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      Probing the mechanical landscape – new insights into podosome architecture and mechanics

      1 , 2 , 3 , 3
      Journal of Cell Science
      The Company of Biologists

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          The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function.

          Podosomes and invadopodia are actin-based dynamic protrusions of the plasma membrane of metazoan cells that represent sites of attachment to - and degradation of - the extracellular matrix. The key proteins in these structures include the actin regulators cortactin and neural Wiskott-Aldrich syndrome protein (N-WASP), the adaptor proteins Tyr kinase substrate with four SH3 domains (TKS4) and Tyr kinase substrate with five SH3 domains (TKS5), and the metalloprotease membrane type 1 matrix metalloprotease (MT1MMP; also known as MMP14). Many cell types can produce these structures, including invasive cancer cells, vascular smooth muscle and endothelial cells, and immune cells such as macrophages and dendritic cells. Recently, progress has been made in our understanding of the regulatory and functional aspects of podosome and invadopodium biology and their role in human disease.
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            Focal Contacts as Mechanosensors

            The transition of cell–matrix adhesions from the initial punctate focal complexes into the mature elongated form, known as focal contacts, requires GTPase Rho activity. In particular, activation of myosin II–driven contractility by a Rho target known as Rho-associated kinase (ROCK) was shown to be essential for focal contact formation. To dissect the mechanism of Rho-dependent induction of focal contacts and to elucidate the role of cell contractility, we applied mechanical force to vinculin-containing dot-like adhesions at the cell edge using a micropipette. Local centripetal pulling led to local assembly and elongation of these structures and to their development into streak-like focal contacts, as revealed by the dynamics of green fluorescent protein–tagged vinculin or paxillin and interference reflection microscopy. Inhibition of Rho activity by C3 transferase suppressed this force-induced focal contact formation. However, constitutively active mutants of another Rho target, the formin homology protein mDia1 (Watanabe, N., T. Kato, A. Fujita, T. Ishizaki, and S. Narumiya. 1999. Nat. Cell Biol. 1:136–143), were sufficient to restore force-induced focal contact formation in C3 transferase-treated cells. Force-induced formation of the focal contacts still occurred in cells subjected to myosin II and ROCK inhibition. Thus, as long as mDia1 is active, external tension force bypasses the requirement for ROCK-mediated myosin II contractility in the induction of focal contacts. Our experiments show that integrin-containing focal complexes behave as individual mechanosensors exhibiting directional assembly in response to local force.
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              Analysis of the myosinII-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation

              Focal adhesions (FAs) undergo myosinII-mediated maturation wherein they grow and change composition to modulate integrin signaling for cell migration, growth and differentiation. To determine how FA composition is modulated by myosinII activity, we performed proteomic analysis of isolated FAs and compared protein abundance in FAs from cells with and without myosinII inhibition. We identified FA 905 proteins, 459 of which changed in FA abundance with myosinII inhibition, defining the myosinII-responsive FA proteome. FA abundance of 73% of proteins was enhanced by contractility, including those involved in Rho-mediated FA maturation and endocytosis- and calpain-dependent FA disassembly. 27% of proteins, including those involved in Rac-mediated lamellipodial protrusion, were enriched in FA by myosinII inhibition, establishing for the first time negative regulation of FA protein recruitment by contractility. We focused on the Rac guanine nucleotide exchange factor, β-PIX, documenting its role in negative regulation of FA maturation and promotion of lamellipodial protrusion, FA turnover to drive cell migration.
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                Author and article information

                Journal
                Journal of Cell Science
                J Cell Sci
                The Company of Biologists
                0021-9533
                1477-9137
                December 13 2019
                December 15 2019
                December 13 2019
                December 15 2019
                : 132
                : 24
                : jcs236828
                Affiliations
                [1 ]Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26-28, 6525 GA, Nijmegen, The Netherlands
                [2 ]Institut für medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
                [3 ]Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UMR5089, 205 route de Narbonne, BP64182 31077 Toulouse, France
                Article
                10.1242/jcs.236828
                31836688
                7128b06b-7c9a-42ab-a913-cabcbb389547
                © 2019

                http://www.biologists.com/user-licence-1-1

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