Phosphorylation of Helicobacter pylori CagA by c-Abl: H. pylori stimulates a drastic motogenic response in infected gastric epithelial host cells, which is enhanced by translocation of the pathogenic factor cytotoxin associated gene A (CagA) into host cells via a specialized type IV secretion system. Once injected into the cytosol CagA is rapidly tyrosine phosphorylated by Src family kinases followed by Src inactivation. Hence, it remained unknown why CagA is constantly phosphorylated in sustained H. pylori infections to induce cell migration, while other substrates of Src kinases are dephosphorylated. We have identified the non-receptor tyrosine kinase c-Abl as a crucial mediator of H. pylori-induced migration and novel CagA kinase in epithelial cells.
HtrA is a new secreted virulence factor that induces disruption of adherence junction complexes: Depolarization and migration of epithelial cells imply the disruption of cell adhesion junctions (AJs) comprising a protein complex of E-cadherin, beta-catenin, p120 and alpha-catenin. In this project, we analyze the disintegration of E-cadherin-mediated AJs and found that loss of E-cadherin-dependent cell-cell contacts is entirely independent of CagA. High-temperature requirement A (HtrA) was identified as a new secreted virulence factor of H. pylori, which cleaves the ectodomain of the cell-adhesion protein E-cadherin. E-cadherin shedding disrupts epithelial barrier functions allowing H. pylori to access the intercellular space.
Differential phospho-proteome profiling and identification of novel target molecules: H. pylori-associated diseases might involve a complex network of signal transduction pathways. Since the cellular aspects of those pathogen-host interactions leading to physiological disorders are only marginally understood, we analyze the phospho-proteome to identify novel phosphorylated proteins and activated signaling pathways in H. pylori-infected cells.
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