?-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 ?-catenin. Erk, which is activated by HBX, associates with GSK-3? through a docking motif (291FKFP) of GSK-3? and phosphorylates GSK-3? at the 43Thr residue, which primes GSK-3? for its subsequent phosphorylation at Ser9 by p90RSK, resulting in inactivation of GSK-3? and upregulation of ?-catenin. This pathway is a general signal, as it was also observed in cell lines in which Erk-primed inactivation of GSK-3? was regulated by IGF-1, TGF-?, 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.