δ-Catenin Increases the Stability of EGFR by Decreasing c-Cbl Interaction and Enhances EGFR/Erk1/2 Signaling in Prostate Cancer
Nensi Shrestha1,5, Hridaya Shrestha1,5, Taeyong Ryu1, Hangun Kim2, Shishli Simkhada1, Young-Chang Cho1, So-Yeon Park2, Sayeon Cho3, Kwang-Youl Lee1, Jae-Hyuk Lee4,*, and Kwonseop Kim1,*
1College of Pharmacy and Research Institute for Drug Development, Chonnam National University, Gwangju 61186, Korea,
2College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Sunchon 57922,
Korea, 3College of Pharmacy, Chung-Ang University, Seoul 06974, Korea, 4Chonnam National University Hwasun Hospital &
Medical School, Hwasun 58128, Korea, 5These authors contributed equally to this work.
*Correspondence: jhlee@jnu.ac.kr (JHL); koskim@jnu.ac.kr (KK)
Received November 7, 2017; Revised January 1, 2018; Accepted January 2, 2018.; Published online April 5, 2018.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

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ABSTRACT
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-cateninmediated 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.
Keywords: δ-Catenin, c-Cbl, EGFR, ubiquitination


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