The minimal cadherin-catenin complex binds to actin filaments under force

Buckley, Craig; Tan, Jiongyi; Anderson, Karen; Hanein, Dorit; Volkmann, Niels; Weis, William I.; Nelson, W. James; Dunn, Alexander R.

doi:10.1126/science.1254211

Cited by 548 publications

(463 citation statements)

References 71 publications

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“…At present, we do not know which formin(s) is (are) regulated by the stiffness of E-cadherin interactions. However, formin1 binds directly to the E-cadherin complex through α-catenin (67), and it is possible that forces at E-cadherin adhesions activate α-catenin binding to formins via force-dependent changes in α-catenin conformation (68), perhaps similar to that required for binding to F-actin (5). In this context, FMNL3 recruitment to junctions is tension dependent and regulated by Cdc42 (14).…”

Section: Discussionmentioning

confidence: 99%

“…Integrins bind to the ECM and intracellular proteins that link to the actin cytoskeleton and important signaling pathways (2). Similarly, cadherins regulate cellcell recognition and adhesion (3) and, through cytoplasmic adaptor proteins (catenins, vinculin) (4,5), also link to the actin cytoskeleton and other proteins with signaling and scaffolding functions (6).…”

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confidence: 99%

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Changes in E-cadherin rigidity sensing regulate cell adhesion

Collins

Denisin

Pruitt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mechanical cues are sensed and transduced by cell adhesion complexes to regulate diverse cell behaviors. Extracellular matrix (ECM) rigidity sensing by integrin adhesions has been well studied, but rigidity sensing by cadherins during cell adhesion is largely unexplored. Using mechanically tunable polyacrylamide (PA) gels functionalized with the extracellular domain of E-cadherin (Ecad-Fc), we showed that E-cadherin-dependent epithelial cell adhesion was sensitive to changes in PA gel elastic modulus that produced striking differences in cell morphology, actin organization, and membrane dynamics. Traction force microscopy (TFM) revealed that cells produced the greatest tractions at the cell periphery, where distinct types of actin-based membrane protrusions formed. Cells responded to substrate rigidity by reorganizing the distribution and size of hightraction-stress regions at the cell periphery. Differences in adhesion and protrusion dynamics were mediated by balancing the activities of specific signaling molecules. Cell adhesion to a 30-kPa Ecad-Fc PA gel required Cdc42-and formin-dependent filopodia formation, whereas adhesion to a 60-kPa Ecad-Fc PA gel induced Arp2/3-dependent lamellipodial protrusions. A quantitative 3D cell-cell adhesion assay and live cell imaging of cell-cell contact formation revealed that inhibition of Cdc42, formin, and Arp2/3 activities blocked the initiation, but not the maintenance of established cell-cell adhesions. These results indicate that the same signaling molecules activated by E-cadherin rigidity sensing on PA gels contribute to actin organization and membrane dynamics during cell-cell adhesion. We hypothesize that a transition in the stiffness of E-cadherin homotypic interactions regulates actin and membrane dynamics during initial stages of cellcell adhesion.C ell adhesion is essential for tissue structure and function. Cells use specialized types of adhesions to interact with the surrounding environment, including integrin-based focal adhesions at cell-extracellular matrix (cell-ECM) contacts and cadherin-based adhesions at cell-cell contacts (1). Integrins bind to the ECM and intracellular proteins that link to the actin cytoskeleton and important signaling pathways (2). Similarly, cadherins regulate cellcell recognition and adhesion (3) and, through cytoplasmic adaptor proteins (catenins, vinculin) (4, 5), also link to the actin cytoskeleton and other proteins with signaling and scaffolding functions (6).Initiation of cell-cell adhesion requires significant reorganization of the actin cytoskeleton and is tightly controlled by the activities of actin nucleating proteins and Rho GTPases. Adhesion is initiated when filopodia from opposing cells come into contact with one another (7,8), and this process is regulated by Cdc42 activity (9, 10) and formin-dependent actin polymerization (11)(12)(13)(14). Intermediate stages of cell-cell contact formation involve lateral expansion of the contact by Rac1-induced and Arp2/3-dependent lamellipodial activity (15, 16). Finally, com...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Changes in E-cadherin rigidity sensing regulate cell adhesion

