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TMEM9‐v‐ATPase Activates Wnt/β‐Catenin Signaling Via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesis
Author(s) -
Jung YounSang,
Stratton Sabrina A.,
Lee Sung Ho,
Kim MoonJong,
Jun Sohee,
Zhang Jie,
Zheng Biyun,
Cervantes Christopher L.,
Cha JongHo,
Barton Michelle C.,
Park JaeIl
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31305
Subject(s) - wnt signaling pathway , microbiology and biotechnology , carcinogenesis , biology , lrp6 , cancer research , beta catenin , protein degradation , catenin , signal transduction , chemistry , cancer , genetics
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 β‐catenin hyperactivation. TMEM9–up‐regulated APC binds to and inhibits nuclear translocation of β‐catenin, independent of HCC‐associated β‐catenin mutations. Pharmacological blockade of TMEM9‐v‐ATPase or lysosomal degradation suppresses Wnt/β‐catenin through APC stabilization and β‐catenin cytosolic retention. Conclusions Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis through lysosomal degradation of APC.