| First Author | Jung YS | Year | 2020 |
| Journal | Hepatology | PubMed ID | 32380568 |
| Mgi Jnum | J:292554 | Mgi Id | MGI:6450309 |
| Doi | 10.1002/hep.31305 | Citation | Jung YS, et al. (2020) TMEM9-v-ATPase Activates Wnt/beta-Catenin Signaling via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesis. Hepatology |
| abstractText | How Wnt signaling is orchestrated in liver regeneration and tumorigenesis remains elusive. Recently, we identified transmembrane protein 9 (TMEM9) as a Wnt signaling amplifier. 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 (CV) and acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased Apc and reduced Wnt signaling. Mechanistically, TMEM9 downregulates APC through lysosomal protein degradation via v-ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain beta-catenin hyperactivation. TMEM9-upregulated 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. Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis via lysosomal degradation of APC. |
