Novel aspects of signal transduction through Rho GTPases: cGMP, proteasomal degradation and mitochondrial homeostasis

自从1992年首次报道Rho GTP酶作为细胞骨架结构的调节因子以来，Rho GTP酶已成为直接或间接控制几乎所有细胞活动的关键信号成分。虽然有关Rho GTP酶的大部分功能信息来自于对Rho、Rac和CDC42亚家族的研究，但它们在趋化和细胞极性中的作用仍有许多方面有待确定。此外，对其他亚家族成员的了解要少得多，特别是最近发现的非典型GTP酶RhoBTB和Miro。通过Rho GTP酶传递信号的三个新方面将被研究。首先，它们在cGMP信号中的作用，因为Rho GTP酶似乎是导致cGMP产生和随后的肌球蛋白II组装的信号通路的一部分，以响应化学诱导剂和渗透胁迫。第二，RhoBTB蛋白RacA作为信号通路和蛋白酶体降解机制之间的纽带，BTB结构域作为依赖于cullin的泛素连接酶复合体的接头发挥作用。第三，Miro亚家族蛋白在细胞质中的信号事件和线粒体内稳态之间的联系作用。

Since the first reports in 1992 on their role as regulators of cytoskeletal structures, Rho GTPases have emerged as pivotal signaling components for the control, directly or indirectly, of almost all cellular activities. While most of the functional information on Rho GTPases has come from studies of Rho, Rac and Cdc42 subfamilies, there are still many aspects of their role in chemotaxis and cell polarity that remain to be established. In addition, much less is known about members of other subfamilies, in particular the recently discovered atypical GTPases RhoBTB and Miro. Three novel aspects of signaling through Rho GTPases will be investigated. First, their role on cGMP signaling, as Rho GTPases appear to be part of the signaling pathways that lead to cGMP production and subsequent myosin II assembly in response to chemoattractants and to osmotic stress. Second, the role of the RhoBTB protein RacA as a link between signaling pathways and the proteasomal degradation machinery, as BTB domains function as adaptors of cullin-dependent ubiquitin ligase complexes. Third, the role of proteins of the Miro subfamily as links between signaling events in the cytosol and mitochondrial homeostasis.