Factors Affecting Adherens Junction complexes and Role of δ-catenin in Cancer
Advisor: Prof. Kim Kwonseop Chonnam National University, South Korea 2012-2017
Overview
This project focuses on understanding the regulation and function of adherens junction proteins, particularly δ-catenin, in cancer progression. Adherens junctions are critical for maintaining cell-cell adhesion and epithelial integrity. Disruption of these junctions is a hallmark of the epithelial-mesenchymal transition (EMT), a key process driving cancer metastasis.
The δ-catenin protein is a member of the p120-catenin subfamily and has been found to be overexpressed in various cancers, including prostate, lung, ovarian, and colorectal cancers. Previous work has shown that δ-catenin can promote E-cadherin processing and activate oncogenic β-catenin signaling, suggesting an important role for δ-catenin in cancer progression. This project aims to further elucidate the mechanisms by which δ-catenin is regulated and how it contributes to cancer development and metastasis.
The project also investigates the role of other adherens junction proteins, such as E-cadherin and p120-catenin, in modulating δ-catenin function and cancer progression. Understanding the interplay between these proteins and their impact on cell-cell adhesion and signaling pathways will provide important insights into the complex regulation of the adherens junction and its implications in cancer. Overall, this project seeks to uncover novel mechanisms underlying the dysregulation of adherens junction proteins and their contribution to the hallmarks of cancer.
Key Findings
δ-Catenin can be degraded by both the proteosomal- and the lysosomal pathways.
β-TrCP interacts with δ-catenin and facilitates its degradation via Ub-proteasome.
Ubiquitination sites on δ-catenin are mainly located at its Lys1049 and Lys1158.
Hakai, an E3 ligase for E-cadherin, stabilizes Src, which inhibits the binding between glycogen synthase kinase-3β and δ-catenin. This interaction leads to reduced proteosomal degradation of δ-catenin, resulting in its stabilization.
δ-Catenin Increases the Stability of EGFR by Decreasing c-Cbl Interaction and Enhances EGFR/Erk1/2 Signaling in Prostate Cancer.
References
2018
Molecules and Cells
δ-Catenin increases the stability of EGFR by decreasing c-Cbl interaction and enhances EGFR/Erk1/2 signaling in prostate cancer
Nensi Shrestha*, Hridaya Shrestha*, Taeyong Ryu, and 8 more authors
δ-Catenin, a member of the p120-catenin subfamily of armadillo proteins, reportedly increases during the late stage of prostate cancer. Our previous study demonstrates that δ-catenin increases the stability of EGFR in prostate cancer cell lines. However, the molecular mechanism behind δ-catenin-mediated enhanced stability of EGFR was not explored. In this study, we hypothesized that δ-catenin enhances the protein stability of EGFR by inhibiting its lysosomal degradation that is mediated by c-casitas b-lineage lymphoma (c-Cbl), a RING domain E3 ligase. c-Cbl monoubiquitinates EGFR and thus facilitates its internalization, followed by lysosomal degradation. We observed that δ-catenin plays a key role in EGFR stability and downstream signaling. δ-Catenin competes with c-Cbl for EGFR binding, which results in a reduction of binding between c-Cbl and EGFR and thus decreases the ubiquitination of EGFR. This in turn increases the expression of membrane bound EGFR and enhances EGFR/Erk1/2 signaling. Our findings add a new perspective on the role of δ-catenin in enhancing EGFR/Erk1/2 signaling-mediated prostate cancer.
2017
Cellular Signalling
Hakai, an E3-ligase for E-cadherin, stabilizes δ-catenin through Src kinase
Hridaya Shrestha, Taeyong Ryu, Young-Woo Seo, and 8 more authors
Hakai ubiquitinates and induces endocytosis of the E-cadherin complex; thus, modulating cell adhesion and regulating development of the epithelial-mesenchymal transition of metastasis. Our previous published data show that δ-catenin promotes E-cadherin processing and thereby activates β-catenin-mediated oncogenic signals. Although several published data show the interactions between δ-catenin and E-cadherin and between Hakai and E-cadherin separately, we found no published report on the relationship between δ-catenin and Hakai. In this report, we show Hakai stabilizes δ-catenin regardless of its E3 ligase activity. We show that Hakai and Src increase the stability of δ-catenin synergistically. Hakai stabilizes Src and Src, which in turn, inhibits binding between glycogen synthase kinase-3β and δ-catenin, resulting in less proteosomal degradation of δ-catenin. These results suggest that stabilization of δ-catenin by Hakai is dependent on Src.
2016
BBA MCR
Investigation of the molecular mechanism of δ-catenin ubiquitination: Implication of β-TrCP-1 as a potential E3 ligase
Hridaya Shrestha*, Tingting Yuan*, Yongfeng He, and 8 more authors
Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 2016
Ubiquitination, a post-translational modification, involves the covalent attachment of ubiquitin to the target protein. The ubiquitin-proteasome pathway and the endosome-lysosome pathway control the degradation of the majority of eukaryotic proteins. Our previous study illustrated that δ-catenin ubiquitination occurs in a glycogen synthase kinase-3 (GSK-3) phosphorylation-dependent manner. However, the molecular mechanism of δ-catenin ubiquitination is still unknown. Here, we show that the lysine residues required for ubiquitination are located mainly in the C-terminal portion of δ-catenin. In addition, we provide evidence that β-TrCP-1 interacts with δ-catenin and functions as an E3 ligase, mediating δ-catenin ubiquitin-proteasome degradation. Furthermore, we prove that both the ubiquitin-proteasome pathway and the lysosome degradation pathway are involved in δ-catenin degradation. Our novel findings on the mechanism of δ-catenin ubiquitination will add a new perspective to δ-catenin degradation and the effects of δ-catenin on E-cadherin involved in epithelial cell-cell adhesion, which is implicated in prostate cancer progression.
Scientific Reports
Interaction of EGFR to δ-catenin leads to δ-catenin phosphorylation and enhances EGFR signaling
Yongfeng He, Taeyong Ryu, Nensi Shrestha, and 7 more authors
Expression of δ-catenin reportedly increases during late stage prostate cancer. Furthermore, it has been demonstrated that expression of EGFR is enhanced in hormone refractory prostate cancer. In this study, we investigated the possible correlation between EGFR and δ-catenin in prostate cancer cells. We found that EGFR interacted with δ-catenin and the interaction decreased in the presence of EGF. We also demonstrated that, on one hand, EGFR phosphorylated δ-catenin in a Src independent manner in the presence of EGF and on the other hand, δ-catenin enhanced protein stability of EGFR and strengthened the EGFR/Erk1/2 signaling pathway. Our findings added a new perspective to the interaction of EGFR to the E-cadherin complex. They also provided novel insights to the roles of δ-catenin in prostate cancer cells.
