The pathogen Helicobacter pylori is the first reported bacterial type-1
carcinogen playing a role in the development of human
malignancies, including gastric
adenocarcinoma.
Cancer cell motility is an important process in this scenario, however, the molecular mechanisms are still not fully understood. Here, we demonstrate that H. pylori subverts the
actin-binding protein cortactin through its
type-IV secretion system and injected
oncoprotein CagA, e.g., by inducing
tyrosine phosphorylation of
cortactin at Y-470, which triggers gastric epithelial cell scattering and motility. During
infection of AGS cells,
cortactin was discovered to undergo
tyrosine dephosphorylation at residues Y-421 and Y-486, which is mediated through inactivation of
Src kinase. However, H. pylori also profoundly activates
tyrosine kinase Abl, which simultaneously phosphorylates
cortactin at Y-470. Phosphorylated
cortactin interacts with the SH2-domain of Vav2, a
guanine nucleotide exchange factor for the Rho-family of
GTPases. The
cortactin/Vav2 complex then stimulates a previously unrecognized activation cascade including the
small GTPase Rac1, to effect actin rearrangements and cell scattering. We hypothesize that injected CagA targets
cortactin to locally open the gastric epithelium in order to get access to certain nutrients. This may disturb the cellular barrier functions, likely contributing to the induction of cell motility, which is important in
gastric cancer development.