Helicobacter pylori-induced activation of beta-catenin involves low density lipoprotein receptor-related protein 6 and Dishevelled.
BACKGROUND
The human microbial pathogen Helicobacter pylori resides in the stomach of about fifty percent of the world's population and represents a risk factor for chronic gastritis, peptic ulcers and, in rare cases, gastric cancer. Alterations of the Wnt/beta-catenin signaling pathway have been described in almost every human cancer disease, due to the regulation of target genes being involved in cell cycle control, differentiation, cell migration or stem cell control. Our study aimed to elucidate the role of proximal Wnt signaling components low density lipoprotein receptor-related protein 6 (LRP6) and Dishevelled (Dvl) in the activation of beta-catenin early after infection of gastric epithelial cells with H. pylori.


RESULTS
Infection of gastric epithelial NCI-N87 cells with H. pylori induces rapid phosphorylation of the Wnt/beta-catenin pathway co-receptor LRP6 independent of the cytotoxin-associated gene A (CagA) or vacuolating cytotoxin A (VacA). However, bacteria lacking a functional type 4 secretion system (T4SS) failed to induce LRP6 phosphorylation. Further, we identified proteins of the Dvl family, namely Dvl2 and Dvl3, which are involved in LRP6 phosphorylation. H. pylori-induced nuclear accumulation of beta-catenin and its transcriptional activation, and expression of Wnt target genes are strongly reduced in stable knockdown cell lines deficient for LRP6, Dvl2 or Dvl3.


CONCLUSIONS
We analysed the H. pylori-induced activation of Wnt-signaling factors and demonstrate for the first time that the canonical Wnt-signaling proteins LRP6 and Dvl2 and Dvl3 are involved in the regulation of beta-catenin.
Gnad
Thorsten
T
Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany.
Feoktistova
Maria
M
Leverkus
Martin
M
Lendeckel
Uwe
U
Naumann
Michael
M
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D000072261:Dishevelled Proteins; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D016481:Helicobacter Infections / Q000378:metabolism; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011973:Receptors, LDL / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; C000606581:DVL2 protein, human; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010750:Phosphoproteins; D011973:Receptors, LDL; D051820:TCF Transcription Factors; D051176:beta Catenin