Allosteric Regulation of E-Cadherin Adhesion

Shashikanth, Nitesh; Petrova, Yuliya; Park, Seong-Jin; Chekan, Jillian; Maiden, Stephanie L.; Spano, Martha; Ha, Taekjip; Gumbiner, Barry M.; Leckband, Deborah

doi:10.1074/jbc.m115.657098

Cited by 45 publications

(45 citation statements)

References 81 publications

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“…We previously showed that E-cadherin–mediated adhesion in colo205 cells could also be activated intracellularly by dephosphorylation of p120-catenin (Petrova et al. , 2012) and that p120-catenin dephosphorylation and adhesion activation can be induced by treatment with LiCl (GSK3b inhibitor) or nocodazole to disassemble microtubules (Shashikanth et al. , 2015; Maiden et al.…”

Section: Resultsmentioning

confidence: 99%

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Roles for E-cadherin cell surface regulation in cancer

Petrova

Schecterson

Gumbiner

2016

MBoC

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218

174

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Section: Resultsmentioning

confidence: 99%

“…From previous work, we know that changes in the molecular structure of the E-cadherin ectodomain at the cell surface are probably involved in allosteric regulation of adhesive binding (Petrova et al. , 2012; Shashikanth et al. , 2015).…”

Section: Discussionmentioning

confidence: 99%

Roles for E-cadherin cell surface regulation in cancer

Petrova

Schecterson

Gumbiner

2016

MBoC

Self Cite

218

174

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“…In controls, beads were coated with either poly-L-Lysine (PLL), blocking anti-E-cadherin antibody DECMA-1 (Sigma-Aldrich, St Louis, MO, U3254) (Ozawa et al, 1990), or with neutral (non-blocking) anti-E-cadherin antibody (Clone 76D5, from Barry Gumbiner, University of Virginia, Charlottesville, VA). The neutral antibody binds the ectodomain, but does not alter the E-cadherin-binding affinity (Petrova et al, 2012;Shashikanth et al, 2015). In all cases, the bead coatings were optimized to bind cells and undergo displacements sufficient to measure the viscoelastic moduli of bead-cell junctions (Barry et al, 2014(Barry et al, , 2015le Duc et al, 2010;Tabdili et al, 2012b;Twiss et al, 2012).…”

Section: Magnetic Twisting Cytometrymentioning

confidence: 99%

E-cadherin-mediated force transduction signals regulate global cell mechanics

Muhamed

Sehgal

et al. 2016

Journal of Cell Science

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104

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This report elucidates an E-cadherin-based force-transduction pathway that triggers changes in cell mechanics through a mechanism requiring epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), and the downstream formation of new integrin adhesions. This mechanism operates in addition to local cytoskeletal remodeling triggered by conformational changes in the E-cadherin-associated protein α-catenin, at sites of mechanical perturbation. Studies using magnetic twisting cytometry (MTC), together with traction force microscopy (TFM) and confocal imaging identified force-activated E-cadherin-specific signals that integrate cadherin force transduction, integrin activation and cell contractility. EGFR is required for the downstream activation of PI3K and myosin-II-dependent cell stiffening. Our findings also demonstrated that α-catenin-dependent cytoskeletal remodeling at perturbed E-cadherin adhesions does not require cell stiffening. These results broaden the repertoire of E-cadherin-based force transduction mechanisms, and define the force-sensitive signaling network underlying the mechano-chemical integration of spatially segregated adhesion receptors.

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“…The binding parameters of cadherin's trans interactions have been determined by NMR spectroscopy and surface plasmon resonance (47,50), but the cis interaction parameters are unknown. Therefore, before studying the process of cell adhesion with the RB model, we first calibrated the model's accuracy by testing it against micropipette measurements obtained with cadherin mutants that only formed trans interactions, such as the previously reported L175D cis interaction mutant (14,51). Specifically, 100 cadherins on planar parallel surfaces were only allowed to form trans dimers.…”

Section: Resultsmentioning

confidence: 99%

“…This protein forms trans bonds but destabilizes lateral clustering by preventing the formation of cis dimers. The experimental data were obtained from adhesion probability measurements between two red blood cells that had been ectopically modified with the E-cadherin ectodomains (51).…”

Section: Resultsmentioning

confidence: 99%

A Computational Model for Kinetic Studies of Cadherin Binding and Clustering

Chen

Newhall

Xie

et al. 2016

Biophysical Journal

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Cadherin is a cell-surface transmembrane receptor that mediates calcium-dependent cell-cell adhesion and is a major component of adhesive junctions. The formation of intercellular adhesive junctions is initiated by trans binding between cadherins on adjacent cells, which is followed by the clustering of cadherins via the formation of cis interactions between cadherins on the same cell membranes. Moreover, classical cadherins have multiple glycosylation sites along their extracellular regions. It was found that aberrant glycosylation affects the adhesive function of cadherins and correlates with metastatic phenotypes of several cancers. However, a mechanistic understanding of cadherin clustering during cell adhesion and the role of glycosylation in this process is still lacking. Here, we designed a kinetic model that includes multistep reaction pathways for cadherin clustering. We further applied a diffusion-reaction algorithm to numerically simulate the clustering process using a recently developed coarse-grained model. Using experimentally measured rates of trans binding between soluble E-cadherin extracellular domains, we conducted simulations of cadherin-mediated cell-cell binding kinetics, and the results are quantitatively comparable to experimental data from micropipette experiments. In addition, we show that incorporating cadherin clustering via cis interactions further increases intercellular binding. Interestingly, a two-phase kinetic profile was derived under the assumption that glycosylation regulates the kinetic rates of cis interactions. This two-phase profile is qualitatively consistent with experimental results from micropipette measurements. Therefore, our computational studies provide new, to our knowledge, insights into the molecular mechanism of cadherin-based cell adhesion.

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Allosteric Regulation of E-Cadherin Adhesion

Cited by 45 publications

References 81 publications

Roles for E-cadherin cell surface regulation in cancer

Roles for E-cadherin cell surface regulation in cancer

E-cadherin-mediated force transduction signals regulate global cell mechanics

A Computational Model for Kinetic Studies of Cadherin Binding and Clustering

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