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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

Authors

  • Ding Q
  • Xia W
  • Liu JC
  • Yang JY
  • Lee DF
  • Xia J
  • Bartholomeusz G
  • Li Y
  • Pan Y
  • Li Z
  • Bargou RC
  • Qin J
  • Lai CC
  • Tsai FJ
  • Tsai CH
  • Hung MC

Journal

Molecular cell

Publication Data

July 22, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: CA 16672
  • Agency: NCI NIH HHS, Id: P01 CA099031
  • Agency: NCI NIH HHS, Id: R01 CA109311
  • Agency: NCI NIH HHS, Id: R01 CA58880

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