Department of Biosciences, University of Oslo, Oslo, Norway.
Centre for Immune Regulation, University of Oslo, Oslo, Norway.
Cell Mol Life Sci. 2019 Jul;76(13):2593-2614. doi: 10.1007/s00018-019-03057-w. Epub 2019 Mar 4.
Rab proteins are master regulators of intracellular membrane trafficking, but they also contribute to cell division, signaling, polarization, and migration. The majority of the works describing the mechanisms used by Rab proteins to regulate cell motility involve intracellular transport of key molecules important for migration. Interestingly, a few studies indicate that Rabs can modulate the activity of Rho GTPases, important regulators for the cytoskeleton rearrangements, but the mechanisms behind this crosstalk are still poorly understood. In this work, we identify Rab6 as a negative regulator of cell migration in vitro and in vivo. We show that the loss of Rab6 promotes formation of actin protrusions and influences actomyosin dynamics by upregulating Cdc42 activity and downregulating myosin II phosphorylation. We further provide the molecular mechanism behind this regulation demonstrating that Rab6 interacts with both Cdc42 and Trio, a GEF for Cdc42. In sum, our results uncover a mechanism used by Rab proteins to ensure spatial regulation of Rho GTPase activity for coordination of cytoskeleton rearrangements required in migrating cells.
Rab 蛋白是细胞内膜运输的主要调节因子，但它们也参与细胞分裂、信号转导、极化和迁移。大多数描述 Rab 蛋白调节细胞迁移所使用的机制的工作都涉及对迁移至关重要的关键分子的细胞内运输。有趣的是，有几项研究表明 Rab 可以调节 Rho GTPases 的活性，Rho GTPases 是细胞骨架重排的重要调节剂，但这种串扰的机制仍知之甚少。在这项工作中，我们确定 Rab6 是体外和体内细胞迁移的负调节剂。我们表明，Rab6 的缺失促进肌动蛋白突起的形成，并通过上调 Cdc42 活性和下调肌球蛋白 II 磷酸化来影响肌动球蛋白动力学。我们进一步提供了这种调节背后的分子机制，表明 Rab6 与 Cdc42 和 Trio（Cdc42 的 GEF）相互作用。总之，我们的结果揭示了 Rab 蛋白用于确保 Rho GTPase 活性的空间调节的机制，以协调迁移细胞中所需的细胞骨架重排。
