Disturbance of cell signaling by H. pylori CagA

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1. Membrane association of CagA is important for the pathogenic action of CagA in gastric epithelial cells and requires the EPIYA motif but is independent of EPIYA tyrosine phosphorylation.2. The activated SHP-2 with CagA directly dephosphorylates phospho-tyrosine residues of FAK, which are the activating phosphorylation sites. Accordingly, FAK activation is abolished in cells, and the inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA.3. Induction of cell morphological change with CagA is due to the Ras-independent modification of Erk signals.4. By screening of CagA-responsive genes using DNA microarray, we identified NFAT. CagA induced nuclear translocation and transcriptional activity of NFAT depending on calcineurin/PLCg pathway. Furthermore, H. pylori VacA toxin counteracted the ability of CagA to activate NFAT.5. Using a series of EPIYA-repeat variants of CagA that represent reported variations in clinical isolates of H. pylori, we show that EPIYA-repeat polymorphism, which is due to differences of both number and order of EPIYA segment, influences the phosphorylation-dependent CagA biological activity.6. We identified CagA multimerization motif that is composed of 16 amino acid residues and mediates an intermolecular interaction between CagA molecules. The CagA multimerization is necessary to express CagA biological activity that relates with cell morphogenetic activity and stimulation of cell motility.