Abstract LB-019: Hakai, an E3-ligase for E-cadherin, stabilizes δ-catenin through Src kinase

Hakai ubiquitinates and induces endocytosis of the E-cadherin complex; thus, modulating cell adhesion and regulating the epithelial-mesenchymal transition in development of metastasis. Our previous published data show that δ-catenin promotes E-cadherin processing and thereby activates β-catenin-mediated oncogenic signals in prostate cancer. Although several published data show the interactions between δ-catenin and E-cadherin; and Hakai and E-cadherin separately, we found no published report on the relationship between δ-catenin and Hakai. In this study, we show Hakai stabilizes δ-catenin regardless of its E3-ligase activity. We found that Hakai and Src increase the stability of δ-catenin synergistically. Furthermore, we show that Hakai stabilizes Src, which in turn inhibits binding between glycogen synthase kinase-3β and δ-catenin, resulting in less glycogen synthase kinase-3β mediated phosphorylation and proteosomal degradation of δ-catenin. Taken together, these results suggest that stabilization of δ-catenin by Hakai is dependent on Src. Our novel findings on the Hakai mediated δ-catenin stabilization in an ubiquitination independent manner will add a new perspective to provide further insight into E3-ligase activity independent role of Hakai in cancer pathogenesis. Citation Format: Hridaya Shrestha, Taeyong Ryu, Young-woo Seo, So-yeon Park, Yongfeng He, Weiye Dai, Eunsook Park, Shishli Simkhada, Hangun Kim, Keesook Lee, Kwonseop Kim. Hakai, an E3-ligase for E-cadherin, stabilizes δ-catenin through Src kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-019. doi:10.1158/1538-7445.AM2017-LB-019