Recent progress in the design and application of artificial cellular microenvironments and nanoenvironments has revealed the extraordinary ability of cells to adjust their cytoskeletal organization, and hence their shape and motility, to minute changes in their immediate surroundings. Integrin-based adhesion complexes, which are tightly associated with the actin cytoskeleton, comprise the cellular machinery that recognizes not only the biochemical diversity of the extracellular neighbourhood, but also its physical and topographical characteristics, such as pliability, dimensionality and ligand spacing. Here, we discuss the mechanisms of such environmental sensing, based on the finely tuned crosstalk between the assembly of one type of integrin-based adhesion complex, namely focal adhesions, and the forces that are at work in the associated cytoskeletal network owing to actin polymerization and actomyosin contraction.

Environmental sensing through focal adhesions

Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all progressive chronic kidney diseases. Renal fibrosis is also a reliable predictor of prognosis and a major determinant of renal insufficiency. Irrespective of the initial causes, renal fibrogenesis is a dynamic and converging process that consists of four overlapping phases: priming, activation, execution and progression. Nonresolving inflammation after a sustained injury sets up the fibrogenic stage (priming) and triggers the activation and expansion of matrix-producing cells from multiple sources through diverse mechanisms, including activation of interstitial fibroblasts and pericytes, phenotypic conversion of tubular epithelial and endothelial cells and recruitment of circulating fibrocytes. Upon activation, matrix-producing cells assemble a multicomponent, integrin-associated protein complex that integrates input from various fibrogenic signals and orchestrates the production of matrix components and their extracellular assembly. Multiple cellular and molecular events, such as tubular atrophy, microvascular rarefaction and tissue hypoxia, promote scar formation and ensure a vicious progression to end-stage kidney failure. This Review outlines our current understanding of the cellular and molecular mechanisms of renal fibrosis, which could offer novel insights into the development of new therapeutic strategies.

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Cellular and molecular mechanisms of renal fibrosis

Cell-directed changes in the ligand-binding affinity ('activation') of integrins regulate cell adhesion and migration, extracellular matrix assembly and mechanotransduction, thereby contributing to embryonic development and diseases such as atherothrombosis and cancer. Integrin activation comprises triggering events, intermediate signalling events and, finally, the interaction of integrins with cytoplasmic regulators, which changes an integrin's affinity for its ligands. The first two events involve diverse interacting signalling pathways, whereas the final steps are immediately proximal to integrins, thus enabling integrin-focused therapeutic strategies. Recent progress provides insight into the structure of integrin transmembrane domains, and reveals how the final steps of integrin activation are mediated by integrin-binding proteins such as talins and kindlins.

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The final steps of integrin activation: the end game

Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions.

The conversion of physical signals, such as contractile forces or external mechanical perturbations, into chemical signaling events is a fundamental cellular process that occurs at cell-extracellular matrix contacts, known as focal adhesions. At these sites, transmembrane integrin receptors are associated via their cytoplasmic domains with the actin cytoskeleton. This interaction with actin is mediated by a submembrane plaque, consisting of numerous cytoskeletal and signaling molecules. Application of intrinsic or external forces to these structures dramatically affects their assembly and triggers adhesion-mediated signaling. In this review, we discuss the structure-function relationships of focal adhesions and the possible mode of action of the putative mechanosensor associated with them. We also discuss the general phenomenon of mechanosensitivity, and the approaches used to measure local forces at adhesion sites, the cytoskeleton-mediated regulation of local contractility, and the nature of the signaling networks that both affect contractility and are affected by it.

Ka Chen

Papers

Osteopetrosis with micro-lacunar resorption because of defective integrin organization.

RSU-1 interaction with prohibitin-2 links cell–extracellular matrix detachment to downregulation of ERK signaling