| First Author | Lade A | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 27 | Pages | 22789-98 |
| PubMed ID | 22613727 | Mgi Jnum | J:316578 |
| Mgi Id | MGI:6840161 | Doi | 10.1074/jbc.M112.378224 |
| Citation | Lade A, et al. (2012) Calpain induces N-terminal truncation of beta-catenin in normal murine liver development: diagnostic implications in hepatoblastomas. J Biol Chem 287(27):22789-98 |
| abstractText | Hepatic competence, specification, and liver bud expansion during development depend on precise temporal modulation of the Wnt/beta-catenin signaling. Also, loss- and gain-of-function studies have revealed pleiotropic roles of beta-catenin in proliferation and hepatocyte and biliary epithelial cell differentiation, but precise mechanisms remain unknown. Here we utilize livers from different stages of murine development to determine beta-catenin signaling and downstream targets. Although during early liver development full-length beta-catenin is the predominant form, at late stages, where full-length beta-catenin localizes to developing biliary epithelial cells only, a 75-kDa truncated beta-catenin species is the principal form localizing at the membrane and in the nucleus of differentiating hepatocytes. The truncated species lacks 95 N-terminal amino acids and is transcriptionally active. Our evidence points to proteolytic cleavage of beta-catenin by calpain as the mechanism of truncation in cell-free and cell-based assays. Intraperitoneal injection of a short term calpain inhibitor to timed pregnant female mice abrogated beta-catenin truncation in the embryonic livers. RNA-seq revealed a unique set of targets transcribed in cells expressing truncated versus full-length beta-catenin, consistent with different functionalities. A further investigation using N- and C-terminal-specific beta-catenin antibodies on human hepatoblastomas revealed a correlation between full-length versus truncated beta-catenin and differentiation status, with embryonal hepatoblastomas expressing full-length beta-catenin and fetal hepatoblastomas expressing beta-catenin lacking its N terminus. Thus we conclude that calpain-mediated cleavage of beta-catenin plays a role in regulating hepatoblast differentiation in mouse and human liver, and the presence of the beta-catenin N terminus correlates with differentiation status in hepatoblastomas. |
