scholarly journals E-cadherin endocytosis is modulated by p120-catenin through the opposing actions of RhoA and Arf1

2018 ◽  
Author(s):  
Joshua Greig ◽  
Natalia A. Bulgakova
Keyword(s):  
Plasma Membrane ◽  
Cell Adhesion ◽  
Actin Dynamics ◽  
P120 Catenin ◽  
Vital Importance ◽  
C Terminus ◽  
Opposing Effects ◽  
Actin Remodelling ◽  
Tissue Tension ◽  
E Cadherin

AbstractThe regulation of E-cadherin at the plasma membrane by endocytosis is of vital importance for developmental and disease. p120-catenin, which binds to the E-cadherin C-terminus, can both promote and inhibit E-cadherin endocytosis. However, little is known about what determines the directionality of p120-catenin activity, and the molecules downstream. Here, we have discovered that p120-catenin fine-tunes the clathrin-mediated endocytosis of E-cadherin in Drosophila embryonic epidermal cells. It simultaneously activated two actin-remodelling pathways with opposing effects: RhoA, which stabilized E-cadherin at the membrane, and Arf1, which promoted internalization. Epistasis experiments revealed that RhoA additionally inhibited Arf1. E-cadherin was efficiently endocytosed only in the presence of intermediate p120-catenin amounts with too little and too much p120-catenin inhibiting E-cadherin endocytosis. Finally, we found that p120-catenin levels altered the tension of the plasma membrane. Altogether, this shows that p120-catenin is a central hub which co-ordinates cell adhesion, endocytosis, and actin dynamics with tissue tension.

scholarly journals Interplay between actomyosin and E-cadherin dynamics regulates cell shape in the Drosophila embryonic epidermis

2020 ◽  
Vol 133 (15) ◽  
pp. jcs242321
Author(s):  
Joshua Greig ◽  
Natalia A. Bulgakova
Keyword(s):  
Plasma Membrane ◽  
Cell Adhesion ◽  
Cell Elongation ◽  
Cell Shape ◽  
Intercellular Adhesion ◽  
Epithelial Tissue ◽  
P120 Catenin ◽  
Endocytic Machinery ◽  
E Cadherin

ABSTRACTPrecise regulation of cell shape is vital for building functional tissues. Here, we study the mechanisms that lead to the formation of highly elongated anisotropic epithelial cells in the Drosophila epidermis. We demonstrate that this cell shape is the result of two counteracting mechanisms at the cell surface that regulate the degree of elongation: actomyosin, which inhibits cell elongation downstream of RhoA (Rho1 in Drosophila) and intercellular adhesion, modulated via clathrin-mediated endocytosis of E-cadherin (encoded by shotgun in flies), which promotes cell elongation downstream of the GTPase Arf1 (Arf79F in Drosophila). We show that these two mechanisms do not act independently but are interconnected, with RhoA signalling reducing Arf1 recruitment to the plasma membrane. Additionally, cell adhesion itself regulates both mechanisms – p120-catenin, a regulator of intercellular adhesion, promotes the activity of both Arf1 and RhoA. Altogether, we uncover a complex network of interactions between cell–cell adhesion, the endocytic machinery and the actomyosin cortex, and demonstrate how this network regulates cell shape in an epithelial tissue in vivo.

P120 catenin potentiates constitutive E-cadherin dimerization at the plasma membrane and regulates trans binding

2021 ◽  
Author(s):  
Vinh Vu ◽  
Taylor Light ◽  
Brendan Sullivan ◽  
Diana Greiner ◽  
Kalina Hristova ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
P120 Catenin ◽  
E Cadherin

scholarly journals p120 catenin induces opposing effects on tumor cell growth depending on E-cadherin expression

