Regulation of Rho GTPases by p120-catenin

Anastasiadis, Panos Z.; Reynolds, Albert B.

doi:10.1016/s0955-0674(00)00258-1

Cited by 245 publications

(203 citation statements)

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“…The anchoring of cadherins to the actin cytoskeleton via numerous scaffolding proteins also may be required. For example, cadherins bind to and sequester p120-catenin; cytoplasmic p120-catenin inactivates RhoA, and cadherin binding is thought to inhibit this inactivation (Noren et al, 2000;Anastasiadis and Reynolds, 2001;Grosheva et al, 2001;Magie et al, 2002). This mechanism is consistent with the time courses of p120-catenin localization and RhoA activation in our study.…”

Section: Discussionmentioning

confidence: 99%

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

Nelson

Pirone

Tan

et al. 2004

MBoC

165

137

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Changes in vascular endothelial (VE)-cadherin-mediated cell-cell adhesion and integrin-mediated cell-matrix adhesion coordinate to affect the physical and mechanical rearrangements of the endothelium, although the mechanisms for such cross talk remain undefined. Herein, we describe the regulation of focal adhesion formation and cytoskeletal tension by intercellular VE-cadherin engagement, and the molecular mechanism by which this occurs. Increasing the density of endothelial cells to increase cell-cell contact decreased focal adhesions by decreasing cell spreading. This contact inhibition of cell spreading was blocked by disrupting VE-cadherin engagement with an adenovirus encoding dominant negative VE-cadherin. When changes in cell spreading were prevented by culturing cells on a micropatterned substrate, VE-cadherin-mediated cell-cell contact paradoxically increased focal adhesion formation. We show that VE-cadherin engagement mediates each of these effects by inducing both a transient and sustained activation of RhoA. Both the increase and decrease in cell-matrix adhesion were blocked by disrupting intracellular tension and signaling through the Rho-ROCK pathway. In all, these findings demonstrate that VE-cadherin signals through RhoA and the actin cytoskeleton to cross talk with cell-matrix adhesion and thereby define a novel pathway by which cell-cell contact alters the global mechanical and functional state of cells. INTRODUCTIONCoordinated changes between cell adhesion to the extracellular matrix (ECM) and to neighboring cells are crucial for the many physical transformations that cells must undergo during development, tissue homeostasis, and wound healing. In the endothelium, where a single layer of cells separates tissues from their blood supply, the concerted regulation of cell-cell and cell-ECM adhesion drives rapid changes in cell shape and vascular architecture essential to vascular remodeling in both normal and disease processes (Vestweber, 2000;Dudek and Garcia, 2001). Dynamic changes in cell-cell and cell-matrix adhesion and mechanical forces are responsible for regulating vascular permeability, and agents that alter permeability invariably affect both types of adhesion complexes (Dudek and Garcia, 2001). During blood vessel sprouting and migration in angiogenesis, endothelial cells must disassemble and reform their cell-cell and cell-ECM contacts in synchrony to generate appropriate structures. These two adhesion systems each regulate their functional effects through both biochemical and mechanical signals.Changes in integrin binding to ECM not only alter signals that regulate cell proliferation, migration, and survival (Assoian and Schwartz, 2001;Hood and Cheresh, 2002;Stupack and Cheresh, 2002) but also modulate cell mechanics by affecting focal adhesion (FA) maturation, adhesion strength, cytoskeletal contractility, and cell shape (Geiger and Bershadsky, 2002;Juliano, 2002). Likewise, changes in the engagement of vascular endothelial (VE)-cadherin, the principal junctional molecule in endothe...

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Section: Discussionmentioning

confidence: 99%

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

Nelson

Pirone

Tan

et al. 2004

MBoC

165

137

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“…It was further suggested that in fibroblasts p120 could affect other cell functions such as organization of the actin cytoskeleton and cell motility by virtue of its influence on the activity of Rho GTPases (Noren et al, 2000;Anastasiadis and Reynolds, 2001;Grosheva et al, 2001). In this study, the observations of prototypic epithelial cells expressing full-length and N-terminus deleted alleles of p120, while supporting the proposed roles for p120, provide new relevant elements for the understanding of epithelial Figure 7.…”

Section: Discussionmentioning

confidence: 99%

p120 Catenin Is Required for Growth Factor–dependent Cell Motility and Scattering in Epithelial Cells

Cozzolino

Stagni

Spinardi

et al. 2003

MBoC

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Cadherin-mediated cell-cell adhesion is dynamically modulated during epithelial-mesenchymal transition triggered by activation of receptor tyrosine kinases (RTK) in epithelial cells. Several cadherin-binding proteins have been identified that control cell-cell adhesion. However, the mechanisms by which intercellular adhesion and cell motility are coregulated are still unknown. Here, we delineate a hitherto uncharted cooperation between RTKs, RhoA GTPase, and p120 catenin in instructing a motile behavior to epithelial cells. We found that expression of an N-terminus-deleted p120 catenin in a variety of epithelial cell types, including primary keratinocytes, effectively competes for endogenous p120 at cadherin binding sites and abrogates EGFstimulated cell motility as well as HGF-induced cell scattering. The deleted mutant also inhibits the PI3K-dependent RhoA activation ensuing receptor activation. Conversely, we also show that the ectopic expression of full-length p120 in epithelial cells promotes cytoskeletal changes, stimulates cell motility, and activates RhoA. Both motogenic response to p120 and RhoA activation require coactivation of signaling downstream of RTKs as they are suppressed by ablation of the Ras/PI3K pathway. These studies demonstrate that p120 catenin is a necessary target of RTKs in regulating cell motility and help define a novel pathway leading to RhoA activation, which may contribute to the early steps of metastatic invasion.

