Reciprocal integrin/integrin antagonism through kindlin-2 and Rho GTPases regulates cell cohesion and collective migration

Bijl, Ivo van der; Nawaz, Kalim; Kazlauskaite, Ugne; Stalborch, Anne-Marieke D. van; Tol, Simon; Orgaz, Ana Jimenez; Bout, Iman van den; Reinhard, Nathalie R.; Sonnenberg, Arnoud; Margadant, Coert

doi:10.1016/j.matbio.2020.05.005

Cited by 19 publications

(15 citation statements)

References 92 publications

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“…The interaction between FN and α5β1 induces robust RhoA activation, which in turn triggers the assembly of FN fibrils and associated fibrillar adhesions (FBs), a special kind of tension-bearing adhesion complexes located in the cell center that facilitate cytoskeletal contractility and cell contraction [22][23][24]. Indeed, we and others have previously found that α5β1 disrupts cadherin-dependent cell-cell junctions through RhoA-dependent contractility, in a variety of cell types including endothelial cells [18,19,25,26]. Furthermore, blocking β1 integrins was recently shown to protect from LPS-induced barrier disruption and vascular leakage in mice [18,19].…”

Section: Introductionmentioning

confidence: 99%

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

Amado-Azevedo¹,

Stalborch

Valent³

et al. 2021

Angiogenesis

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Endothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved adhesion to the extracellular matrix. We further show that Arg is activated in the endothelium during inflammation, both in murine lungs exposed to barrier-disruptive agents, and in pulmonary microvessels of septic patients. Importantly, Arg-depleted endothelial cells were less sensitive to barrier-disruptive agents. Despite the formation of F-actin stress fibers and myosin light chain phosphorylation, Arg depletion diminished adherens junction disruption and intercellular gap formation, by reducing the disassembly of cell-matrix adhesions and cell retraction. In vivo, genetic deletion of Arg diminished vascular leak in the skin and lungs, in the presence of a normal immune response. Together, our data indicate that Arg is a central and non-redundant regulator of endothelial barrier integrity, which contributes to cell retraction and gap formation by increasing the dynamics of adherens junctions and cell-matrix adhesions in a Rho GTPase-dependent fashion. Therapeutic inhibition of Arg may provide a suitable strategy for the treatment of a variety of clinical conditions characterized by vascular leak.

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Section: Introductionmentioning

confidence: 99%

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

Amado-Azevedo¹,

Stalborch

Valent³

et al. 2021

Angiogenesis

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“…FCL assembly requires αvβ5-vitronectin interaction and recruitment of clathrin adaptors such as ARH, Numb, and EPS15/EPS15L1 to the β5 cytoplasmic tail [ 59 ]. Integrin cytoplasmic tails can induce profound differences in the behavior of distinct integrins, even when they bind the same ligand [ 64 ], which is most likely due to differences in the relative affinities for specific proteins. The cytotail of αvβ5 contains an insert of eight amino acids, as compared with integrin β1 or β3 tails [ 34 ], and may have an exceptionally high affinity for clathrin adaptors.…”

Section: Integrin Crosstalk With the Endocytic Machinery Regulates Admentioning

confidence: 99%

Integrins Control Vesicular Trafficking; New Tricks for Old Dogs

Nolte

Hoen

Margadant³

2021

Trends in Biochemical Sciences

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Integrins are transmembrane receptors that transduce biochemical and mechanical signals across the plasma membrane and promote cell adhesion and migration. In addition, integrin adhesion complexes are functionally and structurally linked to components of the intracellular trafficking machinery and accumulating data now reveal that they are key regulators of endocytosis and exocytosis in a variety of cell types. Here, we highlight recent insights into integrin control of intracellular trafficking in processes such as degranulation, mechanotransduction, cell–cell communication, antibody production, virus entry, Toll-like receptor signaling, autophagy, and phagocytosis, as well as the release and uptake of extracellular vesicles. We discuss the underlying molecular mechanisms and the implications for a range of pathophysiological contexts, including hemostasis, immunity, tissue repair, cancer, and viral infection.

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“…[40] Additionally, the antagonistic relation between integrin 5 1 and V 3 in regulating activities of Rho and Rac GTPases, cell adhesion, and spreading, was shown to be mediated by kindlin-2. [41] Notably, FAs contain a multitude of other proteins, collectively referred to as the integrin adhesome. Many proteomic studies have provided insight into the molecular composition of FAs and revealed that the FA composition can vary extensively between cell types and experimental conditions.…”

Section: Mechanotransduction At Focal Adhesionsmentioning

confidence: 99%

Crosstalk between Cell Adhesion Complexes in Regulation of Mechanotransduction

2020

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Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin cytoskeleton are primarily transmitted through integrin-containing focal adhesions and cadherin-containing adherens junctions. Crosstalk between these complexes is well established and modulates the mechanical landscape of the cell. However, integrins and cadherins constitute large families of adhesion receptors and form multiple complexes by interacting with different ligands, adaptor proteins, and cytoskeletal filaments. Recent findings indicate that integrin-containing hemidesmosomes oppose force transduction and traction force generation by focal adhesions. The cytolinker plectin mediates this crosstalk by coupling intermediate filaments to the actin cytoskeleton. Similarly, cadherins in desmosomes might modulate force generation by adherens junctions. Moreover, mechanotransduction can be influenced by podosomes, clathrin lattices, and tetraspanin-enriched microdomains. This review discusses mechanotransduction by multiple integrin-and cadherin-based cell adhesion complexes, which together with the associated cytoskeleton form an integrated network that allows cells to sense, process, and respond to their physical environment.

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Reciprocal integrin/integrin antagonism through kindlin-2 and Rho GTPases regulates cell cohesion and collective migration

Cited by 19 publications

References 92 publications

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation

Integrins Control Vesicular Trafficking; New Tricks for Old Dogs

Crosstalk between Cell Adhesion Complexes in Regulation of Mechanotransduction

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