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      Epithelial junctions and Rho family GTPases: the zonular signalosome

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          Abstract

          The establishment and maintenance of epithelial cell-cell junctions is crucially important to regulate adhesion, apico-basal polarity and motility of epithelial cells, and ultimately controls the architecture and physiology of epithelial organs. Junctions are supported, shaped and regulated by cytoskeletal filaments, whose dynamic organization and contractility are finely tuned by GTPases of the Rho family, primarily RhoA, Rac1 and Cdc42. Recent research has identified new molecular mechanisms underlying the cross-talk between these GTPases and epithelial junctions. Here we briefly summarize the current knowledge about the organization, molecular evolution and cytoskeletal anchoring of cell-cell junctions, and we comment on the most recent advances in the characterization of the interactions between Rho GTPases and junctional proteins, and their consequences with regards to junction assembly and regulation of cell behavior in vertebrate model systems. The concept of “zonular signalosome” is proposed, which highlights the close functional relationship between proteins of zonular junctions ( zonulae occludentes and adhaerentes) and the control of cytoskeletal organization and signaling through Rho GTPases, transcription factors, and their effectors.

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          Most cited references162

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          alpha-Catenin as a tension transducer that induces adherens junction development.

          Adherens junctions (AJs), which are organized by adhesion proteins and the underlying actin cytoskeleton, probably sense pulling forces from adjacent cells and modulate opposing forces to maintain tissue integrity, but the regulatory mechanism remains unknown at the molecular level. Although the possibility that alpha-catenin acts as a direct linker between the membrane and the actin cytoskeleton for AJ formation and function has been minimized, here we show that alpha-catenin recruits vinculin, another main actin-binding protein of AJs, through force-dependent changes in alpha-catenin conformation. We identified regions in the alpha-catenin molecule that are required for its force-dependent binding of vinculin by introducing mutant alpha-catenin into cells and using in vitro binding assays. Fluorescence recovery after photobleaching analysis for alpha-catenin mobility and the existence of an antibody recognizing alpha-catenin in a force-dependent manner further supported the notion that alpha-catenin is a tension transducer that translates mechanical stimuli into a chemical response, resulting in AJ development.
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            Adherens junctions: from molecules to morphogenesis.

            How adhesive interactions between cells generate and maintain animal tissue structure remains one of the most challenging and long-standing questions in cell and developmental biology. Adherens junctions (AJs) and the cadherin-catenin complexes at their core are therefore the subjects of intense research. Recent work has greatly advanced our understanding of the molecular organization of AJs and how cadherin-catenin complexes engage actin, microtubules and the endocytic machinery. As a result, we have gained important insights into the molecular mechanisms of tissue morphogenesis.
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              Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton.

              Regulation of the actin cytoskeleton by microtubules is mediated by the Rho family GTPases. However, the molecular mechanisms that link microtubule dynamics to Rho GTPases have not, as yet, been identified. Here we show that the Rho guanine nucleotide exchange factor (GEF)-H1 is regulated by an interaction with microtubules. GEF-H1 mutants that are deficient in microtubule binding have higher activity levels than microtubule-bound forms. These mutants also induce Rho-dependent changes in cell morphology and actin organization. Furthermore, drug-induced microtubule depolymerization induces changes in cell morphology and gene expression that are similar to the changes induced by the expression of active forms of GEF-H1. Furthermore, these effects are inhibited by dominant-negative versions of GEF-H1. Thus, GEF-H1 links changes in microtubule integrity to Rho-dependent regulation of the actin cytoskeleton.
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                Author and article information

                Journal
                Small GTPases
                Small GTPases
                KSGT
                Small GTPases
                Taylor & Francis
                2154-1248
                2154-1256
                2014
                11 November 2014
                : 5
                : 4
                : 1-15
                Affiliations
                [1 ]Department of Cell Biology; University of Geneva ; Geneva, Switzerland
                [2 ]Institute of Genetics and Genomics of Geneva; University of Geneva ; Switzerland
                Author notes
                [* ]Correspondence to: Sandra Citi; Email: sandra.citi@ 123456unige.ch
                Article
                973760
                10.4161/21541248.2014.973760
                4601189
                25483301
                4cc75bda-35ca-49db-ade2-3a33dc6ea883
                © 2014 The Author(s). Published with license by Taylor & Francis Group, LLC© Sandra Citi, Diego Guerrera, Domenica Spadaro, and Jimit Shah

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                : 6 November 2013
                : 2 June 2014
                : 5 September 2014
                Page count
                Figures: 4, Tables: 0, References: 183, Pages: 15
                Categories
                Review

                Molecular biology
                junctions,rho,rac,cdc42,cytoseleton,epithelium
                Molecular biology
                junctions, rho, rac, cdc42, cytoseleton, epithelium

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