E-cadherin is under constitutive actomyosin-generated tension that is increased at cell–cell contacts upon externally applied stretch

Borghi, Nicolas; Sorokina, Maria; Shcherbakova, Olga G.; Weis, William I.; Pruitt, Beth L.; Nelson, W. James; Dunn, Alexander R.

doi:10.1073/pnas.1204390109

Cited by 536 publications

(605 citation statements)

References 59 publications

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“…Substrates immobilized with Ecad-Fc mimic cell-cell interactions, and cellular E-cadherin protein dynamics at the Ecad-Fc interface are similar to those found at endogenous cellcell junctions (27,28). Saturating amounts of Ecad-Fc were bound to substrates to ensure maximum engagement of E-cadherin in adhering cells (23).…”

Section: Resultsmentioning

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: Resultsmentioning

confidence: 99%

“…Cadherins are also mechanosensitive proteins (21,22). E-cadherin is under constitutive tension at cell-cell junctions and dynamically responds to changes in tension (23). Cellular responses to exogenous tension applied directly to cadherins using functionalized beads have been studied extensively (22,24,25).…”

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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“…The reality is that molecular changes to the architecture of cell-cell junctions likely accompany force driven detachment of cell-cell adhesion. In fact, it may be impossible to distinguish these events, as linkage of cadherin-based adhesions to actin appears to be tension dependent 120,121 and changes in cellular contractility would alter the molecular architecture at sites of cell-cell adhesion. In fact, a model whereby cell spreading precedes contractility and cellcell detachment is attractive in this light, as the relaxation of myosin-based contractility occurring in cell spreading may in fact prime cell-cell junctions by releasing actin anchoring of cadherin complex just before cellular contractility is increased to rupture now weakened cell-cell junctions.…”

Section: Discussionmentioning

confidence: 99%

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

2016

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Epithelial tissues use adherens junctions to maintain tight interactions and coordinate cellular activities. Adherens junctions are remodeled during epithelial morphogenesis, including instances of epithelialmesenchymal transition, or EMT, wherein individual cells detach from the tissue and migrate as individual cells. EMT has been recapitulated by growth factor induction of epithelial scattering in cell culture. In culture systems, cells undergo a highly reproducible series of cell morphology changes, most notably cell spreading followed by cellular compaction and cell migration. These morphology changes are accompanied by striking actin rearrangements. The current evidence suggests that global changes in actomyosin-based cellular contractility, first a loss of contractility during spreading and its activation during cell compaction, are the main drivers of epithelial scattering. In this review, we focus on how spreading and contractility might be controlled during epithelial scattering. While we propose a central role for RhoA, which is well known to control cellular contractility in multiple systems and whose role in epithelial scattering is well accepted, we suggest potential roles for additional cellular systems whose role in epithelial cell biology has been less well documented. In particular, we propose critical roles for vesicle recycling, calcium channels, and calcium-dependent kinases.

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“…For example, there are few tools for quantify ing how cells push and pull on each other in a tissue. Stanford University chemical engineer Alexander Dunn and his colleagues were able to measure these forces by integrating Grashoff and Schwartz's FRET sensor into E cadherin, a protein that couples cells together 8 .…”

Section: Reprinted From H Van Hoorn Et Almentioning

confidence: 99%

A measure of molecular muscle

Eisenstein¹

2017

Nature

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E-cadherin is under constitutive actomyosin-generated tension that is increased at cell–cell contacts upon externally applied stretch

Cited by 536 publications

References 59 publications

Changes in E-cadherin rigidity sensing regulate cell adhesion

Changes in E-cadherin rigidity sensing regulate cell adhesion

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

A measure of molecular muscle

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