Cyclooxygenase‐2 and RhoA Signaling Disrupts Cell‐Cell Adhesion by the Regulation of the Transcriptional Repressor, ZEB‐1

Epithelia migrate as physically coherent populations of cells. Earlier studies revealed that mechanical stress accumulates in these cellular layers as they move. These stresses are characteristically tensile in nature and have often been inferred to arise when moving cells pull upon the cell-cell adhesions that hold them together. We now report that epithelial tension at adherens junctions between migrating cells also reflects an increase in RhoAmediated junctional contractility. We find that active RhoA levels were stimulated by p114 RhoGEF at the junctions between migrating MCF-7 monolayers, and this is accompanied by increased levels of actomyosin and mechanical tension. By applying a strategy to restore active RhoA specifically at adherens junctions by manipulating its scaffold, anillin, we found that this junctional RhoA signal was necessary to stabilize junctional E-cadherin during epithelial migration. We suggest that stabilization of E-cadherin by RhoA serves to increase cell-cell adhesion against the mechanical stresses of migration.

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The Heterotaxy Gene CCDC11 is Essential for Cytokinesis and Cell-Cell Adhesion via RhoA Regulation

10.1101/452631 ◽

2018 ◽

Author(s):

Saurabh Kulkarni ◽

Rachel E. Stephenson ◽

Sarah Amalraj ◽

Ewelina Betleja ◽

James J. Moresco ◽

...

Keyword(s):

Cell Adhesion ◽

Small Gtpase ◽

Loss Of Function ◽

Contractile Ring ◽

Internal Organs ◽

Protein Levels ◽

Rhoa Protein ◽

Rhoa Signaling ◽

Multiple Patients ◽

Cell Cell

SUMMARYMutations in CCDC11 have been identified in multiple patients with heterotaxy (Htx), a disorder of left-right (LR) patterning of the internal organs. In Xenopus, depletion of Ccdc11 causes defects in LR patterning, recapitulating the patient phenotype. Upon Ccdc11 depletion, normally monociliated cells of the Left-Right Organizer (LRO) exhibit multiple cilia per cell. Unexpectedly, we found that Ccdc11 is necessary for successful cytokinesis, and the multiciliation observed in Ccdc11-depleted cells was due to failed cytokinesis. Furthermore, CCDC11 depletion alters cell-cell adhesion with reduction in junctional localization of adhesion molecules. The small GTPase RhoA is critical for cytokinesis and cell-cell adhesion. Because the CCDC11 depletion phenotypes are reminiscent of RhoA loss of function, we investigated a possible connection to regulation of RhoA signaling. We demonstrate that CCDC11 is localized to the cytokinetic contractile ring overlapping with RhoA during cytokinesis and regulates total RhoA protein levels. Our results suggest that CCDC11 connects cytokinesis and LR patterning via RhoA regulation, providing a potential mechanism for heterotaxy disease pathogenesis.

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Enhanced RhoA signaling stabilizes E-cadherin in migrating epithelial monolayers

Journal of Cell Science ◽

10.1242/jcs.258767 ◽

2021 ◽

Author(s):

Shafali Gupta ◽

Kinga Duszyc ◽

Suzie Verma ◽

Srikanth Budnar ◽

Xuan Liang ◽

...

Keyword(s):

Cell Adhesion ◽

Mechanical Stress ◽

Adherens Junctions ◽

Mechanical Tension ◽

Epithelial Migration ◽

Epithelial Monolayers ◽

Rhoa Signaling ◽

Mcf 7 ◽

E Cadherin ◽

Cell Cell

Epithelia migrate as physically coherent populations of cells. Earlier studies revealed that mechanical stress accumulates in these cellular layers as they move. These stresses are characteristically tensile in nature and have often been inferred to arise when moving cells pull upon the cell-cell adhesions that hold them together. We now report that epithelial tension at adherens junctions between migrating cells also increases due to an increase in RhoA-mediated junctional contractility. We find that active RhoA levels were stimulated by p114 RhoGEF at the junctions between migrating MCF-7 monolayers, and this was accompanied by increased levels of actomyosin and mechanical tension. Applying a strategy to restore active RhoA specifically at adherens junctions by manipulating its scaffold, anillin, we found that this junctional RhoA signal was necessary to stabilize junctional E-cadherin during epithelial migration and promoted orderly collective movement. We suggest that stabilization of E-cadherin by RhoA serves to increase cell-cell adhesion against the mechanical stresses of migration.

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