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Oncogenesis, Aug 19 2013, 2 (8) | https://doi.org/10.1038/oncsis.2013.28 Deubiquitination of Dishevelled by Usp14 is required for Wnt signaling

H Jung ¹, B-G Kim ², WH Han ³, JH Lee ⁴, J-Y Cho ⁵, WS Park ⁶, MM Maurice ⁷, J-K Han ³, MJ Lee ^{4 *}, D Finley^{8 *} and E-h Jho ^{1 *}

¹Department of Life Science, The University of Seoul, Seoul, Korea
²Medicinal Bioconvergence Research Center, Seoul National University, Advanced institute of Convergence Technology, Suwon-si, Korea
³Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Korea
⁴Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin-si, Korea
⁵Department of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul, Korea
⁶Department of Pathology, College of Medicine, the Catholic University of Korea, Seoul, Korea
⁷Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands
⁸Department of Cell Biology, Harvard Medical School, Boston, MA, USA.

^*Corresponding authors: correspondence to MJ Lee or E-h Jho

Abstract

Dishevelled (Dvl) is a key regulator of Wnt signaling both in the canonical and non-canonical pathways. Here we report the identification of a regulatory domain of ubiquitination (RDU) in the C-terminus of Dvl. Mutations in the RDU resulted in accumulation of polyubiquitinated forms of Dvl, which were mainly K63 linked. Small interfering RNA-based screening identified Usp14 as a mediator of Dvl deubiquitination. Genetic and chemical suppression of Usp14 activity caused an increase in Dvl polyubiquitination and significantly impaired downstream Wnt signaling. These data suggest that Usp14 functions as a positive regulator of the Wnt signaling pathway. Consistently, tissue microarray analysis of colon cancer revealed a strong correlation between the levels of Usp14 and β-catenin, which suggests an oncogenic role for Usp14 via enhancement of Wnt/β-catenin signaling.

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