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.

Adhesion-dependent cell mechanosensitivity.

Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation.

PINCH-1 Is an Obligate Partner of Integrin-linked Kinase (ILK) Functioning in Cell Shape Modulation, Motility, and Survival

PINCH, integrin-linked kinase (ILK) and calponin homology-containing ILK-binding protein (CH-ILKBP) form a ternary complex that plays crucial roles at cell-extracellular matrix adhesion sites. To understand the mechanism underlying the complex formation and recruitment to cell-adhesion sites we have undertaken a combined structural, mutational and cell biological analysis. Three-dimensional structure-based point mutations identified specific PINCH and ILK sites that mediate the complex formation. Analyses of the binding defective point mutants revealed that the assembly of the PINCH-ILK-CH-ILKBP complex is essential for their localization to cell-extracellular matrix adhesion sites. The formation of the PINCH-ILK-CH-ILKBP complex precedes integrin-mediated cell adhesion and spreading. Furthermore, inhibition of protein kinase C, but not that of actin polymerization, inhibited the PINCH-ILK-CH-ILKBP complex formation, suggesting that the PINCH-ILK-CH-ILKBP complex likely serves as a downstream effector of protein kinase C in the cellular control of focal adhesion assembly. Finally, we provide evidence that the formation of the PINCH-ILK-CH-ILKBP complex, while necessary, is not sufficient for ILK localization to cell-extracellular matrix adhesion sites. These results provide new insights into the molecular mechanism underlying the assembly and regulation of cell-matrix adhesion structures.

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Assembly of the PINCH-ILK-CH-ILKBP complex precedes and is essential for localization of each component to cell-matrix adhesion sites.

The MIG-2/Integrin Interaction Strengthens Cell-Matrix Adhesion and Modulates Cell Motility

https://www.cell.com/molecular-cell/pdf/S1097-2765(09)00869-7.pdf

Ka Chen

Papers

Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation.

PINCH-1 Is an Obligate Partner of Integrin-linked Kinase (ILK) Functioning in Cell Shape Modulation, Motility, and Survival

Assembly of the PINCH-ILK-CH-ILKBP complex precedes and is essential for localization of each component to cell-matrix adhesion sites.

The MIG-2/Integrin Interaction Strengthens Cell-Matrix Adhesion and Modulates Cell Motility

The Pseudoactive Site of ILK Is Essential for Its Binding to α-Parvin and Localization to Focal Adhesions