Erk Associates with and Primes GSK-3β for Its Inactivation Resulting in Upregulation of β-Catenin

Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Molecular Cell (Impact Factor: 14.02). 08/2005; 19(2):159-70. DOI: 10.1016/j.molcel.2005.06.009
Source: PubMed


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.

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Available from: Ralf C Bargou, Dec 27, 2013
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    • "Similarly, in cultured human renal tubular epithelial cells and corneal fibroblasts, GSK3 inhibition reduced TGF-β1-induced SMAD3 activity (Choi et al., 2011; Zhang et al., 2007). On the other hand, TGF-β inhibits GSK3β via ERK-MAPK in hepatocellular carcinoma (Ding et al., 2005) and cultured peritoneal mesothelial cells (Jang et al., 2013), and GSK3 inhibition can lead to SMAD3 activation and fibrosis in cultured cardiac myocytes and fibroblasts (Hua et al., 2010; Lal et al., 2014). In the kidney, GSK3 inhibition has been associated with EMT in unilateral ureteral obstruction (UUO) in vivo and renal epithelial cells in vitro by increasing TGF-β1-induced β-catenin and Snail accumulation Fig. 4. GSK3 inhibition reduced proinflammatory cytokines and macrophage infiltration following I/R. "
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