H. pylori selectively blocks EGFR endocytosis via the non-receptor kinase c-Abl and CagA.
Helicobacter pylori infection is a primary cause of peptic ulcers and is associated with gastric carcinogenesis. The H. pylori-induced pathophysiology may be linked to the deregulation of EGFR signalling. Elevated mucosal levels of EGF and the EGFR have been found in antral gastric biopsies of H. pylori-infected patients. A critical mechanism for regulating EGFR signalling is ligand-induced endocytosis. The internalized receptor recycles back to the plasma membrane for continued signalling or is targeted for degradation terminating receptor signalling. Here, we show that H. pylori blocks EGFR endocytosis and receptor degradation upon prolonged infection of gastric epithelial cells. Moreover, this inhibition occurs via a CagA-dependent, but CagA phosphorylation-independent activation of the non-receptor kinase c-Abl, which in turn phosphorylates the EGFR target site pY1173. This suggests a novel CagA-induced host cell response that is independent of CagA tyrosine phosphorylation. Our data indicate an intriguing strategy of H. pylori in host cell manipulations by altering selective receptor populations via a CagA-dependent endocytic mechanism. Furthermore, we identified a new role for c-Abl in phosphorylation of the EGFR target site pY1173 during H. pylori infection.
Bauer
Bianca
B
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, Campus Charité Mitte, 10117 Berlin, Germany.
Bartfeld
Sina
S
Meyer
Thomas F
TF
D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004705:Endocytosis; D004847:Epithelial Cells / Q000382:microbiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori; C512478:EGFR protein, human; D066246:ErbB Receptors; D016315:Proto-Oncogene Proteins c-abl