Adhesion signalling complexes

Abstract

Intercellular communication in metazoa not only requires autocrine, paracrine and exocrine signalling systems, but it also relies on the structural and positional information encoded in extracellular matrices (ECMs). Most cells in tissues are structurally and functionally integrated with their surrounding ECM in a highly organised manner involving thousands of dynamic connections. On the intracellular face of these linkages, adhesion receptors - principally integrins and syndecans - link the cytoskeleton to the plasma membrane and compartmentalise cytoplasmic signalling events, whereas at the extracellular face the same receptors direct and organise the deposition of the ECM itself. Adhesion receptors transduce mechanical force bidirectionally across the plasma membrane by tethering variably deformable ECMs to the contractile cytoskeleton (Figure 1), and they translate the topography and composition of the ECM into chemical signals that determine behaviour. The membrane-proximal functions of adhesion receptors in turn trigger distal processes within cells, such as alterations in the direction of cell movement and the regulation of gene transcription, and long-range effects outside cells, such as the construction of ECM networks and consequent shaping of higher-order tissue structure. Given the diverse and fundamental roles attributed to adhesion, it is understandable that adhesion receptor engagement has been reported to alter the flux through virtually all major signalling pathways.

Figure 1. Adhesion complexes integrate the ECM with the actin cytoskeleton.

Integrin-mediated adhesion complexes regulate dynamic integration of the fibrillar extracellular environment with the contractile cytoskeletal machinery, promoting bidirectional application of force, cell migration and ECM remodelling. Fibroblasts plated on cell-derived matrices (blue, fibronectin) exhibit bundled actin fibres (red) that terminate at multimolecular adhesion complexes (green, vinculin) at sites of cell–ECM interaction.

Figure 2. Regulation of adhesion complex dynamics.

Schematic representation of the different factors that can regulate focal adhesion dynamics (including GTPase activity, integrin activation, integrin–syndecan synergy, receptor trafficking, heterodimer-specific integrin engagement and microtubule targeting) and the potential for crosstalk between these different processes.

Figure 3. Molecular complexity of integrin adhesion complexes.

Engagement of different ECM ligands by a cell (left) results in the recruitment of specific adhesion complexes that vary dramatically in composition and scale (right). Proteins recruited to an α5β1–fibronectin complex (A) and an α4β1–vascular cell adhesion molecule-1 (VCAM-1) complex (B) as determined by mass spectrometry are displayed as interaction network models. Proteins (circles) are connected by potential protein–protein interactions (lines). Proteins are coloured according to their relative enrichment to fibronectin (blue) or VCAM-1 (red); β1 integrin is shown in green. Proteins identified in both integrin–ligand complexes have a black border. Only proteins within two path lengths of β1 integrin are displayed.