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      The integrin adhesome network at a glance

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          ABSTRACT

          The adhesion nexus is the site at which integrin receptors bridge intracellular cytoskeletal and extracellular matrix networks. The connection between integrins and the cytoskeleton is mediated by a dynamic integrin adhesion complex (IAC), the components of which transduce chemical and mechanical signals to control a multitude of cellular functions. In this Cell Science at a Glance article and the accompanying poster, we integrate the consensus adhesome, a set of 60 proteins that have been most commonly identified in isolated IAC proteomes, with the literature-curated adhesome, a theoretical network that has been assembled through scholarly analysis of proteins that localise to IACs. The resulting IAC network, which comprises four broad signalling and actin-bridging axes, provides a platform for future studies of the regulation and function of the adhesion nexus in health and disease.

          Abstract

          Summary: We have generated a new depiction of the integrin adhesome network that integrates experimentally derived IAC proteomes with the literature-curated adhesome to bridge the knowledge gap between these two resources.

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          Most cited references41

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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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            β1- and αv-class integrins cooperate to regulate myosin II during rigidity sensing of fibronectin-based microenvironments.

            How different integrins that bind to the same type of extracellular matrix protein mediate specific functions is unclear. We report the functional analysis of β1- and αv-class integrins expressed in pan-integrin-null fibroblasts seeded on fibronectin. Reconstitution with β1-class integrins promotes myosin-II-independent formation of small peripheral adhesions and cell protrusions, whereas expression of αv-class integrins induces the formation of large focal adhesions. Co-expression of both integrin classes leads to full myosin activation and traction-force development on stiff fibronectin-coated substrates, with αv-class integrins accumulating in adhesion areas exposed to high traction forces. Quantitative proteomics linked αv-class integrins to a GEF-H1-RhoA pathway coupled to the formin mDia1 but not myosin II, and α5β1 integrins to a RhoA-Rock-myosin II pathway. Our study assigns specific functions to distinct fibronectin-binding integrins, demonstrating that α5β1integrins accomplish force generation, whereas αv-class integrins mediate the structural adaptations to forces, which cooperatively enable cells to sense the rigidity of fibronectin-based microenvironments.
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              Molecular complexity and dynamics of cell-matrix adhesions.

              Currently >50 proteins have been reported to be associated with focal contacts and related ECM adhesions. Most of these contain multiple domains through which they can interact with different molecular partners, potentially forming a dense and heterogeneous protein network at the cytoplasmic faces of the adhesion site. The molecular and structural diversity of this 'submembrane plaque' is regulated by a wide variety of mechanisms, including competition between different partner proteins for the same binding sites, interactions triggered or suppressed by tyrosine phosphorylation, and conformational changes in component proteins, which can affect their reactivity. Indeed, integrin-mediated adhesions can undergo dynamic changes in structure and molecular properties from dot-like focal complexes to stress-fiber-associated focal contacts, which can further 'mature' to form fibronectin-bound fibrillar adhesions. These changes are driven by mechanical force generated by the actin- and myosin-containing contractile machinery of the cells, or by external forces applied to the cells, and regulated by matrix rigidity.
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                Author and article information

                Journal
                J Cell Sci
                J. Cell. Sci
                JCS
                joces
                Journal of Cell Science
                The Company of Biologists Ltd
                0021-9533
                1477-9137
                15 November 2016
                15 November 2016
                : 129
                : 22
                : 4159-4163
                Affiliations
                Wellcome Trust Centre for Cell-Matrix Research , Faculty of Biology, Medicine and Health, University of Manchester , Manchester M13 9PT, UK
                Author notes
                [*]

                Present address: Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen DK-2200, Denmark.

                []Author for correspondence ( martin.humphries@ 123456manchester.ac.uk )
                Author information
                http://orcid.org/0000-0001-9530-9585
                http://orcid.org/0000-0002-8953-7079
                http://orcid.org/0000-0002-4331-6967
                Article
                JCS192054
                10.1242/jcs.192054
                5117201
                27799358
                94597309-e51a-4af6-be19-0ea2b1437410
                © 2016. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                Funding
                Funded by: Wellcome Trust, http://dx.doi.org/10.13039/100004440;
                Award ID: 092015
                Funded by: Cancer Research UK, http://dx.doi.org/10.13039/501100000289;
                Award ID: C13329/A21671
                Funded by: Biotechnology and Biological Sciences Research Council, http://dx.doi.org/10.13039/501100000268;
                Categories
                129
                Cell Science at A Glance

                Cell biology
                adhesion,cytoskeleton,integrin,integrin adhesion complex,adhesome
                Cell biology
                adhesion, cytoskeleton, integrin, integrin adhesion complex, adhesome

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