Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin

Mol Cell. 2005 Jul 22;19(2):159-70. doi: 10.1016/j.molcel.2005.06.009.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs / physiology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Carcinoma, Hepatocellular / metabolism*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Genes, erbB-2 / physiology
  • Glycogen Synthase Kinase 3 / metabolism*
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Liver Neoplasms / metabolism*
  • Phosphorylation
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Tumor Cells, Cultured
  • Up-Regulation
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • Trans-Activators
  • beta Catenin
  • hepatitis B virus X protein
  • Insulin-Like Growth Factor I
  • Extracellular Signal-Regulated MAP Kinases
  • Glycogen Synthase Kinase 3