A novel role for p120 catenin in E-cadherin function

Abstract

Îndirect evidence suggests that p120-catenin (p120) can both positively and negatively affect cadherin adhesiveness. Here we show that the p120 gene is mutated in SW48 cells, and that the cadherin adhesion system is impaired as a direct consequence of p120 insufficiency. Restoring normal levels of p120 caused a striking reversion from poorly differentiated to cobblestone-like epithelial morphology, indicating a crucial role for p120 in reactivation of E-cadherin function. The rescue efficiency was enhanced by increased levels of p120, and reduced by the presence of the phosphorylation domain, a region previously postulated to confer negative regulation. Surprisingly, the rescue was associated with substantially increased levels of E-cadherin. E-cadherin mRNA levels were unaffected by p120 expression, but E-cadherin half-life was more than doubled. Direct p120–E-cadherin interaction was crucial, as p120 deletion analysis revealed a perfect correlation between E-cadherin binding and rescue of epithelial morphology. Interestingly, the epithelial morphology could also be rescued by forced expression of either WT E-cadherin or a p120-uncoupled mutant. Thus, the effects of uncoupling p120 from E-cadherin can be at least partially overcome by artificially maintaining high levels of cadherin expression. These data reveal a cooperative interaction between p120 and E-cadherin and a novel role for p120 that is likely indispensable in normal cells.

The regulatory or phosphorylation domain of p120 catenin controls E-cadherin dynamics at the plasma membrane

“…Ireton, et al reported that forced p120 expression in p120-defective SW48 cells reactivated E-cadherin function and rescued an epithelial-like morphology [31]. This is consistent with our data showing that p120-deficient S2-013 cells recovered epithelial celljunctions upon forced expression of p120.…”

“…This is consistent with our data showing that p120-deficient S2-013 cells recovered epithelial celljunctions upon forced expression of p120. The Ireton study illustrates the controversial nature of the role of p120 in regulating cadherin activity because this study showed that forced expression of the regulatory domain of p120 alone had a negative effect on cadherin adhesion in SW48 cells [31]. These data are consistent with a separate report using Colo205 cells, where expression of full-length p120 prevented E-cadherin activity, but expression of an N-terminally deleted version did not [15].…”

“…Retroviral constructs containing mouse p120 isoform 3A, mouse p120 isoform 3A with six residues of S/T (S252, S268, S288, T310, S312, 7916) mutated to alanine, and mouse p120 isoform 4A have been described [31,32].…”

The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC

“…23 The p120-catenin is the best known inhibitor of cadherin endocytosis, as its binding to the E-cadherin juxtamembrane domain is required for maintenance and stability of E-cadherin molecules at the PM and, simultaneously, it physically blocks the interaction with proteins from the endocytic machinery, such as clathrin adaptor proteins and Hakai. [29][30][31][32][33] Importantly, Hakai binds directly to E-cadherin and, being an E3 ubiquitin ligase, it ubiquitinates and induces E-cadherin endocytosis. 33 Taking into account the present knowledge about E-cadherin regulation, we tested whether and how the E-cadherin cytoplasmic mutations interfere with key trafficking-related partners, leading to abnormal E-cadherin expression, localization and function, supporting their pathogenic relevance.…”

“…27,28 At the PM, p120-catenin binds to the cadherin juxtamembrane domain, stabilizing and preventing the entry of E-cadherin into degradative endocytic pathways. [29][30][31][32] E-cadherin deprived of p120 is prone to interact with other proteins, such as clathrin adapter proteins and Hakai, promoting E-cadherin internalization. 32,33 After internalization, E-cadherin can be recycled back to the PM or targeted for degradation.…”