2008 ◽  
Vol 183 (4) ◽  
pp. 737-749 ◽  
Author(s):  
Edwin Soto ◽  
Masahiro Yanagisawa ◽  
Laura A. Marlow ◽  
John A. Copland ◽  
Edith A. Perez ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Tumor Cell Growth ◽  
P120 Catenin ◽  
Opposing Effects ◽  
E Cadherin

p120 catenin regulates the activity of the Rho family guanosine triphosphatases (including RhoA and Rac1) in an adhesion-dependent manner. Through this action, p120 promotes a sessile cellular phenotype when associated with epithelial cadherin (E-cadherin) or a motile phenotype when associated with mesenchymal cadherins. In this study, we show that p120 also exerts significant and diametrically opposing effects on tumor cell growth depending on E-cadherin expression. Endogenous p120 acts to stabilize E-cadherin complexes and to actively promote the tumor-suppressive function of E-cadherin, potently inhibiting Ras activation. Upon E-cadherin loss during tumor progression, the negative regulation of Ras is relieved; under these conditions, endogenous p120 promotes transformed cell growth both in vitro and in vivo by activating a Rac1–mitogen-activated protein kinase signaling pathway normally activated by the adhesion of cells to the extracellular matrix. These data indicate that both E-cadherin and p120 are important regulators of tumor cell growth and imply roles for both proteins in chemoresistance and targeted therapeutics.

The homeodomain transcription factors Cdx1 and Cdx2 induce E-cadherin adhesion activity by reducing β- and p120-catenin tyrosine phosphorylation

2007 ◽  
Vol 293 (1) ◽  
pp. G54-G65 ◽  
Author(s):  
Toshihiko Ezaki ◽  
Rong-Jun Guo ◽  
Hong Li ◽  
Albert B. Reynolds ◽  
John P. Lynch
Keyword(s):  
Transcription Factors ◽  
Cell Adhesion ◽  
Tyrosine Phosphorylation ◽  
Intestinal Cell ◽  
Specific Gene ◽  
P120 Catenin ◽  
Cdx2 Expression ◽  
E Cadherin ◽  
Cell Cell ◽  
Homeodomain Transcription Factors

The homeodomain transcription factors Cdx1 and Cdx2 are regulators of intestine-specific gene expression. They also regulate intestinal cell differentiation and proliferation; however, these effects are poorly understood. Previously, we have shown that expression of Cdx1 or Cdx2 in human Colo 205 cells induces a mature colonocyte morphology characterized by the induction of a polarized, columnar shape with apical microvilli and strong cell-cell adhesion. To elucidate the mechanism underlying this phenomenon, we investigated the adherens junction complex. Cdx1 or Cdx2 expression reduced Colo 205 cell migration and invasion in vitro, suggesting a physiologically significant change in cadherin function. However, Cdx expression did not significantly effect E-cadherin, α-, β-, or γ-catenin, or p120-catenin protein levels. Additionally, no alteration in their intracellular distribution was observed. Cdx expression did not alter the coprecipitation of β-catenin with E-cadherin; however, it did reduce p120-catenin-E-cadherin coprecipitation. Tyrosine phosphorylation of β- and p120-catenin is known to disrupt E-cadherin-mediated cell adhesion and is associated with robust p120-catenin/E-cadherin interactions. We specifically investigated β- and p120-catenin for tyrosine phosphorylation and found that it was significantly diminished by Cdx1 or Cdx2 expression. We restored β- and p120-catenin tyrosine phosphorylation in Cdx2-expressing cells by knocking down the expression of protein tyrosine phosphatase 1B and noted a significant decline in cell-cell adhesion. We conclude that Cdx expression in Colo 205 cells induces E-cadherin-dependent cell-cell adhesion by reducing β- and p120-catenin tyrosine phosphorylation. Ascertaining the mechanism for this novel Cdx effect may improve our understanding of the regulation of cell-cell adhesion in the colonic epithelium.

scholarly journals A core function for p120-catenin in cadherin turnover

2003 ◽  
Vol 163 (3) ◽  
pp. 525-534 ◽  
Author(s):  
Michael A. Davis ◽  
Renee C. Ireton ◽  
Albert B. Reynolds
Keyword(s):  
Cell Adhesion ◽  
Cell Surface ◽  
Complete Loss ◽  
Vascular Endothelial ◽  
P120 Catenin ◽  
Epithelial Cadherin ◽  
Sirna Expression ◽  
Core Function ◽  
Dose Dependent ◽  
E Cadherin

p120-catenin stabilizes epithelial cadherin (E-cadherin) in SW48 cells, but the mechanism has not been established. Here, we show that p120 acts at the cell surface to control cadherin turnover, thereby regulating cadherin levels. p120 knockdown by siRNA expression resulted in dose-dependent elimination of epithelial, placental, neuronal, and vascular endothelial cadherins, and complete loss of cell–cell adhesion. ARVCF and δ-catenin were functionally redundant, suggesting that proper cadherin-dependent adhesion requires the presence of at least one p120 family member. The data reveal a core function of p120 in cadherin complexes, and strongly predict a dose-dependent loss of E-cadherin in tumors that partially or completely down-regulate p120.

