P120 Catenin Regulates the Actin Cytoskeleton via Rho Family Gtpases

Abstract

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.

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

“…Although the mechanism by which p120 ctn regulates Rac1/Cdc42 activation is still obscure, we found that p120 ctn translocation to the cytoplasm seems to be a crucial factor. In support of our finding, others have shown that p120 ctn in the cytoplasmic pool is important for the complex formation between p120 ctn and the guanine nucleotide exchange factor, Vav2, in the regulation of Rac1 and Cdc42 (Noren et al, 2000). In addition to cytoskeletal changes, cytoplasmic p120 ctn is also thought to be important for regulating invasion-related genes through binding to the transcriptional repressor Kaiso (Soubry et al, 2005).…”

“…These results indicate that p120 ctn contributes to the migratory/invasive behavior and suggest that the effect was mediated through the cytoplasmic localization of p120 ctn . p120 ctn mediates GnRH-induced cell migration and invasion through Rac1 and Cdc42 Given the ability of p120 ctn to regulate the activity of Rho family GTPase and the potential contribution of these GTPases to the invasive/metastatic phenotype (Nobes and Hall, 1999;Noren et al, 2000), we examined the activities of Rac1, Cdc42, and RhoA using pull-down assays. A significant increase in the levels of GTP-bound (active) Rac1 (3.4-fold) and Cdc42 (2.5-fold) was detected in P-cadherin-overexpressing cells when compared with control cells (Figure 8a; Po0.05).…”

“…For example, b-catenin mediates Wnt signaling pathway through its interaction with LEF/TCF transcription factors for target gene activation (Clevers, 2006). p120 ctn , originally identified as an Src substrate, was subsequently shown to signal through its activity on the Rho family GTPases (for example, Rac1, Cdc42, RhoA), which mediate cytoskeletal dynamics in cell migration (Nobes and Hall, 1999;Noren et al, 2000).…”

Turn‐off, drop‐out: Functional state switching of cadherins

“…Additionally, phosphorylation on either tyrosine or serine/threonine residues may determine whether p120ctn is a positive or negative regulator of cadherin-mediated adhesion (reviewed in ; see also Aono et al, 1999;Ozawa and Ohkubo, 2000;Zondag et al, 2000). p120 ctn also alters the relative activities of the small G-proteins Rho A, Rac, and Cdc42 Grosheva et al, 2000;Noren et al, 2000). This may well be related to changes in the activities of these proteins initiated by adhesion Noren et al, 2001) and involved in actin-driven cadherin clustering (Braga et al, 1997(Braga et al, , 1999Jou and Nelson, 1998;Takaishi et al, 1997).…”

Neuroprotective roles of the P2Y2 receptor

“…The N-terminal extracellular domain of VEcadherin provides tight adhesion between endothelial cells through Ca 2+ -dependent homophilic interaction, whereas the cytoplasmic domain interacts with various intracellular binding partners, including α-, β-, and p120 catenins, providing a linkage to the actin cytoskeleton [268]. Modulation of cell-cell contacts that regulate cell adhesion and cell motility likely requires interactions between cadherins and catenins, and it has been shown that p120 catenin regulates actin cytoskeletal organization and cell motility by activation of Rho GTPases [269][270][271]. In addition, VEcadherin associates with VEGFR-2, known to be transactivated by the P2Y 2 R [20,89], and also with Src, Shc, Csk [272,273], and the vascular endothelial protein tyrosine phosphatase, VE-PTP [274].…”