scholarly journals Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue

Cell Reports ◽  
2016 ◽  
Vol 14 (1) ◽  
pp. 152-167 ◽  
Author(s):  
Zahra Erami ◽  
David Herrmann ◽  
Sean C. Warren ◽  
Max Nobis ◽  
Ewan J. McGhee ◽  
...  
Keyword(s):  
Cell Junctions ◽  
Dynamic Regulation ◽  
Live Tissue ◽  
Drug Dependent ◽  
E Cadherin ◽  
Cell Cell

scholarly journals HGF Converts ErbB2/Neu Epithelial Morphogenesis to Cell Invasion

2005 ◽  
Vol 16 (2) ◽  
pp. 550-561 ◽  
Author(s):  
Hanane Khoury ◽  
Monica A. Naujokas ◽  
Dongmei Zuo ◽  
Veena Sangwan ◽  
Melanie M. Frigault ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Invasion ◽  
Single Cells ◽  
Epithelial Morphogenesis ◽  
Cell Junctions ◽  
Junction Protein ◽  
Hepatocyte Growth ◽  
E Cadherin ◽  
Cell Cell

Activation of the hepatocyte growth factor receptor Met induces a morphogenic response and stimulates the formation of branching tubules by Madin-Darby canine kidney (MDCK) epithelial cells in three-dimensional cultures. A constitutively activated ErbB2/Neu receptor, NeuNT, promotes a similar invasive morphogenic program in MDCK cells. Because both receptors are expressed in breast epithelia, are associated with poor prognosis, and hepatocyte growth factor (HGF) is expressed in stroma, we examined the consequence of cooperation between these signals. We show that HGF disrupts NeuNT-induced epithelial morphogenesis, stimulating the breakdown of cell-cell junctions, dispersal, and invasion of single cells. This correlates with a decrease in junctional proteins claudin-1 and E-cadherin, in addition to the internalization of the tight junction protein ZO-1. HGF-induced invasion of NT-expressing cells is abrogated by pretreatment with a pharmacological inhibitor of the mitogen-activated protein kinase kinase (MEK) pathway, which restores E-cadherin and ZO-1 at cell-cell junctions, establishing the involvement of MEK-dependent pathways in this process. These results demonstrate that physiological signals downstream from the HGF/Met receptor synergize with ErbB2/Neu to enhance the malignant phenotype, promoting the breakdown of cell-cell junctions and enhanced cell invasion. This is particularly important for cancers where ErbB2/Neu is overexpressed and HGF is a physiological growth factor found in the stroma.

scholarly journals Cortical Tension Initiates the Positive Feedback Loop Between E-cadherin and F-actin

2021 ◽  
Author(s):  
Qilin Yu ◽  
William R. Holmes ◽  
Jean P. Thiery ◽  
Rodney B. Luwor ◽  
Vijay Rajagopal
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Adherens Junctions ◽  
Force Balance ◽  
Intercellular Junction ◽  
Cell Junctions ◽  
Positive Feedback Loop ◽  
Cortical Tension ◽  
E Cadherin ◽  
Cell Cell

AbstractAdherens junctions (AJs) physically link two cells at their contact interface via extracellular homophilic interactions between cadherin molecules and intracellular connections between cadherins and the actomyosin cortex. Both cadherin and actomyosin cytoskeletal dynamics are reciprocally regulated by mechanical and chemical signals, which subsequently determine the strength of cell-cell adhesions and the emergent organization and stiffness of the tissues they form. However, an understanding of the integrated system is lacking. We present a new mechanistic computational model of intercellular junction maturation in a cell doublet to investigate the mechano-chemical crosstalk that regulates AJ formation and homeostasis. The model couples a 2D lattice-based model of cadherin dynamics with a continuum, reaction-diffusion model of the reorganizing actomyosin network through its regulation by Rho signaling at the intercellular junction. We demonstrate that local immobilization of cadherin induces cluster formation in a cis less dependent manner. We further investigate how cadherin and actin regulate and cooperate. By considering the force balance during AJ maturation and the force-sensitive property of the cadherin/F-actin linking molecules, we show that cortical tension applied on the contact rim can explain the ring distribution of cadherin and F-actin on the cell-cell contact of the cell-doublet. Meanwhile, the positive feedback loop between cadherin and F-actin is necessary for maintenance of the ring. Different patterns of cadherin distribution can be observed as an emergent property of disturbances of this feedback loop. We discuss these findings in light of available experimental observations on underlying mechanisms related to cadherin/F-actin binding and the mechanical environment.Significance StatementThe formation, maintenance and disassembly of adherens junctions (AJs) is fundamental to organ development, tissue integrity as well as tissue function. E-cadherins and F-actin are two major players of the adherens junctions (AJs). Although it is well known that cadherins and F-actin affect each other, how these two players work together to maintain the intercellular contact is unclear. Using a novel mechano-chemical model of E-cadherin and F-actin remodeling, we demonstrate that a positive feedback loop between cadherins and F-actin allows them to stabilize each other locally. Mechanical and chemical stimuli applied to the cell adhesion change E-cadherin and F-actin distribution by consolidating or interrupting the feedback loop locally. Our study mechanistically links mechanical force to E-cadherin patterning at cell-cell junctions.

