Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin.
Beta-catenin is upregulated in many human cancers and considered to be an oncogene. Hepatocellular carcinoma (HCC) is one of the most prevalent human malignancies, and individuals who are chronic hepatitis B virus (HBV) carriers have a greater than 100-fold increased relative risk of developing HCC. Here we report a mechanism by which HBV-X protein (HBX) upregulates beta-catenin. Erk, which is activated by HBX, associates with GSK-3beta through a docking motif ((291)FKFP) of GSK-3beta and phosphorylates GSK-3beta at the (43)Thr residue, which primes GSK-3beta for its subsequent phosphorylation at Ser9 by p90RSK, resulting in inactivation of GSK-3beta and upregulation of beta-catenin. This pathway is a general signal, as it was also observed in cell lines in which Erk-primed inactivation of GSK-3beta was regulated by IGF-1, TGF-beta, and receptor tyrosine kinase HER2, and is further supported by immunohistochemical staining in different human tumors, including cancers of the liver, breast, kidney, and stomach.
Pubmed ID: 16039586 RIS Download
Amino Acid Motifs | Breast Neoplasms | Carcinoma, Hepatocellular | Cytoskeletal Proteins | Enzyme Activation | Extracellular Signal-Regulated MAP Kinases | Female | Genes, erbB-2 | Glycogen Synthase Kinase 3 | Humans | Insulin-Like Growth Factor I | Liver Neoplasms | Phosphorylation | Trans-Activators | Tumor Cells, Cultured | Up-Regulation | beta Catenin