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      Myosin-II controls cellular branching morphogenesis and migration in 3D by minimizing cell surface curvature

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          In many cases cell function is intimately linked to cell shape control. We utilized endothelial cell branching morphogenesis as a model to understand the role of myosin-II in shape control of invasive cells migrating in 3D collagen gels. We applied principles of differential geometry and mathematical morphology to 3D image sets to parameterize cell branch structure and local cell surface curvature. We find that Rho/ROCK-stimulated myosin-II contractility minimizes cell-scale branching by recognizing and minimizing local cell surface curvature. Utilizing micro-fabrication to constrain cell shape identifies a positive feedback mechanism in which low curvature stabilizes myosin-II cortical association, where it acts to maintain minimal curvature. The feedback between myosin-II regulation by and control of curvature drives cycles of localized cortical myosin-II assembly and disassembly. These cycles in turn mediate alternating phases of directionally biased branch initiation and retraction to guide 3D cell migration.

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          Most cited references 18

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          Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase).

          The small GTPase Rho is implicated in physiological functions associated with actin-myosin filaments such as cytokinesis, cell motility, and smooth muscle contraction. We have recently identified and molecularly cloned Rho-associated serine/threonine kinase (Rho-kinase), which is activated by GTP Rho (Matsui, T., Amano, M., Yamamoto, T., Chihara, K., Nakafuku, M., Ito, M., Nakano, T., Okawa, K., Iwamatsu, A., and Kaibuchi, K. (1996) EMBO J. 15, 2208-2216). Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. Thus, it is likely that once Rho is activated, then it can interact with Rho-kinase and activate it. The activated Rho-kinase subsequently phosphorylates MLC. This may partly account for the mechanism by which Rho regulates cytokinesis, cell motility, or smooth muscle contraction.
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            Random versus directionally persistent cell migration.

            Directional migration is an important component of cell motility. Although the basic mechanisms of random cell movement are well characterized, no single model explains the complex regulation of directional migration. Multiple factors operate at each step of cell migration to stabilize lamellipodia and maintain directional migration. Factors such as the topography of the extracellular matrix, the cellular polarity machinery, receptor signalling, integrin trafficking, integrin co-receptors and actomyosin contraction converge on regulation of the Rho family of GTPases and the control of lamellipodial protrusions to promote directional migration.
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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.

                Author and article information

                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                16 December 2014
                26 January 2015
                February 2015
                01 August 2015
                : 17
                : 2
                : 137-147
                [1 ]Department of Cell Biology, Harvard Medical School, Boston, MA
                [2 ]Cell Biology and Physiology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda MD
                [3 ]Department of Biological Sciences, University of the Sciences, Philadelphia, PA
                [4 ]Department of Bioengineering, University of Pennsylvania, Philadelphia, PA
                [5 ]Department of Biomedical Engineering, Boston University, Boston, MA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA
                [6 ]Genetics and Developmental Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda MD
                Author notes
                [t ]Correspondence to: fischerr2@ 123456nhlbi.nih.gov , watermancm@ 123456nhlbi.nih.gov , Cell Biology and Physiology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Building 50 South Drive, Room 4537 MSC 8019, Bethesda Maryland 20892-8019. gaudenz.danuser@ 123456utsouthwestern.edu , Department of Cell Biology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390

                equal contribution.

                Current address: Image and Data Analysis Core, Harvard Medical School, Boston, MA


                Cell biology


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