Cdx1 or Cdx2 expression activates E-cadherin-mediated cell-cell adhesion and compaction in human COLO 205 cells

2004 ◽  
Vol 287 (1) ◽  
pp. G104-G114 ◽  
Author(s):  
Matthew S. Keller ◽  
Toshihiko Ezaki ◽  
Rong-Jun Guo ◽  
John P. Lynch
Keyword(s):  
Gene Expression ◽  
Cell Adhesion ◽  
Gene Expression Pattern ◽  
Cell Junctions ◽  
Specific Gene ◽  
Specific Response ◽  
Specific Gene Expression ◽  
Cdx2 Expression ◽  
E Cadherin ◽  
Cell Cell

A mature columnar intestinal epithelium develops late in embryogenesis and is maintained throughout the life of the organism. Although the mechanisms driving intestine-specific gene expression have been well studied, those promoting the acquisition of cell-cell junctions, columnar morphogenesis, and polarization have been less studied. The Cdx homeodomain transcription factors (Cdx1 and Cdx2) regulate intestine-specific gene expression and intestinal epithelial differentiation. We report here that Cdx expression induces E-cadherin activity and cell-cell adhesion in human COLO 205 cancer cells. Within days of Cdx1 or Cdx2 expression, a new homotypic cell-cell adhesion phenotype is induced. This is a specific response to Cdx, inasmuch as a Cdx1 mutant failed to elicit the effect. Additionally, Cdx-expressing COLO 205 cells demonstrate a reduced proliferative capacity and an increase in the mRNA expression of differentiation-associated genes. Electron micrographs of these cells demonstrate induction of tight, adherens, and desmosomal junctions, as well as a columnar shape and apical microvilli. Investigations of the adhesion phenotype determined that it was Ca2+dependent and could be blocked by an E-cadherin-blocking antibody. However, E-cadherin protein levels and intracellular distribution were unchanged. Cdx expression restored the ability of the cell membranes to adhere and undergo compaction. We conclude that Cdx1 or Cdx2 expression is sufficient to induce an E-cadherin-dependent adhesion of COLO 205 cells. This adhesion is associated with polarization and cell-cell membrane compaction, as well as induction of a differentiated gene-expression pattern. Ascertaining the mechanism for this novel Cdx effect may yield insight into the development of mature colonic epithelium.

scholarly journals mDia2 formin selectively interacts with catenins and not E-cadherin to regulate Adherens Junction formation

2019 ◽  
Author(s):  
Yuqi Zhang ◽  
Krista M. Pettee ◽  
Kathryn N. Becker ◽  
Kathryn M. Eisenmann
Keyword(s):  
Single Cell ◽  
Actin Polymerization ◽  
Plasma Membranes ◽  
Adherens Junctions ◽  
Single Cells ◽  
Critical Role ◽  
Cell Junctions ◽  
Hek 293 ◽  
E Cadherin ◽  
Cell Cell

AbstractBackgroundEpithelial ovarian cancer (EOC) cells disseminate within the peritoneal cavity, in part, via the peritoneal fluid as single cells, clusters, or spheroids. Initial single cell egress from a tumor can involve disruption of cell-cell adhesions as cells are shed from the primary tumor into the peritoneum. In epithelial cells, Adherens Junctions (AJs) are characterized by homotypic linkage of E-cadherins on the plasma membranes of adjacent cells. AJs are anchored to the intracellular actin cytoskeletal network through a complex involving E-cadherin, p120 catenin, β-catenin, and αE-catenin. However, the specific players involved in the interaction between the junctional E-cadherin complex and the underlying F-actin network remains unclear. Recent evidence indicates that mammalian Diaphanous-related (mDia) formins plays a key role in epithelial cell AJ formation and maintenance through generation of linear actin filaments. Binding of αE-catenin to linear F-actin inhibits association of the branched-actin nucleator Arp2/3, while favoring linear F-actin bundling. We previously demonstrated that loss of mDia2 was associated with invasive single cell egress from EOC spheroids through disruption of junctional F-actin.ResultsIn the current study, we now show that mDia2 has a role at adherens junctions (AJs) in EOC OVCA429 cells and human embryonic kidney (HEK) 293 cells through its association with αE-catenin and β-catenin. mDia2 depletion in EOC cells leads to reduction in actin polymerization and disruption of cell-cell junctions with decreased interaction between β-catenin and E-cadherin.ConclusionsOur results support a necessary role for mDia2 in AJ stability in EOC cell monolayers and indicate a critical role for mDia formins in regulating EOC AJs during invasive transitions.

