361 p120-catenin regulates epidermal inflammation in a cadherin-dependent manner

Regulation of cell adhesion is essential for epidermal homeostasis. E-cadherin (E-cad) plays a central role in keratinocyte cell-cell adhesion and is critical for skin barrier function. E-cad associates with cytoplasmic proteins such as β-catenin, which links E-cad to the cytoskeleton, and p120-catenin (p120), which inhibits cadherin endocytosis and degradation. Previous studies indicate that p120 gene ablation in mouse epidermis causes severe inflammation and lethality due to loss of p120 regulation of RhoA and NF-κB. However, p120 knock out also causes loss of E-cad cell surface levels, making it difficult to discern if the p120 null phenotype is caused by loss of p120 or reduced cadherin levels. Therefore, we generated a knock-in mouse line harboring an E-cad mutant in which a membrane proximal di-leucine endocytic motif was mutated (E-cadLL). The E-cadLL mutant was intercrossed with mouse lines harboring a p120 floxed allele and expressing Cre-recombinase from a K14 promotor. In mice expressing wild type E-cad, p120 ablation in the epidermis resulted in a dramatic loss of E-cad protein levels and perinatal lethality. Surviving mice exhibited hair loss and severe epidermal inflammation. Remarkably, E-cad levels were near normal in p120 null mice expressing the E-cadLL endocytic mutant. Further, the E-cadLL mutant rescued both the lethality and inflammatory phenotype in the p120 null epidermis. Histological analysis revealed that the EcadLL mutant also rescued epidermal thickening and hair loss in the p120 null background. To identify E-cad-p120 regulated inflammatory pathways, we investigated gene expression profiles in P3 mouse epidermis by RT-qPCR. IL-6 expression was profoundly upregulated (>100 fold) in epidermis of p120 null mice, but was normal in p120 null mice expressing the E-cadLL mutant. Similar results were obtained for MIP-3α. These findings demonstrate that the primary function of p120 is to regulate cadherin levels and reveal a previously unappreciated role for cadherins in epidermal inflammation.