Neumann Andrew J, Prekeris Rytis
Department of Cell and Developmental Biology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Front Cell Dev Biol. 2023 Sep 6;11:1268922. doi: 10.3389/fcell.2023.1268922. eCollection 2023.
The regulation of machinery involved in cell migration is vital to the maintenance of proper organism function. When migration is dysregulated, a variety of phenotypes ranging from developmental disorders to cancer metastasis can occur. One of the primary structures involved in cell migration is the actin cytoskeleton. Actin assembly and disassembly form a variety of dynamic structures which provide the pushing and contractile forces necessary for cells to properly migrate. As such, actin dynamics are tightly regulated. Classically, the Rho family of GTPases are considered the major regulators of the actin cytoskeleton during cell migration. Together, this family establishes polarity in the migrating cell by stimulating the formation of various actin structures in specific cellular locations. However, while the Rho GTPases are acknowledged as the core machinery regulating actin dynamics and cell migration, a variety of other proteins have become established as modulators of actin structures and cell migration. One such group of proteins is the Rab40 family of GTPases, an evolutionarily and functionally unique family of Rabs. Rab40 originated as a single protein in the bilaterians and, through multiple duplication events, expanded to a four-protein family in higher primates. Furthermore, unlike other members of the Rab family, Rab40 proteins contain a C-terminally located suppressor of cytokine signaling (SOCS) box domain. Through the SOCS box, Rab40 proteins interact with Cullin5 to form an E3 ubiquitin ligase complex. As a member of this complex, Rab40 ubiquitinates its effectors, controlling their degradation, localization, and activation. Because substrates of the Rab40/Cullin5 complex can play a role in regulating actin structures and cell migration, the Rab40 family of proteins has recently emerged as unique modulators of cell migration machinery.
参与细胞迁移的机制调控对于维持机体正常功能至关重要。当迁移失调时，可能会出现从发育障碍到癌症转移等多种表型。细胞迁移涉及的主要结构之一是肌动蛋白细胞骨架。肌动蛋白的组装和解聚形成各种动态结构，为细胞正常迁移提供所需的推力和收缩力。因此，肌动蛋白动力学受到严格调控。传统上，Rho家族的小GTP酶被认为是细胞迁移过程中肌动蛋白细胞骨架的主要调节因子。这个家族共同通过在特定细胞位置刺激各种肌动蛋白结构的形成，在迁移细胞中建立极性。然而，虽然Rho小GTP酶被公认为调节肌动蛋白动力学和细胞迁移的核心机制，但多种其他蛋白质已被确认为肌动蛋白结构和细胞迁移的调节因子。其中一类蛋白质是Rab40家族的小GTP酶，这是一个在进化和功能上独特的Rab家族。Rab40起源于两侧对称动物中的单一蛋白质，并通过多次复制事件，在高等灵长类动物中扩展为一个由四种蛋白质组成的家族。此外，与Rab家族的其他成员不同，Rab40蛋白含有位于C末端的细胞因子信号抑制因子（SOCS）盒结构域。通过SOCS盒，Rab40蛋白与Cullin5相互作用形成E3泛素连接酶复合物。作为该复合物的成员，Rab40使它的效应器泛素化，控制它们的降解、定位和激活。由于Rab40/Cullin5复合物的底物可以在调节肌动蛋白结构和细胞迁移中发挥作用，Rab40家族蛋白最近已成为细胞迁移机制的独特调节因子。
