Conformationally active integrin endocytosis and traffic: why, where, when and how? (original) (raw)
Related papers
Regulation of adhesion site dynamics by integrin traffic
Current Opinion in Cell Biology, 2012
The dynamic control of integrin-mediated cell adhesion to extracellular matrix proteins is crucial for several physiological and pathological phenomena as diverse as embryonic morphogenesis, muscle contraction, tissue repair, and cancer cell dissemination. On one hand, the intrinsic conformational plasticity of integrins, which can be bidirectionally modulated by their ligands and cytosolic adaptors in combination with physical forces, is a key regulatory parameter. On the other hand, endo-exocytic integrin traffic logistics represent an additional important mode of control. Herein, we highlight how these two apparently parallel and independent strategies for tuning integrin function appear instead to be indissolubly intermingled, as eukaryotic cells have evolved distinct molecular strategies and endosomal pathways to traffic ligand-bound and ligand-free integrins.
Regulation of integrins by conformation and traffic: it takes two to tango
Molecular BioSystems, 2011
In multicellular organisms, the execution of complex morphogenetic events, such as gastrulation or vascular morphogenesis, depends on the dynamic modulation of adhesion. Guidance cues, such as chemokines, growth factors, and semaphorins control the attachment of cells to extracellular matrix proteins by regulating the conformational activation of integrin receptors. The endo-exocytic traffic of integrins back and forth from the plasma membrane represents another crucial regulatory aspect in cell adhesion and motility. Recent work added an additional layer of complexity by indicating that distinct molecular machineries are required for trafficking active and inactive integrins.
Endocytic Trafficking of Integrins in Cell Migration
Current Biology, 2015
Integrins are a family of heterodimeric receptors that bind to components of the extracellular matrix and influence cellular processes as varied as proliferation and migration. These effects are achieved by tight spatiotemporal control over intracellular signalling pathways, including those that mediate cytoskeletal reorganisation. The ability of integrins to bind to ligands is governed by integrin conformation, or activity, and this is widely acknowledged to be an important route to the regulation of integrin function. Over the last 15 years, however, the pathways that regulate endocytosis and recycling of integrins have emerged as major players in controlling integrin action, and studying integrin trafficking has revealed fresh insight into the function of this fascinating class of extracellular matrix receptors, in particular in the context of cell migration and invasion. Here, we review our current understanding of the contribution of integrin trafficking to cell motility.
Mechanisms of integrin activation and trafficking
Current Opinion in Cell Biology, 2011
Integrin adhesion receptors are essential for the normal function of most multicellular organisms, and defective integrin activation or integrin signaling is associated with an array of pathological conditions. Integrins are regulated by conformational changes, clustering, and trafficking, and regulatory mechanisms differ strongly between individual integrins and between cell types. Whereas integrins in circulating blood cells are activated by an inside-out-induced conformational change that favors high-affinity ligand binding, b1-integrins in adherent cells can be activated by force or clustering. In addition, endocytosis and recycling play an important role in the regulation of integrin turnover and integrin redistribution in adherent cells, especially during dynamic processes such as cell migration and invasion. Integrin trafficking is strongly regulated by their cytoplasmic tails, and the mechanisms are now being identified.
Quarterly Reviews of Biophysics, 2019
Integrins are large heterodimeric type 1 membrane proteins expressed in all nucleated mammalian cells. Eighteenα-chains and eightβ-chains can combine to form 24 different integrins. They are cell adhesion proteins, which bind to a large variety of cellular and extracellular ligands. Integrins are required for cell migration, hemostasis, translocation of cells out from the blood stream and further movement into tissues, but also for the immune response and tissue morphogenesis. Importantly, integrins are not usually active as such, but need activation to become adhesive. Integrins are activated by outside-in activation through integrin ligand binding, or by inside-out activation through intracellular signaling. An important question is how integrin activity is regulated, and this topic has recently drawn much attention. Changes in integrin affinity for ligand binding are due to allosteric structural alterations, but equally important are avidity changes due to integrin clustering in ...
Integrin Structure, Allostery, and Bidirectional Signaling
Annual Review of Cell and Developmental Biology, 2005
αβ heterodimeric integrins mediate dynamic adhesive cell-cell and cell-extracellular matrix (ECM) interactions in metazoa that are critical in growth and development, hemostasis, and host defense. A central feature of these receptors is their capacity to change rapidly and reversibly their adhesive functions by modulating their ligand-binding affinity. This is normally achieved through interactions of the short cytoplasmic integrin tails with intracellular proteins, which trigger restructuring of the ligand-binding site through long-range conformational changes in the ectodomain. Ligand binding in turn elicits conformational changes that are transmitted back to the cell to regulate diverse responses. The publication of the integrin αVβ3 crystal structure has provided the context for interpreting decades-old biochemical studies. Newer NMR, crystallographic, and EM data, reviewed here, are providing a better picture of the dynamic integrin structure and the allosteric changes that gui...
Coupling integrin dynamics to cellular adhesion behaviors
Biology Open
Visualizing fluorescent proteins is essential for understanding cellular function. While advances in microscopy can now resolve individual molecules, determining whether the labeled molecules report native behaviors and how the measured behaviors can be coupled to cellular outputs remains challenging. Here, we used integrin alpha-beta heterodimers – which connect extracellular matrix (ECM) and the cytoskeleton – to quantify the mobility and conformation of labeled integrins. We found that while unlabeled and labeled integrins all localized to adhesions and support anchorage-dependent cell function, integrin mobility decreased when the beta rather than the alpha subunit was labeled. In contrast to unlabeled and alpha labeled subunits, beta labeled subunits changed cellular behavior; decreasing protrusive activity and increasing adhesion size and the extent of cell spreading. Labeling the beta subunit changed the integrin conformation, extending the molecule and exposing an epitope th...
Integrin α3β1 Engagement Disrupts Intercellular Adhesion
Experimental Cell Research, 2001
During tissue morphogenesis and tumor invasion, epithelial cells must undergo intercellular rearrangement in which cells are repositioned with respect to one another and the surrounding mesenchymal extracellular matrix. Using three-dimensional aggregates of squamous epithelial cells, we show that such intercellular rearrangements can be triggered by activation of 1 integrins after their ligation with extracellular matrices. On nonadherent substrates, multicellular aggregates (MCAs) formed rapidly via E-cadherin junctional complexes and over time became compacted spheroids exhibiting a more epithelial phenotype. After MCAs were replated on culture substrates, the spheroids collapsed to yield tightly arranged cell monolayers. Cell-cell contact induced rapid elevation in E-cadherin levels, which was due to an increase in the metabolic stability of junctional receptors. During MCA remodeling of cell-cell adhesions, and monolayer formation, their E-cadherin levels fell rapidly. Similar behavior was obtained regardless of which ECM ligand-collagen type I, fibronectin, or laminin 1-MCAs were seeded on. In contrast, when seeded onto a matrix elaborated by squamous epithelial cells, cells in the MCA attached, spread, lost cell-cell junctions, and dispersed. Analysis identified laminin 5 as the active ECM ligand in this matrix, and MCA dispersion required functional 1 integrin and specifically ␣31. Furthermore, substrate-immobilized anti-integrin antibody effectively reproduced the epithelial-mesenchymal-like transition induced by the laminin 5 matrix. During the early stages of aggregate rearrangement and collapse, cells on laminin 5 substrates, but not those on collagen I substrates, exhibited intense cortical arrays of F-actin, microspikes, and fascin accumulation at their peripheral surfaces. These results suggest that engagement of specific integrin-ligand pairs regulates cadherin junctional adhesions during events common to epithelial morphogenesis and tumor invasion.