p120 catenin affects cell motility via modulation of activity of Rho-family GTPases: a link between cell-cell contact formation and regulation of cell locomotion

2001 ◽  
Vol 114 (4) ◽  
pp. 695-707 ◽  
Author(s):  
I. Grosheva ◽  
M. Shtutman ◽  
M. Elbaum ◽  
A.D. Bershadsky
Keyword(s):  
Cell Motility ◽  
Small Gtpases ◽  
Cell Junctions ◽  
P120 Catenin ◽  
Contact Formation ◽  
Cell Locomotion ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
E Cadherin ◽  
Cell Cell

The molecular basis for contact inhibition of cell locomotion is still largely unknown. Cadherins, the major receptors mediating cell-cell adhesion, associate in the cytoplasm with armadillo family proteins, including beta- and gamma-catenin and p120 catenin (p120ctn). E-cadherin-mediated contact formation was shown to inhibit cellular motility. We examine whether p120ctn may have a role in this regulation. We show here that overexpression of p120ctn in fibroblasts and epithelial cells induces pronounced changes in cell shape, motility and adhesion to the extracellular matrix. p120ctn-transfected cells display increased filopodial/lamellipodial activity, decreased contractility and focal adhesion formation, and augmented migratory ability. These effects of p120ctn are mediated by small GTPases of the Rho family. Direct assessment of the activity of these GTPases in cells expressing a 5-fold higher level of p120ctn as compared to non-transfected control cells revealed significant augmentation of Cdc42 and Rac activity. Moreover, co-transfection of p120ctn with dominant-negative Cdc42 and Rac, or constitutively active Rho suppressed morphological effects of p120ctn. Confocal immunofluorescence visualization of the distribution of endogenous p120ctn in dense cultures showed that formation of cadherin-mediated cell-cell contacts is accompanied by sequestering of p120ctn to the junction regions. In sparse cultures p120ctn is distributed over the cytoplasm. Co-transfection with an excess of E-cadherin leads to sequestration of exogenous p120ctn to cell-cell junctions or to small cadherin-containing vesicles, and abolishes p120ctn effects on cell morphology. Thus, p120ctn may couple the formation and disruption of cadherin-mediated contacts with regulation of cell motility by triggering pathway(s) affecting Rho family GTPases.

scholarly journals P120 Catenin Regulates the Actin Cytoskeleton via Rho Family Gtpases

2000 ◽  
Vol 150 (3) ◽  
pp. 567-580 ◽  
Author(s):  
Nicole K. Noren ◽  
Betty P. Liu ◽  
Keith Burridge ◽  
Bertolt Kreft
Keyword(s):  
Focal Adhesions ◽  
Dendritic Morphology ◽  
Dominant Negative ◽  
Cell Junctions ◽  
P120 Catenin ◽  
Rhoa Activity ◽  
Juxtamembrane Region ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
Cell Cell

Cadherins are calcium-dependent adhesion molecules responsible for the establishment of tight cell–cell contacts. p120 catenin (p120ctn) binds to the cytoplasmic domain of cadherins in the juxtamembrane region, which has been implicated in regulating cell motility. It has previously been shown that overexpression of p120ctn induces a dendritic morphology in fibroblasts (Reynolds, A.B., J. Daniel, Y. Mo, J. Wu, and Z. Zhang. 1996. Exp. Cell Res. 225:328–337.). We show here that this phenotype is suppressed by coexpression of cadherin constructs that contain the juxtamembrane region, but not by constructs lacking this domain. Overexpression of p120ctn disrupts stress fibers and focal adhesions and results in a decrease in RhoA activity. The p120ctn-induced phenotype is blocked by dominant negative Cdc42 and Rac1 and by constitutively active Rho-kinase, but is enhanced by dominant negative RhoA. p120ctn overexpression increased the activity of endogenous Cdc42 and Rac1. Exploring how p120ctn may regulate Rho family GTPases, we find that p120ctn binds the Rho family exchange factor Vav2. The behavior of p120ctn suggests that it is a vehicle for cross-talk between cell–cell junctions and the motile machinery of cells. We propose a model in which p120ctn can shuttle between a cadherin-bound state and a cytoplasmic pool in which it can interact with regulators of Rho family GTPases. Factors that perturb cell–cell junctions, such that the cytoplasmic pool of p120ctn is increased, are predicted to decrease RhoA activity but to elevate active Rac1 and Cdc42, thereby promoting cell migration.

