A p120 Catenin Isoform Switch Affects Rho Activity, Induces Tumor Cell Invasion, and Predicts Metastatic Disease

Abstract

p120 catenin is a cadherin-associated protein that regulates Rho GTPases and promotes the invasiveness of E-cadherin-deficient cancer cells. Multiple p120 isoforms are expressed in cells via alternative splicing, and all of them are essential for HGF signaling to Rac1. However, only full-length p120 (isoform 1) promotes invasiveness. This selective ability of p120 isoform 1 is mediated by reduced RhoA activity, both under basal conditions and following HGF treatment. All p120 isoforms can bind RhoA in vitro, via a central RhoA binding site. However, only the cooperative binding of RhoA to the central p120 domain and to the alternatively spliced p120 N terminus stabilizes RhoA binding and inhibits RhoA activity. Consistent with this, increased expression of p120 isoform 1, when compared with other p120 isoforms, is predictive of renal tumor micrometastasis and systemic progression, following nephrectomy. Furthermore, ectopic expression of the RhoA-binding, N-terminal domain of p120 is sufficient to block the ability of p120 isoform 1 to inhibit RhoA and to promote invasiveness. The data indicate that the increased expression of p120 isoform 1 during tumor progression contributes to the invasive phenotype of cadherin-deficient carcinomas and that the N-terminal domain of p120 is a valid therapeutic target.During epithelial tumor progression, tumor cells acquire the ability to invade surrounding tissues and eventually metastasize. A number of pathways have been uncovered to date that promote local invasiveness and metastatic tumor spread, and recent evidence argues that most of these converge on the loss of E-cadherin expression or function (1, 2). E-cadherin is the main epithelial cell-cell adhesion molecule, and its loss in most of these tumors coincides with an epithelial to mesenchymal transition (EMT), 2 where cells shed their epithelial characteristics and acquire a more mesenchymal phenotype. EMT is associated with normal development and wound healing, but its aberrant regulation contributes to cancer progression and metastasis (3). External cues, such as growth factors, can promote EMT via signaling pathways that are not well characterized but may involve the function of Snail family transcriptional repressors. The best characterized function of these transcription factors (i.e. Snail, Slug, and SIP1) is down-regulation of E-cadherin expression (4 -7). Consistent with this, experiments in transgenic mice strongly suggest that loss of E-cadherin directly promotes the transition of a benign adenoma into a carcinoma (8). Furthermore, reestablishing E-cadherin function in cadherin-deficient cell lines can reverse the invasive phenotype, suggesting that E-cadherin acts as a suppressor of cell invasion (9). The mechanism by which E-cadherin promotes suppression of invasiveness is still unclear. However, the adhesive function, which is mediated by its extracellular domain, is not thought to be involved in this effect (10). The intracellular domain of E-cadherin interacts directly with ␤-catenin and p120 catenin (p...

Slug (SNAI2) expression in oral SCC cells results in altered cell-cell adhesion and increased motility

“…Different isoforms of p120 arise due to the use of alternative exons containing alternative start codons and expression of the longer isoform 1 is associated with increased invasiveness and increased Rho A activity. 19 UM-SCC-38/neo cells predominantly express isoform 3 while Slug-expressing cells also express the slower migrating isoform 1 in addition to the faster migrating isoform 3.…”

The catenin family at a glance

“…With regards to p120, the expression of isoform 1 (generated from the most N-terminal translational start site) leads to more robust RhoA inhibition and cell invasion than do shorter isoforms, and consequently might be associated with the progression of certain cancers (Yanagisawa et al, 2008). Phosphorylation of p120 at specific residues has also been found to modulate the relationship of p120 with RhoA (Castano et al, 2007).…”

p120catenin alteration in cancer and its role in tumour invasion

“…p120catenin isoform 1, but not the short p120catenin isoform 4, promotes invasiveness, both in vitro and in vivo, and is associated with renal cancer micrometastasis [108]. This may reflect the inability of p120catenin isoform 4 to bind and to inhibit RhoA (figure 1a).…”

“…In vivo data in the mouse epidermis [14] and forebrain [58] confirmed the role of p120catenin in RhoA inhibition. This regulatory process can occur in the cytosol through a direct interaction between RhoA and the amino-terminal domain and a central polybasic region of p120catenin [107,108] (figure 2). p120catenin also inhibits RhoA indirectly by interacting with p190RhoGAP (a RhoA-GAP) via its carboxy-terminal-region [109], but this interaction seems to occur only when p120catenin is at the plasma membrane [59].…”