Actin-Delimited Adhesion-Independent Clustering of E-Cadherin Forms the Nanoscale Building Blocks of Adherens Junctions

Wu, Yao; Kanchanawong, Pakorn; Zaidel-Bar, Ronen

doi:10.1016/j.devcel.2014.12.003

Cited by 183 publications

(251 citation statements)

References 55 publications

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“…This estimation approaches the spatial resolution limit of our microscope and, therefore, may overestimate the diameter of E-cadherin clusters. The size of these puncta is similar to that of E-cadherin clusters at cell-cell contacts in A431D cells (112 nm), but larger than that of E-cadherin clusters in EphA4 cells (60 nm) (60). It is possible that E-cadherin cluster size differs in distinct cell types and at different stages of cell-cell adhesion (61), but additional studies at high resolution are required to track E-cadherin puncta size and organization over time.…”

Section: Discussionmentioning

confidence: 63%

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: 63%

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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“…The K 2D values of WT and L175D mouse E-cadherin were the same, although L175D reduces the sizes of cadherin clusters larger than 20 nm (58).…”

Section: Discussionmentioning

confidence: 69%

“…Based on STORM images, clusters of the mouse E-cadherin L175D cis mutant expressed on A431 cells were significantly smaller than WT E-cadherin (58). Fig.…”

Section: Colo 205 Treatment With Staurosporine Increases the E-cadhermentioning

confidence: 99%

“…The E-cadherin Mutant L175D Does Not Alter the transBinding Affinity-Cadherin clustering appears to involve both the extracellular and cytoplasmic domains (18,19,37,58). Here we tested how disrupting a putative cis-interaction (63) between extracellular domains affected the fitted kinetic parameters.…”

Section: Colo 205 Treatment With Staurosporine Increases the E-cadhermentioning

confidence: 99%

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Allosteric Regulation of E-Cadherin Adhesion

Shashikanth¹,

Petrova

Park³

et al. 2015

Journal of Biological Chemistry

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Background: Measured binding kinetics between Colo 205 cells tested the postulate that E-cadherin adhesion is allosterically regulated. Results: p120 catenin dephosphorylation or cell treatment with activating anti-E-cadherin antibody increased E-cadherin binding affinities by 2-3-fold. Conclusion: Perturbations that do not directly affect the binding site enhanced the adhesive function of E-cadherin. Significance: These biophysical measurements demonstrated that E-cadherin is allosterically regulated.

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“…Studies with E-cadherin (E-cad)-coated substrates have revealed the existence of E-cad nanoclusters as fundamental units for cell-cell adhesion, and their existence has been confirmed by super-resolution imaging of mammalian cellcell contacts (Wu et al, 2015;Strale et al, 2015), as well as in Drosophila (Truong Quang et al, 2013). In addition, both E-and N-cad-coated deformable pillars allow the measurement of the traction forces that are exerted by a single cell across cadherin bonds.…”

Section: Ecm Sensingmentioning

confidence: 99%

How cells respond to environmental cues – insights from bio-functionalized substrates

Ruprecht

Monzo

Ravasio

et al. 2016

Journal of Cell Science

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Biomimetic materials have long been the (he)art of bioengineering. They usually aim at mimicking in vivo conditions to allow in vitro culture, differentiation and expansion of cells. The past decade has witnessed a considerable amount of progress in soft lithography, bioinspired micro-fabrication and biochemistry, allowing the design of sophisticated and physiologically relevant micro-and nanoenvironments. These systems now provide an exquisite toolbox with which we can control a large set of physicochemical environmental parameters that determine cell behavior. Biofunctionalized surfaces have evolved from simple protein-coated solid surfaces or cellular extracts into nano-textured 3D surfaces with controlled rheological and topographical properties. The mechanobiological molecular processes by which cells interact and sense their environment can now be unambiguously understood down to the single-molecule level. This Commentary highlights recent successful examples where bio-functionalized substrates have contributed in raising and answering new questions in the area of extracellular matrix sensing by cells, cell-cell adhesion and cell migration. The use, the availability, the impact and the challenges of such approaches in the field of biology are discussed.

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Actin-Delimited Adhesion-Independent Clustering of E-Cadherin Forms the Nanoscale Building Blocks of Adherens Junctions

Cited by 183 publications

References 55 publications

Changes in E-cadherin rigidity sensing regulate cell adhesion

Changes in E-cadherin rigidity sensing regulate cell adhesion

Allosteric Regulation of E-Cadherin Adhesion

How cells respond to environmental cues – insights from bio-functionalized substrates

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