Transmembrane crosstalk between the extracellular matrix and the cytoskeleton

KEY POINTS * Cell adhesions represent the interaction interfaces between cells and the extracellular matrix. Their study provides exciting insights into the interplay between physical forces

and molecular signalling in cell regulation. * Cells use transmembrane actin–integrin adhesion complexes as mechanosensors to probe the rigidity of the extracellular environment, mediate

adhesion, trigger signalling, and remodel the extracellular matrix (ECM). * Local physical forces induce transitions in the types and functions of these cell–matrix adhesions: Focal

complexes transform into focal adhesions, which serve as the source of fibrillar adhesions. * Integrin translocation appears to stretch fibronectin molecules, exposing cryptic sites that

mediate matrix assembly into extracellular fibrils. * A key mechanism in these transitions appears to be conformational changes induced by force or a local reorganization of scaffold or

signalling molecules to promote multimolecular assembly. * Both intracellular molecular-complex formation at adhesion sites and ECM assembly are regulated by Rho-family GTPases. * The main

challenges for the future include:  The identification of the full repertoire of adhesion-associated molecules.  Comparison of the various 'focal complex'-like structures.  

Characterization of the molecular and cellular nature of the mechanosensors involved in cell–matrix adhesion.  Characterization of the regulation and functional integration of the various

forms of adhesions, which change depending on the state of differentiation, tissue location, and application of local forces.  Exploring the structure and function of cell–matrix adhesions

in three-dimensional microenvironments _in vivo_ and explaining the roles of complex carbohydrates in cell–matrix interactions. ABSTRACT Integrin-mediated cell adhesions provide dynamic,

bidirectional links between the extracellular matrix and the cytoskeleton. Besides having central roles in cell migration and morphogenesis, focal adhesions and related structures convey

information across the cell membrane, to regulate extracellular-matrix assembly, cell proliferation, differentiation, and death. This review describes integrin functions, mechanosensors,

molecular switches and signal-transduction pathways activated and integrated by adhesion, with a unifying theme being the importance of local physical forces. Access through your institution

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OTHERS CANONICAL AND NON-CANONICAL INTEGRIN-BASED ADHESIONS DYNAMICALLY INTERCONVERT Article Open access 07 March 2024 ORGANIZATION, DYNAMICS AND MECHANOREGULATION OF INTEGRIN-MEDIATED

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B.G. is the incumbent of the E. Neter Chair in Cell and Tumor Biology, A.B. holds the J. Moss Chair of Biomedical Research. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel Benjamin Geiger & Alexander Bershadsky * Craniofacial Developmental Biology and Regeneration Branch,

National Institute of Craniofacial and Dental Research, National Institutes of Health, Bethesda, 20892, MD, USA Roumen Pankov & Kenneth M. Yamada Authors * Benjamin Geiger View author

publications You can also search for this author inPubMed Google Scholar * Alexander Bershadsky View author publications You can also search for this author inPubMed Google Scholar * Roumen

Pankov View author publications You can also search for this author inPubMed Google Scholar * Kenneth M. Yamada View author publications You can also search for this author inPubMed Google

Scholar CORRESPONDING AUTHOR Correspondence to Benjamin Geiger. RELATED LINKS RELATED LINKS DATABASES INTERPRO: SH2 domain  LOCUSLINK: 14-3-3-β α-actinin ASAP1 calpain II caveolin dynamin

fibronectin filamin ILK α4 integrin α9 integrin LAR mDia1 PAK PI3K ponsin ROCK tensin uPAR VASP/Ena  SWISS-PROT: caldesmon DOCK180 DRAL dystroglycan gelsolin GRAF α3 integrin α5 integrin α6

integrin αv integrin β1 integrin β3 integrin layilin paxillin SHIP-2 SHPS-1 SHP-2 syndecan-4 talin vinculin vinexin vitronectin GLOSSARY * INTEGRINS A group of heterodimeric transmembrane

adhesion receptors for extracellular-matrix proteins such as fibronectin and vitronectin. * BASEMENT MEMBRANE A dense, sheet-like, laminated extracellular matrix that separates epithelia,

muscle, or other tissues from connective tissue. * LAMELLIPODIUM A thin, flat extension at the cell periphery, which is filled with a branching meshwork of actin filaments. * RHO-FAMILY

