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      Centrosome guides spatial activation of Rac to control cell polarization and directed cell migration

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          Abstract

          The centrosome acts as a controller by balancing the formation of centrosomal and acentrosomal microtubules, the modulation of focal adhesion signaling and the activation of local Rac1 at the cell front, which then coordinates cell polarization during directed cell migration.

          Abstract

          Directed cell migration requires centrosome-mediated cell polarization and dynamical control of focal adhesions (FAs). To examine how FAs cooperate with centrosomes for directed cell migration, we used centrosome-deficient cells and found that loss of centrosomes enhanced the formation of acentrosomal microtubules, which failed to form polarized structures in wound-edge cells. In acentrosomal cells, we detected higher levels of Rac1-guanine nucleotide exchange factor TRIO (Triple Functional Domain Protein) on microtubules and FAs. Acentrosomal microtubules deliver TRIO to FAs for Rac1 regulation. Indeed, centrosome disruption induced excessive Rac1 activation around the cell periphery via TRIO, causing rapid FA turnover, a disorganized actin meshwork, randomly protruding lamellipodia, and loss of cell polarity. This study reveals the importance of centrosomes to balance the assembly of centrosomal and acentrosomal microtubules and to deliver microtubule-associated TRIO proteins to FAs at the cell front for proper spatial activation of Rac1, FA turnover, lamillipodial protrusion, and cell polarization, thereby allowing directed cell migration.

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          Most cited references 54

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          Rho GTPases Control Polarity, Protrusion, and Adhesion during Cell Movement

          Cell movement is essential during embryogenesis to establish tissue patterns and to drive morphogenetic pathways and in the adult for tissue repair and to direct cells to sites of infection. Animal cells move by crawling and the driving force is derived primarily from the coordinated assembly and disassembly of actin filaments. The small GTPases, Rho, Rac, and Cdc42, regulate the organization of actin filaments and we have analyzed their contributions to the movement of primary embryo fibroblasts in an in vitro wound healing assay. Rac is essential for the protrusion of lamellipodia and for forward movement. Cdc42 is required to maintain cell polarity, which includes the localization of lamellipodial activity to the leading edge and the reorientation of the Golgi apparatus in the direction of movement. Rho is required to maintain cell adhesion during movement, but stress fibers and focal adhesions are not required. Finally, Ras regulates focal adhesion and stress fiber turnover and this is essential for cell movement. We conclude that the signal transduction pathways controlled by the four small GTPases, Rho, Rac, Cdc42, and Ras, cooperate to promote cell movement.
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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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              Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta.

              We describe here a signal transduction pathway controlling the establishment of mammalian cell polarity. Scratching a confluent monolayer of primary rat astrocytes leads to polarization of cells at the leading edge. The microtubule organizing center, the microtubule cytoskeleton, and the Golgi reorganize to face the new free space, and directed cell protrusion and migration specifically occur perpendicularly to the scratch. We show here that the interaction of integrins with extracellular matrix at the newly formed cell front leads to the activation and polarized recruitment of Cdc42, which in turn recruits and activates a cytoplasmic mPar6/PKCzeta complex. Localized PKCzeta activity, acting through the microtubule motor protein dynein, is required for all aspects of induced polarity in these cells.
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                Author and article information

                Journal
                Life Sci Alliance
                Life Sci Alliance
                lsa
                lsa
                Life Science Alliance
                Life Science Alliance LLC
                2575-1077
                8 February 2019
                February 2019
                8 February 2019
                : 2
                : 1
                Affiliations
                [1 ]Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
                [2 ]Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
                [3 ]Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan
                [4 ]Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
                Author notes
                Correspondence: jckuo@ 123456ym.edu.tw
                [*]

                Hung-Wei Cheng and Cheng-Te Hsiao contributed equally to this work

                Article
                LSA-2018-00135
                10.26508/lsa.201800135
                6369537
                30737247
                © 2019 Cheng et al.

                This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

                Product
                Funding
                Funded by: Taiwan Ministry of Science and Technology;
                Award ID: MOST 103-2628-B-010-003-MY4
                Award ID: MOST 106-2633-B-010-002-
                Award ID: MOST 107-2633-B-010-001-
                Award ID: MOST 107-2320-B-010-049-
                Award Recipient :
                Funded by: Taiwan Ministry of Science and Technology Academic Excellence Program;
                Award ID: MOST 107-2633-B-009-003
                Funded by: Cancer Progression Research Center (National Yang-Ming University) from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan;
                Funded by: Yen Tjing Ling Medical Foundation;
                Funded by: Ministry of Education’s “Aim for the Top University Plan.”;
                Categories
                Research Article
                Research Articles
                4

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