Integrins are transmembrane cell-adhesion molecules that carry signals from the outside to the inside of the cell and vice versa. Like other cell surface receptors, integrins signal in response to ligand binding; however, events within the cell can also regulate the affinity of integrins for ligands. This feature is important in physiological situations such as those in blood, in which cells are always in close proximity to their ligands, yet cell-ligand interactions occur only after integrin activation in response to specific external cues. This review focuses on the mechanisms whereby two key proteins, talin and the kindlins, regulate integrin activation by binding the tails of integrin-beta subunits.

The ternary complex of integrin-linked kinase (ILK), PINCH and parvin functions as a signalling platform for integrins by interfacing with the actin cytoskeleton and many diverse signalling pathways. All these proteins have synergistic functions at focal adhesions, but recent work has indicated that these proteins might also have separate roles within a cell. They function as regulators of gene transcription or cell-cell adhesion.

Integrins are cell surface transmembrane receptors that recognize and bind to extracellular matrix proteins and counter receptors. Binding of activated integrins to their ligands induces a vast number of structural and signaling changes within the cell. Large, multimolecular complexes assemble onto the cytoplasmic tails of activated integrins to engage and organize the cytoskeleton, and activate signaling pathways that ultimately lead to changes in gene expression. Additionally, integrin-mediated signaling intersects with growth factor-mediated signaling through various levels of cross-talk. This review discusses recent work that has tremendously broadened our understanding of the complexity of integrin-mediated signaling.

The adhesive interactions of cells with their environment through the integrin family of transmembrane receptors have key roles in regulating multiple aspects of cellular physiology, including cell proliferation, viability, differentiation and migration. Consequently, failure to establish functional cell adhesions, and thus the assembly of associated cytoplasmic scaffolding and signalling networks, can have severe pathological effects. The roles of specific constituents of integrin-mediated adhesions, which are collectively known as the 'integrin adhesome', in diverse pathological states are becoming clear. Indeed, the prominence of mutations in specific adhesome molecules in various human diseases is now appreciated, and experimental as well as in silico approaches provide insights into the molecular mechanisms underlying these pathological conditions.

Coordinated navigation within tissues is essential for cells of the innate immune system to reach the sites of inflammatory processes, but the signals involved are incompletely understood. Here we demonstrate that NG2(+) pericytes controlled the pattern and efficacy of the interstitial migration of leukocytes in vivo. In response to inflammatory mediators, pericytes upregulated expression of the adhesion molecule ICAM-1 and released the chemoattractant MIF. Arteriolar and capillary pericytes attracted and interacted with myeloid leukocytes after extravasating from postcapillary venules, 'instructing' them with pattern-recognition and motility programs. Inhibition of MIF neutralized the migratory cues provided to myeloid leukocytes by NG2(+) pericytes. Hence, our results identify a previously unknown role for NG2(+) pericytes as an active component of innate immune responses, which supports the immunosurveillance and effector function of extravasated neutrophils and macrophages.

Cells recognize and respond to their extracellular environment through transmembrane receptors such as integrins, which physically connect the extracellular matrix to the cytoskeleton. Integrins provide the basis for the assembly of intracellular signaling platforms that link to the cytoskeleton and influence nearly every aspect of cell physiology; however, integrins possess no enzymatic or actin-binding activity of their own and thus rely on adaptor molecules, which bind to the short cytoplasmic tails of integrins, to mediate and regulate these functions. Many adaptors compete for relatively few binding sites on integrin tails, so regulatory mechanisms have evolved to reversibly control the spatial and temporal binding of specific adaptors. This Commentary discusses the adaptor proteins that bind directly to the tails of β integrins and, using talin, tensin, filamin, 14-3-3 and integrin-linked kinase (ILK) as examples, describes the ways in which their binding is regulated. Science 122,[187][188][189][190][191][192][193][194][195][196][197][198] Published by The Company of Biologists 2009Biologists doi:10.1242 Journal of Cell Science 188 an interaction with the NHL-domain protein Wech (Löer et al., 2008). The interconnectedness of protein-protein interactions that are mediated by adaptors is key to the assembly of the complex structural and signaling platform of the focal adhesion. Journal of CellFluorescence ratio imaging experiments have shown that adaptor molecules assemble into focal-adhesion sites in a sequential manner (Laukaitis et al., 2001;Zaidel-Bar et al., 2003;Zaidel-Bar et al., 2004;Zamir et al., 1999), so that the maturation of adhesion sites can in part be characterized by the specific composition of adaptor molecules that are incorporated within them. The adaptor integrincytoplasmic-domain-associated protein 1α (ICAP1α) localizes with β1 integrins before the formation of focal complexes and regulates adhesion assembly, perhaps by controlling the binding of talin to β1-integrin tails (Bouvard et al., 2003; Fournier et al., 2002; MillonFrémillon et al., 2008). As focal complexes mature into focal adhesions they lose ICAP1α (Fournier et al., 2002) and the actinbinding protein vinculin (Katz et al., 2000;Zamir et al., 1999), and acquire the actin-regulatory protein zyxin. In some cell types, the integrin adaptor tensin only becomes recruited when focal adhesions progress to fibrillar adhesions (Papp et al., 2007;Zaidel-Bar et al., 2003;Zaidel-Bar et al., 2004;Zamir et al., 1999). The fact that tensin is only found at certain stages of adhesion-structure formation indicates that its binding to integrin tails is tightly regulated.This Commentary describes how adaptor proteins bind to β-integrin tails, and discusses the strategies by which this binding is regulated. We use specific examples -the binding of talin vs tensin, the binding of 14-3-3 vs filamin, and the co-adaptor-mediated binding of ILK -to demonstrate how the regulated binding of adaptors occurs, and how it can alter the functional pr...

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For many years the extracellular matrix was viewed as a benign scaffold for arranging cells within connective tissues, but it is now being redefined as a dynamic, mobile, and flexible key player in defining cellular behavior. Gene targeting, transgene expression, and spontaneous mutations of extracellular matrix proteins in mice have greatly accelerated our mechanistic view of the structural and instructive functions of the extracellular matrix in developmental and regenerative processes. This review summarizes the phenotypes of genetic mouse models carrying mutations in extracellular matrix proteins, with specific emphasis on recent advances. The application of reverse genetics has demonstrated the multifunctionality of matrix proteins in a biological context and, in addition, has brought a novel perspective to the understanding of human pathologies.