Activation of Abl by Helicobacter pylori: a novel kinase for CagA and crucial mediator of host cell scattering.

摘要: Background & Aims: The pathogenesis of Helicobacter pylori (Hp)-associated diseases depends on a specialized type IV secretion system. This system injects the cytotoxin-associated gene A (CagA) effector protein into target cells where CagA becomes phosphorylated tyrosine residues by Src. Src then is inactivated rapidly, suggesting presence another host kinase to ensure constant phosphorylation in sustained Hp infections. We aimed identify this kinase. Methods: By using AGS gastric epithelial cell model, we performed detailed functional characterization Abl signaling during Results: showed that activated and novel crucial mediator First, Abl-specific inhibitors SKI-DV2-43 or STI571 (Gleevec, Novartis) knockdown c-Abl/Abl-related Arg small hairpin interfering RNAs efficiently inhibit scattering. Second, infection, rapidly autophosphorylation at Y-412. Third, both Y-899, Y-918, Y-972 CagA. Fourth, found substrate CrkII Y-221 vivo. Fifth, overexpression kinase-dead (K290M) blocked Hp-induced actin cytoskeletal rearrangements. further activity required maintain state. Moreover, forms physical complex with Conclusions: propose model which has evolved mechanism use least 2 kinases, Src, for subsequent actin-cytoskeletal rearrangements leading scattering elongation.