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?V-class integrins exert dual roles on ?5?1 integrins to strengthen adhesion to fibronectin.

ABSTRACT: Upon binding to the extracellular matrix protein, fibronectin, ?V-class and ?5?1 integrins trigger the recruitment of large protein assemblies and strengthen cell adhesion. Both integrin classes have been functionally specified, however their specific roles in immediate phases of cell attachment remain uncharacterized. Here, we quantify the adhesion of ?V-class and/or ?5?1 integrins expressing fibroblasts initiating attachment to fibronectin (?120?s) by single-cell force spectroscopy. Our data reveals that ?V-class integrins outcompete ?5?1 integrins. Once engaged, ?V-class integrins signal to ?5?1 integrins to establish additional adhesion sites to fibronectin, away from those formed by ?V-class integrins. This crosstalk, which strengthens cell adhesion, induces ?5?1 integrin clustering by RhoA/ROCK/myosin-II and Arp2/3-mediated signalling, whereas overall cell adhesion depends on formins. The dual role of both fibronectin-binding integrin classes commencing with an initial competition followed by a cooperative crosstalk appears to be a basic cellular mechanism in assembling focal adhesions to the extracellular matrix.

SUBMITTER: Bharadwaj M

PROVIDER: S-EPMC5290147 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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αV-class integrins exert dual roles on α5β1 integrins to strengthen adhesion to fibronectin.

Bharadwaj Mitasha M Strohmeyer Nico N Colo Georgina P GP Helenius Jonne J Beerenwinkel Niko N Schiller Herbert B HB Fässler Reinhard R Müller Daniel J DJ

Nature communications 20170127

Upon binding to the extracellular matrix protein, fibronectin, αV-class and α5β1 integrins trigger the recruitment of large protein assemblies and strengthen cell adhesion. Both integrin classes have been functionally specified, however their specific roles in immediate phases of cell attachment remain uncharacterized. Here, we quantify the adhesion of αV-class and/or α5β1 integrins expressing fibroblasts initiating attachment to fibronectin (≤120 s) by single-cell force spectroscopy. Our data r ...[more]

PMID: 28128308

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Project description:Objective- Alterations in extracellular matrix quantity and composition contribute to atherosclerosis, with remodeling of the subendothelial basement membrane to an FN (fibronectin)-rich matrix preceding lesion development. Endothelial cell interactions with FN prime inflammatory responses to a variety of atherogenic stimuli; however, the mechanisms regulating early atherogenic FN accumulation remain unknown. We previously demonstrated that oxLDL (oxidized low-density lipoprotein) promotes endothelial proinflammatory gene expression by activating the integrin α5β1, a classic mediator of FN fibrillogenesis. Approach and Results- We now show that oxLDL drives robust endothelial FN deposition and inhibiting α5β1 (blocking antibodies, α5 knockout cells) completely inhibits oxLDL-induced FN deposition. Consistent with this, inducible endothelial-specific α5 integrin deletion in ApoE knockout mice significantly reduces atherosclerotic plaque formation, associated with reduced early atherogenic inflammation. Unlike TGFβ (transforming growth factor β)-induced FN deposition, oxLDL does not induce FN expression (mRNA, protein) or the endothelial-to-mesenchymal transition phenotype. In addition, we show that cell-derived and plasma-derived FN differentially affect endothelial function, with only cell-derived FN capable of supporting oxLDL-induced VCAM-1 (vascular cell adhesion molecule 1) expression, despite plasma FN deposition by oxLDL. The inclusion of alternative exon EIIIA (EDA) of FN (EIIIA) and alternative exon EIIIB (EDB) of FN (EIIIB) domains in cell-derived FN mediates this effect, as EIIIA/EIIIB knockout endothelial cells show diminished oxLDL-induced inflammation. Furthermore, our data suggest that EIIIA/EIIIB-positive cellular FN is required for maximal α5β1 recruitment to focal adhesions and FN fibrillogenesis. Conclusions- Taken together, our data demonstrate that endothelial α5 integrins drive oxLDL-induced FN deposition and early atherogenic inflammation. Additionally, we show that α5β1-dependent endothelial FN deposition mediates oxLDL-dependent endothelial inflammation and FN fibrillogenesis.

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?V-class integrins exert dual roles on ?5?1 integrins to strengthen adhesion to fibronectin.

Publications

αV-class integrins exert dual roles on α5β1 integrins to strengthen adhesion to fibronectin.

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