title: Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ding
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Jaw-Ching
authors.initials: JC
authors.lastname: Liu
authors.forename: Jer-Yen
authors.initials: JY
authors.lastname: Yang
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xia
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bartholomeusz
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Bargou
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Tsai
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin; C057628:hepatitis B virus X protein; D007334:Insulin-Like Growth Factor I; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3