p120 catenin is essential for mesenchymal cadherin–mediated regulation of cell motility and invasiveness

Abstract

During epithelial tumor progression, the loss of E-cadherin expression and inappropriate expression of mesenchymal cadherins coincide with increased invasiveness. Reexpression experiments have established E-cadherin as an invasion suppressor. However, the mechanism by which E-cadherin suppresses invasiveness and the role of mesenchymal cadherins are poorly understood. We show that both p120 catenin and mesenchymal cadherins are required for the invasiveness of E-cadherin–deficient cells. p120 binding promotes the up-regulation of mesenchymal cadherins and the activation of Rac1, which are essential for cell migration and invasiveness. p120 also promotes invasiveness by inhibiting RhoA activity, independently of cadherin association. Furthermore, association of endogenous p120 with E-cadherin is required for E-cadherin–mediated suppression of invasiveness and is accompanied by a reduction in mesenchymal cadherin levels. The data indicate that p120 acts as a rheostat, promoting a sessile cellular phenotype when associated with E-cadherin or a motile phenotype when associated with mesenchymal cadherins.

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

“…Figure S3B, C. The Xp120 catenin mRNAs injected was also calibrated to the maximum amount that produced no deleterious embryos as shown in Figure 3A (50 pg Xp120 mRNA). Higher levels of Xp120 catenin gave a phenotype similar to the down-regulation of p120 catenin d1 by the d1 splice-MO, which is not surprising since in cell cultures excess p120 catenin promotes branching filopodia, activated lamellipodia, and invasiveness (Reynolds et al 1996;Noren et al, 2000;Yanagisawa and Anastasiadis, 2006). Importantly, although 4 ng of d1 splice-MO caused abnormal morphology (Fig.…”

“…Defects seen with p120 catenin d1 knockdown resemble those with overexpression of Rac1 GTPase (Yanagisawa and Anastasiadis, 2006). We hypothesize that when free in the cytosol, p120 catenin d1 interacts with Cdc42 and Rac1 GTPases to stimulate, respectively, filopodia and lamellar extension required for directed cell migration.…”

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

“…Taken together, these results suggest that E-cadherin, by the assembly of adherens junctions, regulates Egr1 and PTEN expression by modulating b-catenin signaling. Discussion E-cadherin is known to suppress tumor cell growth and invasion, and re-expression of E-cadherin in E-cadherindeficient carcinomas reverts cells to a less invasive, less aggressive phenotype (St Croix et al, 1998;Gottardi et al, 2001;Yanagisawa and Anastasiadis, 2006;Soto et al, 2008). On the other hand, the expression of E-cadherin supports cohesive, collective cell migration/ invasion (Friedl and Gilmour, 2009).…”

p120catenin alteration in cancer and its role in tumour invasion

“…The function of p120catenin in the regulation of cadherin levels suggests that loss of p120catenin may be responsible for E-cadherin downregulation during tumour progression, but direct evidence is still lacking [11]. Conversely, membraneassociated p120catenin restrains the invasion of tumour cell lines derived from breast, kidney and vulva cancers [72,73]. Another scenario is at play in highly lethal forms of breast tumours, in which membrane-associated p120catenin appears to be pro-invasive (figure 3c).…”

“…The pro-invasive function of p120catenin could then be explained by its ability to sustain the expression of mesenchymal cadherins (figure 3c). Indeed, in some cellular contexts, stabilizing the highly labile P/N- [73,78].…”