GTPASES A family of monomeric G proteins — comprising Rho, Rac and Cdc42 — that are homologous to Ras. These are important molecular switches, which control cytoskeletal assembly and

contraction. * MACROPHAGE A white blood cell that is specialized for phagocytosis. * OSTEOCLAST A specialized cell that is involved in active bone resorption. * FIBRONECTIN MODULES Subunits

of fibronectin are comprised of repeating structural modules of three types (I, II, III). Each module is encoded by one or two exons with introns that precisely separate repeats. There are

12 type I modules, each around 45 amino-acids long and clustered into three groups; two type 2 modules, each 60 amino acids-long; and 15–17 type III repeats, each about 90 amino-acids long

(see Fig. 6). * BDM (2,3-Butanedione monoxime) An inhibitor of myosin ATPase. * ML-7 (1-(5-iodonaphthalene-1-sulphonyl)-1-H-hexahydro-1, 4-diazepine) A kinase inhibitor thought to be

relatively specific for myosin light-chain kinase. * H-7 (1-(5-isoquinolinylsulphonyl)-2-methylpiperazine) A broad-spectrum serine–threonine kinase inhibitor that blocks myosin light-chain

kinase, Rho kinase and certain other kinases. * LASER TWEEZERS Microscope-based device that traps micron-sized particles in a focused laser beam. Can be used to move or to stop such

particles. * LEADING EDGE The leading region of the advancing lamellipodium in a motile cell. * CELL-INDUCED SUBSTRATE WRINKLING An approach for visualizing cellular contractility that is

based on wrinkling of a thin and flexible silicone rubber film on which the cell is cultured. * MICRO-CANTILEVER TILTING DEVICE A microscopic device in which cells are attached to a surface

that consists of arrays of cantilevers. Local forces that are applied to this surface induce tilting of these cantilevers, which can be measured. * DEFORMATION OF ELASTIC GELS Polymeric

elastic gels that either contain impregnated beads or are surface micro-patterned are used as substrates for cultured cells. Local forces that are applied to these substrates can be

measured, based on the distortion of these patterns. * CONNECTIVE TISSUES Tissues that form the architectural framework of the vertebrate body. In these tissues, the extracellular matrix is

plentiful and cells are sparsely distributed within it. * GRANULATION TISSUE A contractile, myofibroblast-containing tissue formed in wounds. * ISOMETRIC TENSION A condition in which

contraction of muscle, non-muscle cells or the actomyosin network is opposed by an equal load that prevents net shortening, even though tension increases. * LATRUNCULIN-A A macrolide that is

derived from the Red Sea sponge _Latrunculia magnifica_, which binds and sequesters actin molecules, and thereby prevents the assembly of actin filaments. * TREADMILLING A special state in

polymer dynamics, when monomer addition at one end occurs at the same rate as monomer dissociation at the other end, which keeps the polymer length unchanged. * BARBED END The

fast-polymerizing end of actin filaments (defined by the arrowhead-shaped decoration of actin filaments with myosin fragments). * STEERED MOLECULAR DYNAMICS SIMULATION A computer simulation

method for studying force-induced reactions in biopolymers. * RGD ADHESION SEQUENCE The primary adhesive motif in many extracellular matrix molecules, which contains the amino-acid triplet,

Arg–Gly–Asp. * TRANSGLUTAMINASE An enzyme (such as factor XIIIa) that helps to crosslink fibronectin and other molecules through isopeptide linkages. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Geiger, B., Bershadsky, A., Pankov, R. _et al._ Transmembrane crosstalk between the extracellular matrix and the cytoskeleton. _Nat Rev Mol

Cell Biol_ 2, 793–805 (2001). https://doi.org/10.1038/35099066 Download citation * Issue Date: 01 November 2001 * DOI: https://doi.org/10.1038/35099066 SHARE THIS ARTICLE Anyone you share

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