scholarly journals Association of ARVCF with Zonula Occludens (ZO)-1 and ZO-2: Binding to PDZ-Domain Proteins and Cell-Cell Adhesion Regulate Plasma Membrane and Nuclear Localization of ARVCF

2004 ◽  
Vol 15 (12) ◽  
pp. 5503-5515 ◽  
Author(s):  
P. Jaya Kausalya ◽  
Dominic C.Y. Phua ◽  
Walter Hunziker
Keyword(s):  
Plasma Membrane ◽  
Cell Adhesion ◽  
Nuclear Localization ◽  
Pdz Domain ◽  
Cell Contact ◽  
Binding Motif ◽  
Zonula Occludens ◽  
Pdz Domain Proteins ◽  
E Cadherin ◽  
Cell Cell

ARVCF, an armadillo-repeat protein of the p120ctnfamily, associates with classical cadherins and is present in adherens junctions, but its function is poorly understood. Here, we show that ARVCF interacts via a C-terminal PDZ-binding motif with zonula occludens (ZO)-1 and ZO-2. ARVCF and ZO-1 partially colocalize in the vicinity of the apical adhesion complex in polarized epithelial Madin-Darby canine kidney cells. ARVCF, ZO-1, and E-cadherin form a complex and are recruited to sites of initial cell-cell contact in sparse cell cultures. E-cadherin binding and plasma membrane localization of ARVCF require the PDZ-binding motif. Disruption of cell-cell adhesion releases ARVCF from the plasma membrane and an increased fraction of the protein localizes to the nucleus. Nuclear localization of ARVCF also requires the PDZ-binding motif and can be mediated by the PDZ domains of ZO-2. Thus, the interaction of ARVCF with distinct PDZ-domain proteins determines its subcellular localization. Interactions with ZO-1 and ZO-2, in particular, may mediate recruitment of ARVCF to the plasma membrane and the nucleus, respectively, possibly in response to cell-cell adhesion cues.

scholarly journals Downregulation of Rap1GAP in Human Tumor Cells Alters Cell/Matrix and Cell/Cell Adhesion

2010 ◽  
Vol 30 (13) ◽  
pp. 3262-3274 ◽  
Author(s):  
Oxana M. Tsygankova ◽  
Changqing Ma ◽  
Waixing Tang ◽  
Christopher Korch ◽  
Michael D. Feldman ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Tumor Cells ◽  
Adherens Junction ◽  
Protein Distribution ◽  
P120 Catenin ◽  
Cell Contacts ◽  
Cell Matrix ◽  
Junction Protein ◽  
E Cadherin ◽  
Cell Cell

ABSTRACT Rap1GAP expression is decreased in human tumors. The significance of its downregulation is unknown. We show that Rap1GAP expression is decreased in primary colorectal carcinomas. To elucidate the advantages conferred on tumor cells by loss of Rap1GAP, Rap1GAP expression was silenced in human colon carcinoma cells. Suppressing Rap1GAP induced profound alterations in cell adhesion. Rap1GAP-depleted cells exhibited defects in cell/cell adhesion that included an aberrant distribution of adherens junction proteins. Depletion of Rap1GAP enhanced adhesion and spreading on collagen. Silencing of Rap expression normalized spreading and restored E-cadherin, β-catenin, and p120-catenin to cell/cell contacts, indicating that unrestrained Rap activity underlies the alterations in cell adhesion. The defects in adherens junction protein distribution required integrin signaling as E-cadherin and p120-catenin were restored at cell/cell contacts when cells were plated on poly-l-lysine. Unexpectedly, Src activity was increased in Rap1GAP-depleted cells. Inhibition of Src impaired spreading and restored E-cadherin at cell/cell contacts. These findings provide the first evidence that Rap1GAP contributes to cell/cell adhesion and highlight a role for Rap1GAP in regulating cell/matrix and cell/cell adhesion. The frequent downregulation of Rap1GAP in epithelial tumors where alterations in cell/cell and cell/matrix adhesion are early steps in tumor dissemination supports a role for Rap1GAP depletion in tumor progression.

