Precise regulation of signal transduction is required to control normal biological processes. Pathogens developed fascinating strategies to deregulate cellular signaling pathways, which have been related to a number of disorders, ranging from relatively non-life-threatening disorders to extremely virulent diseases such as cancer as a consequence of growth control loss and resistance to apoptosis. Focus of our research is the investigation of the molecular mechanisms of how the bacterial class-I carcinogen Helicobacter pylori interferes with host cell functions leading to gastric carcinogenesis.
H. pylori induces depolarization and migration of epithelial cells, which is enhanced by translocation of the pathogenic factor CagA into host cells. Once injected into the cytosol CagA is rapidly phosphorylated by Src family kinases. We identified the non-receptor tyrosine kinase c-Abl as an additional crucial mediator of H. pylori-induced migration and novel CagA kinase, which maintains CagA phosphorylation in epithelial cells. As Src and c-Abl kinases are important in driving cells toward neoplastic transformation they represent a promising field in future treatments of gastric cancer progression. In current projects we investigate those derailed non-receptor tyrosine kinases in H. pylori associated carcinogenesis.
Depolarization of epithelial cells also implies the disruption of E-cadherin-mediated adhesion junctions (AJs). We analyze the disintegration of E-cadherin-dependent AJs and identified the serine protease HtrA as a new secreted virulence factor of H. pylori that directly cleaves the E-cadherin ectodomain leading to the disruption of the epithelial barrier functions and allow H. pylori to access the intercellular space. Since HtrA-mediated E-cadherin cleavage appears to a prevalent mechanism in bacterial infections we analyze the functional consequences of HtrA activity in the pathogenesis of a wide range of further gastrointestinal pathogens (e.g. Campylobacter jejuni, or Listeria monocytogenses, etc.) and develop inhibitory compounds to prevent HtrA-dependent pathogenesis.
