Rho GTPases: masters of cell migration

Abstract

Since their discovery in the late eighties, the role of Rho GTPases in the regulation of cell migration has been extensively studied and has mainly focused on the hallmark family members Rho, Rac, and Cdc42. Recent technological advances in cell biology, such as Rho-family GTPase activity biosensors, studies in 3D, and unbiased RNAi-based screens, have revealed an increasingly complex role for Rho GTPases during cell migration, with many inter-connected functions and a strong dependency on the physical and chemical properties of the surrounding environment. This review aims to give an overview of recent studies on the role of Rho-family GTPase members in the modulation of cell migration in different environments, and discuss future directions.

Keywords: Rho GTPases; cell migration; microenvironment.

Figure 1. Crosstalk between classical Rho-family GTPases regulates actin remodeling during cell migration. Rho promotes actomyosin contractility through ROCK-dependent phosphorylation, and subsequent inhibition, of MLC phosphatase MYPT. ROCK also phosphorylates LIMK, leading to inhibition of cofilin activity. Another effector of Rho is the formin mDia, which promotes actin polymerization during cell migration. Rho antagonizes Rac-mediated signaling through ROCK/contractility-dependent activation of the RacGAP ARHGAP22. Rac promotes actin polymerization and lamellopodia formation through activation of WAVE and PAK and controls directionality through recruitment of Arpin, which inhibits WAVE-dependent activation of Arp2/3. Rac also antagonizes Rho-mediated signaling through a WAVE-dependent mechanism, and through activation of Nox-depednent ROS production, which promotes activation of p190RhoGAP, leading to inhibition of Rho. Cdc42 connects with both Rac and Rho, promoting actomyosin contractility through activation of MRCK, which phosphorylates MTPT and induces filopodia formation via WASP-mediated activation of Arp2/3.

Figure 2. Interplay between atypical and classical Rho-family GTPases during cell migration. RhoD, Rnd1, Rnd3, and RhoJ antagonize the Rho-mediated actin remodelling during cell migration. In endothelial cells Rnd2 and Rnd3 promote RhoB-induced stress fiber formation. RhoD regulates the reorganization of actin through the activation of Arp2/3 and ZIPK. RhoG activates Rac by recruiting the ELMO/DOCK complex. RhoU promotes cell migration through activation of Rac, whereas RhoH antaintergonizes Rac-mediated actin reorganization and cell migration. RhoV also antagonizes cell migration by promoting PAK degradation. RhoF activates mDia and is involved in the targeting of active ROCK to the cell cortex.