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“…Cdc42 GTPase Is Downstream of p120 Catenin d1 and Requires Cycling of GTP Several Rho GTPases participate in the signaling pathway downstream of p120 catenin d1 (Noren et al, 2000;Anastasiadis and Reynolds, 2001;McCrea and Park, 2007). Their activities are controlled by guanine nucleotide exchange factors (GEFs) that promote exchange of GDP for GTP.…”

Section: Defects From Knockdown Of P120 Catenin D1 Persist In Later-smentioning

confidence: 99%

“…Cadherins mediate adhesion between cells by their extracellular domains and couple to intracellular processes through a group of core cytoplasmic binding partners called ''catenins'' (i.e., b-catenin, g-catenin or plakoglobin, and p120-catenins) (Shibamoto et al, 1995;Thoreson et al, 2000;Peifer and Yap, 2003;Anastasiadis and Reynolds, 2001;McCrea and Park, 2007;Zhao et al, 2011). p120 catenin and b-catenin are the prototypic members of a small family of armadillo repeat domain proteins (Daniel and Reynolds, 1995;Hatzfeld and Nachtsheim, 1996;Hatzfeld et al, 2003;Gu et al, 2009;Zhao et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Cdc42 GTPase and Rac1 GTPase act downstream of p120 catenin and require GTP exchange during gastrulation of zebrafish mesoderm

Hsu

Muerdter

Knickerbocker

et al. 2012

Developmental Dynamics

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Background: We investigated the roles of p120 catenin, Cdc42, Rac1, and RhoA GTPases in regulating migration of presomitic mesoderm cells in zebrafish embryos. p120 catenin has dual roles: It binds the intracellular and juxtamembrane region of cadherins to stabilize cadherin-mediated adhesion with the aid of RhoA GTPase, and it activates Cdc42 GTPase and Rac1 GTPase in the cytosol to initiate cell motility. Results: During gastrulation of zebrafish embryos, knockdown of the synthesis of zygotic p120 catenind1 mRNAs with a splice-site morpholino caused lateral widening and anterior-posterior shortening of the presomitic mesoderm and somites and a shortened anterior-posterior axis. These phenotypes indicate a cell-migration effect. Co-injection of low amounts of wild-type Cdc42 or wild-type Rac1 or dominant-negative RhoA mRNAs, but not constitutively-active Cdc42 mRNA, rescued these p120 catenin d1-depleted embryos. Conclusions: These downstream small GTPases require appropriate spatiotemporal stimulation or cycling of GTP to guide mesodermal cell migration. A delicate balance of Rho GTPases and p120 catenin underlies normal development. Developmental Dynamics 241:1545-1561, 2012. V C 2012 Wiley Periodicals Inc.Key words: p120 Catenin (CTNND1); ARVCF; Delta-catenin (CTNND2b); Cdc42 GTPase; Rac1 GTPase, RhoA GTPase; gastrulation; presomitic mesoderm; somites; zebrafish Key findings p120 catetin is required for extension of the dorsal axis and normal migration of the presomitic mesoderm. Cdc42 and Rac1 GTPases are downstream of p120 catenin d1 signaling and require exchange of GTP for GDP. Local stimulation of the exchange of GTP for GDP in Cdc42 and Rac GTPases mediates directional migration of the presomitic mesoderm. A balance of the amount of p120 catenin d1 and localized activation or turnover of Cdc42, Rac1, and Rho GTPase are required for normal zebrafish cell migration. Accepted 31 July 2012 Developmental DynamicsABBREVIATIONS Ab antibody ARVCF armadillo repeat gene deleted in velo-cardio-facial syndrome CA constitutively active Chr chromosome C(t) relative amount of RT-PCR product hpf hours post-fertilization DN dominant negative d1 splice-MO antisense morpholino oligonucleotide to the 12 th splice site of zebrafish p120 catenin d1 p120 catenin d1 (CTNND1) also called p120 catenin, Xenopus p120 catenin is a CTNND1 p120 catenin d2b (CTNND2b) also called Delta-catenin Rok1 Rho kinase1 RT reverse transcriptase minus-RT controls without reverse transcriptase qRT-PCR quantitative real-time PCR WT wild-type Xp120 catenin mRNA Xenopus p120 catenin d1 mRNA.Additional Supporting Information may be found in the online version of this article.

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Regulation of Rho GTPases by p120-catenin

Cited by 245 publications

References 45 publications

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

Vascular Endothelial-Cadherin Regulates Cytoskeletal Tension, Cell Spreading, and Focal Adhesions by Stimulating RhoA

p120 Catenin Is Required for Growth Factor–dependent Cell Motility and Scattering in Epithelial Cells

Cdc42 GTPase and Rac1 GTPase act downstream of p120 catenin and require GTP exchange during gastrulation of zebrafish mesoderm

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