Cytotoxin-associated gene A (CagA) is an oncoprotein and a major virulence factor of H. pylori. CagA is delivered into gastric epithelial cells via a type IV secretion system and causes cellular transformation. The loss of epithelial adhesion that accompanies the epithelial-mesenchymal transition (EMT) is a hallmark of gastric cancer. Although CagA is a causal factor in gastric cancer, the link between CagA and the associated EMT has not been elucidated. Here, we show that CagA induces the EMT by stabilizing Snail, a transcriptional repressor of E-cadherin expression. Mechanistically we show that CagA binds GSK-3 in a manner similar to Axin and causes it to shift to an insoluble fraction, resulting in reduced GSK-3 activity. We also find that the level of Snail protein is increased in H. pylori infected epithelium in clinical samples. These results suggest that H. pylori CagA acts as a pathogenic scaffold protein that induces a Snail-mediated EMT via the depletion of GSK-3.
Bibliographical noteFunding Information:
We thank Professor H.S. Cho for helpful discussion of CagA and GSK-3 structure, and for providing recombinant GSK-3b. We also thank E. Tunkle for preparation of the manuscript and K.Y. Kim for statistical analysis. This work was supported by grants from the National Research Foundation of Korea (NRF-2009-0094027, NRF-2010-0010739, NRF-2012M3A9B2052523, NRF-2013R1A1A1011652, NRF-2014R1A2A1A05004670).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)