Potentiation of Helicobacter pylori CagA protein virulence through homodimerization.

摘要: Chronic infection with Helicobacter pylori cagA-positive strains is associated atrophic gastritis, peptic ulceration, and gastric carcinoma. The cagA gene product, CagA, delivered into epithelial cells via type IV secretion, where it undergoes tyrosine phosphorylation at the EPIYA motifs. Tyrosine-phosphorylated CagA binds aberrantly activates oncogenic phosphatase SHP2, which mediates induction of elongated cell morphology (hummingbird phenotype) that reflects virulence. also inhibits polarity-regulating kinase partitioning-defective 1 (PAR1)/microtubule affinity-regulating (MARK) multimerization (CM) sequence independently phosphorylation. Because PAR1 exists as a homodimer, two proteins appear to be passively dimerized through complex formation dimer in cells. Interestingly, mutant lacks CM displays reduced SHP2 binding activity exhibits an attenuated ability induce hummingbird phenotype, indicating CagA-PAR1 interaction influences morphological transformation. Here we investigated role dimerization phenotype use chemical dimerizer, coumermycin. We found markedly stabilizes CagA-SHP2 thereby potentiates deregulation, causing increase number Protrusions induced by are further simultaneous inhibition PAR1. This study revealed amplifying magnitude deregulation which, conjunction sequence-mediated PAR1, evokes transformation vivo