Force-dependent binding of vinculin to α-catenin regulates cell–cell contact stability and collective cell behavior

Seddiki, Rima; Narayana, Gautham Hari Narayana Sankara; Strale, Pierre‐Olivier; Balcıoğlu, Hayri E.; Peyret, Grégoire; Yao, Mingxi; Le, Anh Phuong; Lim, Chwee Teck; Yan, Jie; Ladoux, Benoît; Mège, René-Marc

doi:10.1091/mbc.e17-04-0231

Cited by 105 publications

(121 citation statements)

References 45 publications

(66 reference statements)

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“…Taken together, we propose the following model. In WT contact inhibited cells, the binding of vinculin to α-catenin is essential to keep it in a stretched conformation (Seddiki et al, 2018;Yao et al, 2014), and associated with the actin cytoskeletal network. The stretched α-catenin creates a binding site for the adaptor protein 14-3-3, which in turn binds to p-YAP and sequesters it at the adherens junctions (Schlegelmilch et al, 2011) (Fig 6P).…”

Section: Loss Of Vinculin Affects the Conformation Of α-Catenin At Ajmentioning

confidence: 99%

“…To address the importance of interaction between vinculin and α-catenin at the AJs, we measured the strength of the AJs in α-catenin KO cells transfected with α-cat-L344P-GFP (α-catenin point mutant that is unable to bind vinculin) (Ming, 2019;Seddiki et al, 2018;Yao et al, 2014). Interestingly, in α-cat-L344P cells the strength of the junctions was around ~2.5nN, which was similar to the strength of the junction in α-catenin KO cells ( Fig 5C, I).…”

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confidence: 99%

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Mechanical Instability of Adherens Junctions Overrides Intrinsic Quiescence of Hair Follicle Stem Cells

Biswas

Banerjee

Lembo

et al. 2020

Preprint

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Vinculin, a mechanotransducer associated with both adherens junctions (AJ) and focal adhesions (FA) plays a central role in force transmission through these cell-cell and cellsubstratum contacts. Here we describe the conditional knock out (KO) of vinculin in murine skin. Remarkably, we find that the loss of vinculin function results in the loss of bulge stem cell (BuSC) quiescence. We demonstrate that vinculin KO cells are impaired in force generation resulting in mechanically weak AJs. Mechanistically, vinculin functions by keeping α-catenin in a stretched conformation, which in turn regulates the retention of YAP1, another potent mechanotransducer and regulator of cell proliferation, to the junctions. Conditional KO of α-catenin specifically in the BuSCs further corroborates the importance of stable AJs in the maintenance of quiescence and stemness. Altogether, our data provides definitive mechanistic insights into the hitherto unexplored regulatory link between the mechanical stability of cell-junctions and the maintenance of BuSC quiescence.

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Section: Loss Of Vinculin Affects the Conformation Of α-Catenin At Ajmentioning

confidence: 99%

mentioning

confidence: 99%

Mechanical Instability of Adherens Junctions Overrides Intrinsic Quiescence of Hair Follicle Stem Cells

Biswas

Banerjee

Lembo

et al. 2020

Preprint

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“…Before imaging intercellular forces, we wondered if the addition of DNAMeter would impair the adhesion and mechanical function of cell-cell junctions. We first studied the effect of membrane-anchored EC-DNAMeter on the force-dependent recruitment of vinculin to the adherens junctions 56,57 .…”

Section: Imaging and Quantification Of E-cadherin-mediated Tensile Fomentioning

confidence: 99%

Quantifying Tensile Forces at Cell–Cell Junctions with a DNA-based Fluorescent Probe

Zhao

Xie

et al. 2020

Preprint

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Cells are physically contacting with each other. Direct and precise quantification of forces at cell-cell junctions is still challenging. Herein, we have developed a DNA-based ratiometric fluorescent probe, termed DNAMeter, to quantify intercellular tensile forces. These lipidmodified DNAMeters can spontaneously anchor onto live cell membranes. The DNAMeter consists of two self-assembled DNA hairpins of different force tolerance. Once the intercellular tension exceeds the force tolerance to unfold a DNA hairpin, a specific fluorescence signal will be activated, which enables the real-time imaging and quantification of tensile forces. Using Ecadherin-modified DNAMeter as an example, we have demonstrated an approach to quantify, at the molecular level, the magnitude and distribution of E-cadherin tension among epithelial cells.Compatible with readily accessible fluorescence microscopes, these easy-to-use DNA tension probes can be broadly used to quantify mechanotransduction in collective cell behaviors.

