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.
Mesh Terms:
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
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
Mol. Cell
Date: Jul. 22, 2005
PubMed ID: 16039586
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