Erk associates with and primes GSK-3β for its inactivation resulting in upregulation of β-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-3 beta through a docking Motif ((FKFP)-F-291) of GSK-3 beta and phosphorylates GSK-3 beta at the (43)Thr residue, which primes GSK-3 beta for its subsequent phosphorylation at Ser9 by p90RSK, resulting in inactivation of GSK-3 beta and upregulation of P-catenin. This pathway is a general signal, as it was also observed in cell lines in which Erk-primed inactivation of GSK-3 beta 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.