Collins

Denisin

Pruitt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Strong interaction of this minimal cadherin-catenin complex to actin requires force. 17 Interestingly, binding of vinculin to aEcatenin has also been demonstrated to be stabilized by tension. 18,19 In endothelial cells, force exerted on cell-cell junctions was shown to recruit vinculin, which protected VE-cadherin junctions against opening.…”

Section: Introductionmentioning

confidence: 99%

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

Buul

Timmerman

2016

Small GTPases

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VE-cadherin-based cell-cell junctions form the major restrictive barrier of the endothelium to plasma proteins and blood cells. The function of VE-cadherin and the actin cytoskeleton are intimately linked. Vascular permeability factors and adherent leukocytes signal through small Rho GTPases to tightly regulate actin cytoskeletal rearrangements in order to open and re-assemble endothelial cell-cell junctions in a rapid and controlled manner. The Rho GTPases are activated by guanine nucleotide exchange factors (GEFs), conferring specificity and context-dependent control of cell-cell junctions. Although the molecular mechanisms that couple cadherins to actin filaments are beginning to be elucidated, specific stimulus-dependent regulation of the actin cytoskeleton at VEcadherin-based junctions remains unexplained. Accumulating evidence has suggested that depending on the vascular permeability factor and on the subcellular localization of GEFs, cell-cell junction dynamics and organization are differentially regulated by one specific Rho GTPase. In this Commentary, we focus on new insights how the junctional actin cytoskeleton is specifically and locally regulated by Rho GTPases and GEFs in the endothelium.

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“…• The response of cell adhesion complexes to mechanical forces is diverse, [29][30][31]. Phenomenological theories, based on two state models [32,33], and microscopic theory [34,35] …”

Section: Discussionmentioning

confidence: 99%

Forced-rupture of Cell-Adhesion Complexes Reveals abrupt switch between two Brittle States

Toan

Thirumalai

2017

Preprint

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Cell adhesion complexes (CACs), which are activated by ligand binding, play key roles in many cellular functions ranging from cell cycle regulation to mediation of cell extracellular matrix adhesion.Inspired by single molecule pulling experiments using atomic force spectroscopy on leukocyte function-associated antigen-1 (LFA-1), expressed in T-cells, bound to intercellular adhesion molecules (ICAM), we performed constant loading rate (r f ) and constant force (F ) simulations using the Self-Organized Polymer (SOP) model to describe the mechanism of ligand rupture from CACs. The simulations reproduce the major experimental finding on the kinetics of the rupture process, namely, the dependence of the most probable rupture forces (f * s) on ln r f (r f is the loading rate) exhibits two distinct linear regimes. The first, at low r f , has a shallow slope whereas the the slope at high r f is much larger, especially for LFA-1/ICAM-1 complex with the transition between the two occurring over a narrow r f range. Locations of the two transition states (TSs), extracted from the simulations show an abrupt change from a high value at low r f or F to a low value at high r f or F . This unusual behavior in which the CACs switch from one brittle (TS position is a constant over a range of forces) state to another brittle state is not found in forced-rupture in other protein complexes. We explain this novel behavior by constructing the free energy profiles, F (Λ)s, as a function of a collective reaction coordinate (Λ), involving many key charged residues and a critical metal ion 2 peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/211045 doi: bioRxiv preprint first posted online Oct. 29, 2017; (M g 2+ ). The TS positions in F(Λ), which quantitatively agree with the parameters extracted using the Bell-Evans model, change abruptly at a critical force, demonstrating that it, rather than the molecular extension is a good reaction coordinate. Our combined analyses using simulations performed in both the pulling modes (constant r f and force) reveal a new mechanism for the two loading regimes observed in the rupture kinetics in CACs.

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The minimal cadherin-catenin complex binds to actin filaments under force

Cited by 548 publications

References 71 publications

Changes in E-cadherin rigidity sensing regulate cell adhesion

Changes in E-cadherin rigidity sensing regulate cell adhesion

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

Forced-rupture of Cell-Adhesion Complexes Reveals abrupt switch between two Brittle States

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