Phosphorylation of E-cadherin at threonine 790 by protein kinase Cδ reduces β-catenin binding and suppresses the function of E-cadherin

// Chien-Lin Chen 1 , Shu-Hui Wang 1 , Po-Chao Chan 1 , Meng-Ru Shen 2, 3 , Hong-Chen Chen 1, 4, 5 1 Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan 2 Department of Pharmacology, National Cheng Kung University, Tainan 704, Taiwan 3 Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan 704, Taiwan 4 Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan 5 Rong-Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan Correspondence to: Hong-Chen Chen, email: hcchen@nchu.edu.tw Keywords: PKCδ, E-cadherin, cell junction, phosphorylation Received: October 15, 2015     Accepted: April 10, 2016     Published: May 17, 2016 ABSTRACT Proper control of cell-cell adhesion is crucial for embryogenesis and tissue homeostasis. In this study, we show that protein kinase C (PKC)δ, a member of the novel PKC subfamily, localizes at cell-cell contacts of epithelial cells through its C2-like domain in an F-actin-dependent manner. Upon hepatocyte growth factor stimulation, PKCδ is phosphorylated and activated by Src, which then phosphorylates E-cadherin at Thr790. Phosphorylation of E-cadherin at Thr790 diminishes its interaction with β-catenin and impairs the homophilic interaction between the ectodomains of E-cadherin. The suppression of PKCδ by its dominant-negative mutants or specific short-hairpin RNA inhibits the disruption of cell-cell adhesions induced by hepatocyte growth factor. Elevated PKCδ expression in cancer cells is correlated with increased phosphorylation of E-cadherin at Thr790, reduced binding of E-cadherin to β-catenin, and poor homophilic interaction between E-cadherin. Analysis of surgical specimens confirmed that PKCδ is overexpressed in cervical cancer tissues, accompanied by increased phosphorylation of E-cadherin at Thr790. Together, our findings unveil a negative role for PKCδ in cell-cell adhesion through phosphorylation of E-cadherin.