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Ubiquitylation and degradation of adenomatous polyposis coli by MKRN1 enhances Wnt/β-catenin signaling

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Abstract

The adenomatous polyposis coli (APC) protein has a tumor-suppressor function by acting as a negative regulator of the Wnt signaling pathway. While its role as a tumor suppressor is well-defined, the post-translational modifications that regulate APC stability are not fully understood. Here we showed that MKRN1, an E3 ligase, could directly interact with and ubiquitylate APC, promoting its proteasomal degradation. In contrast, an E3 ligase-defective MKRN1 mutant was no longer capable of regulating APC, indicating that its E3 ligase activity is required for APC regulation by MKRN1. Strengthening these results, MKRN1 ablation resulted in reduced β-catenin activity and decreased expression of Wnt target genes. The ability of the Wnt-dependent pathway to induce cancer cell proliferation, migration, and invasion was impaired by MKRN1 depletion, but restored by simultaneous APC knockdown. Taken together, these results demonstrate that MKRN1 functions as a novel E3 ligase of APC that positively regulates Wnt/β-catenin-mediated biological processes.

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Acknowledgements

We thank Prof. KY Choi (Yonsei University) for providing L929, L929-hWnt3a, and HEK293-TOP-FLASH stable cell lines. This research was supported by a grant from the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581) to J Song.

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Authors and Affiliations

  1. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea

    Hae-Kyung Lee, Jinho Seo, Manhyung Jeong & Jaewhan Song

  2. Metabolic Regulation Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, 34141, Korea

    Eun-Woo Lee

  3. Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do, 10408, Republic of Korea

    Seon-Hyeong Lee & Soo-Youl Kim

  4. Department of Life Science, The University of Seoul, 90 Jeonnong-dong, Dongdaemun-gu, Seoul, 02592, Korea

    Eek-Hoon Jho

  5. Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, Korea

    Chel Hun Choi

  6. Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Joon-Yong Chung

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Lee, HK., Lee, EW., Seo, J. et al. Ubiquitylation and degradation of adenomatous polyposis coli by MKRN1 enhances Wnt/β-catenin signaling. Oncogene 37, 4273–4286 (2018). https://doi.org/10.1038/s41388-018-0267-3

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