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KMID : 0578320180410040320
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Molecules and Cells
2018 Volume.41 No. 4 p.320 ~ p.330
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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
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Shrestha Nensi
Shrestha Hridaya
Ryu Tae-Yong
Kim Han-Gun
Simkhada Shishli
Cho Young-Chang
Park So-Yeon
Cho Sa-Yeon
Lee Kwang-Youl
Lee Jae-Hyuk
Kim Kwon-Seop
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Abstract
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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.
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KEYWORD
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δ-Catenin, c-Cbl, EGFR, ubiquitination
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