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      Rho GTPase signalling in cell migration

      review-article
      Current Opinion in Cell Biology
      Elsevier

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          Abstract

          Cells migrate in multiple different ways depending on their environment, which includes the extracellular matrix composition, interactions with other cells, and chemical stimuli. For all types of cell migration, Rho GTPases play a central role, although the relative contribution of each Rho GTPase depends on the environment and cell type. Here, I review recent advances in our understanding of how Rho GTPases contribute to different types of migration, comparing lamellipodium-driven versus bleb-driven migration modes. I also describe how cells migrate across the endothelium. In addition to Rho, Rac and Cdc42, which are well known to regulate migration, I discuss the roles of other less-well characterized members of the Rho family.

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          Most cited references84

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          Coordination of Rho GTPase activities during cell protrusion

          The GTPases Rac1, RhoA and Cdc42 act in concert to control cytoskeleton dynamics1-3. Recent biosensor studies have shown that all three GTPases are activated at the front of migrating cells4-7 and biochemical evidence suggests that they may regulate one another: Cdc42 can activate Rac18, and Rac1 and RhoA are mutually inhibitory9-12. However, their spatiotemporal coordination, at the seconds and single micron dimensions typical of individual protrusion events, remains unknown. Here, we examine GTPase coordination both through simultaneous visualization of two GTPase biosensors and using a “computational multiplexing” approach capable of defining the relationships between multiple protein activities visualized in separate experiments. We found that RhoA is activated at the cell edge synchronous with edge advancement, whereas Cdc42 and Rac1 are activated 2 μm behind the edge with a delay of 40 sec. This indicates that Rac1 and RhoA operate antagonistically through spatial separation and precise timing, and that RhoA plays a role in the initial events of protrusion, while Rac1 and Cdc42 activate pathways implicated in reinforcement and stabilization of newly expanded protrusions.
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            Steering cell migration: lamellipodium dynamics and the regulation of directional persistence.

            Membrane protrusions at the leading edge of cells, known as lamellipodia, drive cell migration in many normal and pathological situations. Lamellipodial protrusion is powered by actin polymerization, which is mediated by the actin-related protein 2/3 (ARP2/3)-induced nucleation of branched actin networks and the elongation of actin filaments. Recently, advances have been made in our understanding of positive and negative ARP2/3 regulators (such as the SCAR/WAVE (SCAR/WASP family verprolin-homologous protein) complex and Arpin, respectively) and of proteins that control actin branch stability (such as glial maturation factor (GMF)) or actin filament elongation (such as ENA/VASP proteins) in lamellipodium dynamics and cell migration. This Review highlights how the balance between actin filament branching and elongation, and between the positive and negative feedback loops that regulate these activities, determines lamellipodial persistence. Importantly, directional persistence, which results from lamellipodial persistence, emerges as a critical factor in steering cell migration.
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              Cdc42--the centre of polarity.

              All cell types polarize, at least transiently, during division or to generate specialized shapes and functions. This capacity extends from yeast to mammals, and it is now clear that many features of the molecular mechanisms controlling polarization are conserved in all eukaryotic cells. At the centre of the action is Cdc42, a small GTPase of the Rho family. Its activity is precisely controlled both temporally and spatially, and this can be achieved by a wide variety of extracellular cues in multicellular organisms. Moreover, although the functional characteristics of cell polarity are extremely variable (depending on the cell type and the biological context), Cdc42 has an amazing capacity to co-ordinate the control of multiple signal transduction pathways.
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                Author and article information

                Contributors
                Journal
                Curr Opin Cell Biol
                Curr. Opin. Cell Biol
                Current Opinion in Cell Biology
                Elsevier
                0955-0674
                1879-0410
                1 October 2015
                October 2015
                : 36
                : 103-112
                Affiliations
                [0005]Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK
                Article
                S0955-0674(15)00110-6
                10.1016/j.ceb.2015.08.005
                4728192
                26363959
                29fe1724-622b-4b23-a6d2-eddbf0206777
                © 2015 The Author

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Cell biology
                Cell biology

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