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“…Similarly a rate dictates how often adhesions are disassembled for FAs ( , , ) and AJs ( , , ); however, this rate is made dependent on the magnitude of the force carried by the adhesion in such a way that force stabilizes the adhesion reducing the disassembly rate. This is the first way in which mechanosensing is accounted for in this model, and it is based on findings showing that multi-protein adhesion complexes are capable of mechanosensing and are stabilized by force through protein recruitment (11,18,19). Based on modeling of catch bonds (20)…”

Section: Cell Adhesionmentioning

confidence: 99%

Intercellular adhesion stiffness moderates cell decoupling on stiff substrates

Heck

Smeets

et al. 2019

Preprint

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The interplay between cell-cell and cell-substrate interactions is complex yet necessary for the formation and well-functioning of tissues. The same mechanosensing mechanisms used by the cell to sense its extracellular matrix, also play a role in intercellular interactions. We used the discrete element method to develop a computational model of a deformable cell that includes subcellular components responsible for mechanosensing. We modeled a cell pair in 3D on a patterned substrate, a simple laboratory setup to study intercellular interactions. We explicitly modeled focal adhesions between the cells and the substrate, and adherens junctions between cells. These mechanosensing adhesions matured; their disassembly rate was dictated by the force they carry. We also modeled stress fibers which bind the discrete adhesions and contract. The mechanosensing fibers strengthened upon stalling and exerted higher forces. Traction exerted on the substrate was used to generate maps displaying the magnitude of the tractions along the cell-substrate interface. Simulated traction maps are compared to experimental maps obtained via traction force microscopy. The model recreates the dependence on substrate stiffness of the tractions' spatial distribution across the cell-substrate interface, the contractile moment of the cell pair, the intercellular force, and the number of focal adhesions. It also recreates the phenomenon of cell decoupling, in which cells exert forces separately when substrate stiffness increases. More importantly, the model provides viable molecular explanations for decoupling. It shows that the implemented mechanosensing mechanisms are responsible for competition between different fiber-adhesion configurations present in the cell pair. The point at which an increasing substrate stiffness becomes as high as that of the cell-cell interface is the tipping point at which configurations that favor cell-substrate adhesion dominate over those favoring cell-cell adhesion. This competition is responsible for decoupling. Additionally, we learn that extent of decoupling is modulated by adherens junction maturation. Statement of SignificanceCells are sensitive to mechanical factors of their extracellular matrix while simultaneously in contact with other cells. This creates complex intercellular interactions that depend on substrate stiffness and play a role in processes such as development and diseases like cardiac arrhythmia, asthma, and cancer. The simplest cell collective system in vitro is a cell pair on a patterned substrate. We developed a computational model of this system which explains the role of molecular adhesions and contractile fibers in the dynamics of cell-cell interactions on substrates with different stiffness. It is one of the first models of a deformable cell collective based on mechanical principles. It recreates cellular decoupling, a phenomenon in which cells exert forces separately, when substrate stiffness increases.

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Force-dependent binding of vinculin to α-catenin regulates cell–cell contact stability and collective cell behavior

Abstract: Combining cell biology and biomechanical analysis, we show here that the coupling between cadherin complexes and actin through tension-dependent α-catenin/vinculin association is regulating AJ stability and dynamics as well as tissue-scale mechanics.

Cited by 105 publications

References 45 publications

Mechanical Instability of Adherens Junctions Overrides Intrinsic Quiescence of Hair Follicle Stem Cells

Mechanical Instability of Adherens Junctions Overrides Intrinsic Quiescence of Hair Follicle Stem Cells

Quantifying Tensile Forces at Cell–Cell Junctions with a DNA-based Fluorescent Probe

Intercellular adhesion stiffness moderates cell decoupling on stiff substrates

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