%0 Journal Article
%T Apical每basal polarity inhibits epithelial每mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation
%J -
%D 2019
%R https://doi.org/10.1038/s41556-019-0291-8
%X Loss of apical每basal polarity and activation of epithelial每mesenchymal transition (EMT) both contribute to carcinoma progression and metastasis. Here, we report that apical每basal polarity inhibits EMT to suppress metastatic dissemination. Using mouse and human epithelial three-dimensional organoid cultures, we show that the PAR每atypical protein kinase C (aPKC) polarity complex inhibits EMT and invasion by promoting degradation of the SNAIL family protein SNAI1. Under intact apical每basal polarity, aPKC kinases phosphorylate S249 of SNAI1, which leads to protein degradation. Loss of apical每basal polarity prevents aPKC-mediated SNAI1 phosphorylation and stabilizes the SNAI1 protein to promote EMT and invasion. In human breast tumour xenografts, inhibition of the PAR-complex-mediated SNAI1 degradation mechanism promotes tumour invasion and metastasis. Analyses of human breast tissue samples reveal negative correlations between PAR3 and SNAI1 protein levels. Our results demonstrate that apical每basal polarity functions as a critical checkpoint of EMT to precisely control epithelial每mesenchymal plasticity during tumour metastasis
%U https://www.nature.com/articles/s41556-019-0291-8