛋白-肌球蛋白收缩性增加，所有这些都可以通过mTORC 1或ROCK抑制来挽救。这些结果为胞质分裂期间存在新的mTORC 1-Rho-ROCK通路提供了证据，并表明mTORC 1可能在设定哺乳动物细胞分裂的大小方面发挥关键作用。
英文摘要：
Understanding the mechanisms by which cells coordinate their size with their ability to divide has long attracted the interest of biologists. The Target of Rapamycin (TOR) pathway is becoming increasingly recognized as a master regulator of cell size, however less is known how TOR activity might be coupled with the cell cycle. Here, we establish that mTOR complex 1 (mTORC1) promotes cytokinesis through activation of a Rho GTPase-Rho Kinase (ROCK) signaling cascade. Hyperactivation of mTORC1 signaling by depletion of any of its negative regulators: TSC1, TSC2, PTEN, or DEPTOR, induces polyploidy in a rapamycin-sensitive manner. mTORC1 hyperactivation-mediated polyploidization occurs by a prolonged, but ultimately failed attempt at abcission followed by re-fusion. Similar to the effects of ROCK2 overexpression, these mTORC1-driven aberrant cytokinesis events are accompanied by increased Rho-GTP loading, extensive plasma membrane blebbing, and increased actin-myosin contractility, all of which can be rescued by either mTORC1 or ROCK inhibition. These results provide evidence for the existence of a novel mTORC1-Rho-ROCK pathway during cytokinesis and suggest that mTORC1 might play a critical role in setting the size at which a mammalian cell divides.
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