scholarly journals Interplay between cortical actin and E-cadherin dynamics regulates cell shape in the Drosophila embryonic epidermis

2019 ◽  
Author(s):  
Joshua Greig ◽  
Natalia A. Bulgakova
Keyword(s):  
Cell Adhesion ◽  
Cell Elongation ◽  
Cell Shape ◽  
Intercellular Adhesion ◽  
Epithelial Tissue ◽  
Cortical Actin ◽  
P120 Catenin ◽  
Endocytic Machinery ◽  
E Cadherin

AbstractPrecise regulation of cell shape is vital for building functional tissues. Here, we study the mechanisms which lead to the formation of highly elongated anisotropic epithelial cells in the Drosophila epidermis. We demonstrate that this cell shape is the result of two counteracting mechanisms at the cell surface: actomyosin, which inhibits cell elongation downstream of RhoA signalling, and intercellular adhesion, modulated via clathrin-mediated endocytosis of E-cadherin, which promotes cell elongation downstream of the GTPase Arf1. We show that these two mechanisms are interconnected, with RhoA signalling activity reducing Arf1 recruitment to the plasma membrane. Additionally, cell adhesion itself regulates both mechanisms: p120-catenin, a regulator of intercellular adhesion, promotes the activity of both Arf1 and RhoA. Altogether, we uncover a complex network of interactions between cell-cell adhesion, the endocytic machinery, and the actomyosin cortex, and demonstrate how this network regulates cell shape in an epithelial tissue in vivo.

scholarly journals APC regulation of ESRP1 and p120-catenin isoforms in colorectal cancer cells

2020 ◽  
pp. mbc.E20-05-0321
Author(s):  
Maree C. Faux ◽  
Lauren E. King ◽  
Serena R. Kane ◽  
Christopher Love ◽  
Oliver M. Sieber ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Adhesion ◽  
Wnt Signaling ◽  
Cancer Cells ◽  
Full Length ◽  
P120 Catenin ◽  
Colorectal Cancer Cells ◽  
Isoform Switching ◽  
E Cadherin ◽  
Cell Cell

The APC tumor suppressor protein is associated with the regulation of Wnt signaling, however APC also controls other cellular processes including the regulation of cell adhesion and migration. The expression of full-length APC in SW480 colorectal cancer cells (SW480+APC) not only reduces Wnt signaling, but increases membrane E-cadherin and restores cell-cell adhesion. This report describes the effects of full-length, wild-type APC (fl-APC) on cell-cell adhesion genes and p120-catenin isoform switching in SW480 colon cancer cells: fl-APC increased the expression of genes implicated in cell-cell adhesion, whereas the expression of negative regulators of E-cadherin were decreased. Analysis of cell-cell adhesion-related proteins in SW480+APC cells revealed an increase in p120-catenin isoform 3A; similarly, depletion of APC altered the p120-catenin protein isoform profile. Expression of ESRP1 (epithelial splice regulatory protein 1) is increased in SW480+APC cells and its depletion results in reversion to the p120-catenin isoform 1A phenotype and reduced cell-cell adhesion. ESRP1 transcript is reduced in primary CRC and its expression correlates with the level of APC. Pyrvinium pamoate, which inhibits Wnt signaling, promotes ESRP1 expression. We conclude that re-expression of APC restores cell-cell adhesion gene and post-transcriptional regulatory programs leading to p120-catenin isoform switching and associated changes in cell-cell adhesion.

scholarly journals p120-catenin phosphorylation status alters E-cadherin mediated cell adhesion and ability of tumor cells to metastasize

PLoS ONE ◽  
2020 ◽  
Vol 15 (6) ◽  
pp. e0235337 ◽  
Author(s):  
Alisha M. Mendonsa ◽  
Chirosree Bandyopadhyay ◽  
Barry M. Gumbiner
Keyword(s):  
Cell Adhesion ◽  
Tumor Cells ◽  
P120 Catenin ◽  
E Cadherin
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