scholarly journals Actin protrusions push on E-cadherin to maintain epithelial cell-cell adhesion

2019 ◽  
Author(s):  
John Xiao He Li ◽  
Vivian W. Tang ◽  
William M. Brieher
Keyword(s):  
Cell Adhesion ◽  
Actin Polymerization ◽  
Mdck Cells ◽  
Myosin Ii ◽  
Cell Junctions ◽  
Apical Junctions ◽  
Actin Protrusions ◽  
Adhesive Contacts ◽  
E Cadherin ◽  
Cell Cell

AbstractCadherin mediated cell-cell adhesion is actin dependent, but the precise role of actin in maintaining cell-cell adhesion is not fully understood. Actin polymerization-dependent protrusive activity is required to push distally separated cells close enough together to initiate contact. Whether protrusive activity is required to maintain adhesion in confluent sheets of epithelial cells is not known. By electron microscopy as well as live cell imaging, we have identified a population of protruding actin microspikes that operate continuously near apical junctions of polarized MDCK cells. Live imaging shows that microspikes containing E-cadherin extend into gaps between E-cadherin clusters on neighboring cells while reformation of cadherin clusters across the cell-cell boundary triggers microspike withdrawal. We identify Arp2/3, EVL, and CRMP-1 as three actin assembly factors necessary for microspike formation. Depleting these factors from cells using RNAi results in myosin II-dependent unzipping of cadherin adhesive bonds. Therefore, actin polymerization-dependent protrusive activity operates continuously at cadherin cell-cell junctions to keep them shut and to prevent myosin II-dependent contractility from tearing cadherin adhesive contacts apart.

scholarly journals Nectins rather than E-cadherin anchor the actin belts at cell-cell junctions of epithelia

2019 ◽  
Author(s):  
Pierre Mangeol ◽  
Dominique Massey-Harroche ◽  
André Le Bivic ◽  
Pierre-François Lenne
Keyword(s):  
Super Resolution ◽  
Cell Junctions ◽  
Mechanical Tension ◽  
Mechanical Integrity ◽  
Super Resolution Microscopy ◽  
E Cadherin ◽  
Cell Cell

AbstractCell-cell junctions support the mechanical integrity of epithelia by enabling adhesion and tension transmission between neighboring cells. The prevailing mechanistic dogma is that E-cadherin supports and transmits mechanical tension between cells through actin belts in a region named the zonula adherens. Using super-resolution microscopy on human intestinal biopsies and Caco-2 cells, we show that the zonula adherens consists of E-cadherin and nectin belts that are separated by about 150 nm along the apico-basal direction, the nectin belt being in the immediate vicinity of the actin belt. The segregation of nectins and E-cadherin increases as the tissue matures. Our data redefine the structure of the zonula adherens and show that nectins, rather than E-cadherin, are the major connectors of actin belts in epithelia.

scholarly journals β-catenin activation down-regulates cell-cell junction-related genes and induces epithelial-to-mesenchymal transition in colorectal cancers

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Won Kyu Kim ◽  
Yujin Kwon ◽  
Mi Jang ◽  
Minhee Park ◽  
Jiyoon Kim ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Junctions ◽  
Nuclear Accumulation ◽  
Colorectal Cancers ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Nuclear Expression ◽  
E Cadherin ◽  
Cell Cell

AbstractWNT signaling activation in colorectal cancers (CRCs) occurs through APC inactivation or β-catenin mutations. Both processes promote β-catenin nuclear accumulation, which up-regulates epithelial-to-mesenchymal transition (EMT). We investigated β-catenin localization, transcriptome, and phenotypic differences of HCT116 cells containing a wild-type (HCT116-WT) or mutant β-catenin allele (HCT116-MT), or parental cells with both WT and mutant alleles (HCT116-P). We then analyzed β-catenin expression and associated phenotypes in CRC tissues. Wild-type β-catenin showed membranous localization, whereas mutant showed nuclear localization; both nuclear and non-nuclear localization were observed in HCT116-P. Microarray analysis revealed down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT without E-cadherin dysregulation. We found that ZEB1 is a critical EMT factor for mutant β-catenin-mediated loss of E-cadherin and Claudin-7 in HCT116-P and HCT116-MT cells. We also demonstrated that E-cadherin binds to both WT and mutant β-catenin, and loss of E-cadherin releases β-catenin from the cell membrane and leads to its degradation. Alteration of Claudin-7, as well as both Claudin-7 and E-cadherin respectively caused tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased cell motility, and subsequent AJ loss further up-regulated that. Immunohistochemistry analysis of 101 CRCs revealed high (14.9%), low (52.5%), and undetectable (32.6%) β-catenin nuclear expression, and high β-catenin nuclear expression was significantly correlated with overall survival of CRC patients (P = 0.009). Our findings suggest that β-catenin activation induces EMT progression by modifying cell-cell junctions, and thereby contributes to CRC aggressiveness.

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