TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling
- Authors
- Jung, Youn-Sang; Jun, Sohee; Kim, Moon Jong; Lee, Sung Ho; Suh, Han Na; Lien, Esther M.; Jung, Hae-Yun; Lee, Sunhye; Zhang, Jie; Yang, Jung-In; Ji, Hong; Wu, Ji Yuan; Wang, Wenqi; Miller, Rachel K.; Chen, Junjie; McCrea, Pierre D.; Kopetz, Scott; Park, Jae-Il
- Issue Date
- Dec-2018
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- NATURE CELL BIOLOGY, v.20, no.12, pp 1421 - 1433
- Pages
- 13
- Journal Title
- NATURE CELL BIOLOGY
- Volume
- 20
- Number
- 12
- Start Page
- 1421
- End Page
- 1433
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/63815
- DOI
- 10.1038/s41556-018-0219-8
- ISSN
- 1465-7392
1476-4679
- Abstract
- Vesicular acidification and trafficking are associated with various cellular processes. However, their pathologic relevance to cancer remains elusive. We identified transmembrane protein 9 (TMEM9) as a vesicular acidification regulator. TMEM9 is highly upregulated in colorectal cancer. Proteomic and biochemical analyses show that TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking. TMEM9-v-ATPase hyperactivates Wnt/beta-catenin signalling via lysosomal degradation of adenomatous polyposis coli (APC). Moreover, TMEM9 transactivated by beta-catenin functions as a positive feedback regulator of Wnt signalling in colorectal cancer. Genetic ablation of TMEM9 inhibits colorectal cancer cell proliferation in vitro, ex vivo and in vivo mouse models. Moreover, administration of v-ATPase inhibitors suppresses intestinal tumorigenesis of APC mouse models and human patient-derived xenografts. Our results reveal the unexpected roles of TMEM9-controlled vesicular acidification in hyperactivating Wnt/beta-catenin signalling through APC degradation, and propose the blockade of TMEM9-v-ATPase as a viable option for colorectal cancer treatment.
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Collections - College of Natural Sciences > Department of Life Science > 1. Journal Articles
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