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

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-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.

• Authors: Nensi Shrestha, Hridaya Shrestha, Taeyong Ryu, Hangun Kim, Shishli Simkhada, Young-Chang Cho, So-Yeon Park, Sayeon Cho, Kwang-Youl Lee, Jae-Hyuk Lee, Kwonseop Kim
• Journal: Molecules and cells (Mol Cells) Vol. 41 Issue 4 Pg. 320-330 (Apr 30 2018) ISSN: 0219-1032 [Electronic] Korea (South)
• PMID: 29629558 (Publication Type: Journal Article)

Chemical References

• Catenins
• Recombinant Fusion Proteins
• Green Fluorescent Proteins
• Proto-Oncogene Proteins c-cbl
• EGFR protein, human
• ErbB Receptors
• CBL protein, human
• Delta Catenin
• CTNND1 protein, human

Topics

• Catenins (biosynthesis, genetics, metabolism)
• Cell Line, Tumor
• ErbB Receptors (biosynthesis, metabolism)
• Green Fluorescent Proteins (biosynthesis, genetics)
• Humans
• MAP Kinase Signaling System
• Male
• Prostatic Neoplasms (metabolism)
• Protein Stability
• Proto-Oncogene Proteins c-cbl (metabolism)
• Recombinant Fusion Proteins (biosynthesis, genetics)
• Transfection
• Ubiquitination
• Delta Catenin