TMEM9-v-ATPase Activates Wnt/beta-Catenin Signaling Via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesisopen access
- Authors
- Jung, Youn-Sang; Stratton, Sabrina A.; Lee, Sung Ho; Kim, Moon-Jong; Jun, Sohee; Zhang, Jie; Zheng, Biyun; Cervantes, Christopher L.; Cha, Jong-Ho; Barton, Michelle C.; Park, Jae-Il
- Issue Date
- Feb-2021
- Publisher
- WILEY
- Citation
- HEPATOLOGY, v.73, no.2, pp.776 - 794
- Journal Title
- HEPATOLOGY
- Volume
- 73
- Number
- 2
- Start Page
- 776
- End Page
- 794
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/84712
- DOI
- 10.1002/hep.31305
- ISSN
- 0270-9139
- Abstract
- Background and Aims How Wnt signaling is orchestrated in liver regeneration and tumorigenesis remains elusive. Recently, we identified transmembrane protein 9 (TMEM9) as a Wnt signaling amplifier. Approach and Results TMEM9 facilitates v-ATPase assembly for vesicular acidification and lysosomal protein degradation. TMEM9 is highly expressed in regenerating liver and hepatocellular carcinoma (HCC) cells. TMEM9 expression is enriched in the hepatocytes around the central vein and acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased adenomatosis polyposis coli (Apc) and reduced Wnt signaling. Mechanistically, TMEM9 down-regulates APC through lysosomal protein degradation through v-ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain beta-catenin hyperactivation. TMEM9-up-regulated APC binds to and inhibits nuclear translocation of beta-catenin, independent of HCC-associated beta-catenin mutations. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation suppresses Wnt/beta-catenin through APC stabilization and beta-catenin cytosolic retention. Conclusions Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis through lysosomal degradation of APC.
- Files in This Item
- There are no files associated with this item.
- Appears in
Collections - 바이오나노대학 > 생명과학과 > 1. Journal Articles
![qrcode](https://api.qrserver.com/v1/create-qr-code/?size=55x55&data=https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/84712)
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.