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δ-Catenin Increases the Stability of EGFR by Decreasing c-Cbl Interaction and Enhances EGFR/Erk1/2 Signaling in Prostate Cancer

  • Shrestha, Nensi (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Shrestha, Hridaya (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Ryu, Taeyong (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Kim, Hangun (College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University) ;
  • Simkhada, Shishli (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Cho, Young-Chang (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Park, So-Yeon (College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University) ;
  • Cho, Sayeon (College of Pharmacy, Chung-Ang University) ;
  • Lee, Kwang-Youl (College of Pharmacy and Research Institute for Drug Development, Chonnam National University) ;
  • Lee, Jae-Hyuk (Chonnam National University Hwasun Hospital & Medical School) ;
  • Kim, Kwonseop (College of Pharmacy and Research Institute for Drug Development, Chonnam National University)
  • Received : 2017.11.07
  • Accepted : 2018.01.02
  • Published : 2018.04.30

Abstract

${\delta}$-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 ${\delta}$-catenin increases the stability of EGFR in prostate cancer cell lines. However, the molecular mechanism behind ${\delta}$-catenin-mediated enhanced stability of EGFR was not explored. In this study, we hypothesized that ${\delta}$-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 ${\delta}$-catenin plays a key role in EGFR stability and downstream signaling. ${\delta}$-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 ${\delta}$-catenin in enhancing EGFR/Erk1/2 signaling-mediated prostate cancer.

Keywords

${\delta}$-Catenin;c-Cbl;EGFR;ubiquitination

Acknowledgement

Supported by : National Research Foundation of Korea (NRF), Chonnam National University Hwasun Hospital Institute for Biomedical Science

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