Rho-family small GTPases are involved in forskolin-induced cell-cell contact formation of renal glomerular podocytes in vitro

2007 ◽  
Vol 328 (2) ◽  
pp. 391-400 ◽  
Author(s):  
Shuang-yan Gao ◽  
Chun-yu Li ◽  
Tetsuya Shimokawa ◽  
Takehiro Terashita ◽  
Seiji Matsuda ◽  
...  
Keyword(s):  
Small Gtpases ◽  
Cell Contact ◽  
Contact Formation ◽  
Rho Family ◽  
Cell Cell

scholarly journals R-cadherin influences cell motility via Rho family GTPases. Vol. 279 (2004) 31041-31049

2004 ◽  
Vol 279 (42) ◽  
pp. 44229-44230
Author(s):  
Emhonta Johnson ◽  
Christopher S. Theisen ◽  
Keith R. Johnson ◽  
Margaret J. Wheelock
Keyword(s):  
Cell Motility ◽  
Rho Family Gtpases ◽  
Rho Family

scholarly journals Angiomotin Regulates Endothelial Cell-Cell Junctions and Cell Motility

2005 ◽  
Vol 280 (41) ◽  
pp. 34859-34869 ◽  
Author(s):  
Anders Bratt ◽  
Olivier Birot ◽  
Indranil Sinha ◽  
Niina Veitonmäki ◽  
Karin Aase ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Motility ◽  
Cell Junctions ◽  
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.

scholarly journals p120-Catenin Is a Key Component of the Cadherin–γ-Secretase Supercomplex

2008 ◽  
Vol 19 (10) ◽  
pp. 4042-4050 ◽  
Author(s):  
Alexi Kiss ◽  
Regina B. Troyanovsky ◽  
Sergey M. Troyanovsky
Keyword(s):  
Proteolytic Activity ◽  
Cell Contact ◽  
Compelling Evidence ◽  
P120 Catenin ◽  
Low Level ◽  
High Affinity ◽  
Affinity Interaction ◽  
E Cadherin ◽  
Cell Cell

In this work, we show several previously unknown features of p120-catenin in a cadherin–catenin complex that are critical for our understanding of cadherin-based adhesion and signaling. We show that in human epithelial A-431 cells, nearly all p120 molecules engage in high-affinity interaction with E-cadherin–catenin complexes located at the cellular surface. p120 is positioned in proximity to α-catenin in the complex with cadherin. These findings suggest a functional cooperation between p120 and α-catenin in cadherin-based adhesion. A low level of cadherin-free p120 molecules, in contrast, could facilitate p120-dependent signaling. Finally, we present compelling evidence that p120 is a key linker cementing the E-cadherin–catenin complex with the transmembrane protease γ-secretase. The cell–cell contact location of this supercomplex makes it an important candidate for conducting different signals that rely on γ-secretase proteolytic activity.

scholarly journals A mechanism of Rap1-induced stabilization of endothelial cell–cell junctions

2011 ◽  
Vol 22 (14) ◽  
pp. 2509-2519 ◽  
Author(s):  
Jian J. Liu ◽  
Rebecca A. Stockton ◽  
Alexandre R. Gingras ◽  
Ararat J. Ablooglu ◽  
Jaewon Han ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Small Gtpases ◽  
Cell Junctions ◽  
Physical Interaction ◽  
Dependent Manner ◽  
Cardiovascular Development ◽  
Cavernous Malformations ◽  
Cell Cell

Activation of Rap1 small GTPases stabilizes cell–cell junctions, and this activity requires Krev Interaction Trapped gene 1 (KRIT1). Loss of KRIT1 disrupts cardiovascular development and causes autosomal dominant familial cerebral cavernous malformations. Here we report that native KRIT1 protein binds the effector loop of Rap1A but not H-Ras in a GTP-dependent manner, establishing that it is an authentic Rap1-specific effector. By modeling the KRIT1–Rap1 interface we designed a well-folded KRIT1 mutant that exhibited a ∼40-fold-reduced affinity for Rap1A and maintained other KRIT1-binding functions. Direct binding of KRIT1 to Rap1 stabilized endothelial cell–cell junctions in vitro and was required for cardiovascular development in vivo. Mechanistically, Rap1 binding released KRIT1 from microtubules, enabling it to locate to cell–cell junctions, where it suppressed Rho kinase signaling and stabilized the junctions. These studies establish that the direct physical interaction of Rap1 with KRIT1 enables the translocation of microtubule-sequestered KRIT1 to junctions, thereby supporting junctional integrity and cardiovascular development.

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