An E-cadherin endocytic mutant rescues the severe epidermal p120-catenin null phenotype

Cadherins are linked to actin through α- and β -catenin. p120 catenin (p120) also binds to the cadherin cytoplasmic domain and prevents cadherin endocytosis. In mouse epidermis, p120 gene ablation leads to severe skin inflammation and early postnatal lethality. These outcomes have been ascribed to cadherin-independent functions of p120 in RhoA and NFκB inflammatory signaling. However, the downregulation of cadherins in a p120 null background complicates interpretations. We engineered a mouse line in which a di-leucine endocytic motif in the E-cadherin cytoplasmic domain was mutated (EcadLL). Using tissue-level morphometric analyses in parallel to transcriptomics, we find that the EcadLL mutant is epistatic to p120 gene ablation. Mice lacking epidermal p120, but harboring the EcadLL mutant, are viable, fertile, and lack epidermal inflammation and hyperproliferation observed in p120 knock-out epidermis. These findings demonstrate that regulation of cadherin cell surface stability is the essential function of p120 and suggest a role for cadherins in suppressing epidermal inflammatory pathways.