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H. pylori-controlled c-Abl activity as a regulator of cell migration and apoptosis  

Infections with the class-I carcinogen Helicobacter pylori (H. pylori) is associated with the indcution and progression of chronic gastritis, ulceration, mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. While MALT lymphoma can be treated by antibiotics as the first line therapy, the prognosis of gastric cancer is still poor and represents one of the leading causes for cancer-related deaths worldwide. H. pylori stimulates a drastic motogenic response in infected gastric epithelial host cells, which is enhanced by translocation of the pathogenic factor and oncoprotein cytotoxin associated gene A (CagA) into host cells via a specialized type IV secretion system (T4SS). 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. In our studies, we identified the non-receptor tyrosine kinase c-Abl as a crucial mediator of H. pylori-induced migration and novel CagA kinase in epithelial cells.

Signaling

                                                                         from: Posselt et al., 2019, Cell Commun Signal

The role of c-Abl in CagA-dependent pathways is well established; however, the knowledge of CagA-independent c-Abl processes is scarce. We investigated the activity and subcellular localization of c-Abl in vitro and in vivo and unraveled a novel mechanism of c-Abl in CagA-dependent and -independent pathways leading to gastric H. pylori pathogenesis. We identified strong c-Abl threonine 735 phosphorylation (pAbl T735) mediated by the T4SS effector D-glycero-β-D-manno-heptose-1,7-bisphosphate (βHBP) and protein kinase C (PKC) as a new c-Abl kinase. pAbl T735 interacts with 14–3-3 proteins, which causes cytoplasmic retention of c-Abl, where it potentiates H. pylori-mediated cell elongation and migration. Further, the nuclear exclusion of pAbl T735 attenuates caspase-8 and caspase-9-dependent apoptosis. Importantly, in human patients suffering from H. pylori-mediated gastritis, c-Abl expression and pAbl T735 phosphorylation are drastically enhanced as compared to type C gastritis patients or healthy individuals. This is a novel regulatory mechanism in H. pylori-infected gastric epithelial cells by which H. pylori determines the subcellular localization of activated c-Abl to control H. pylori-mediated EMT-like processes while decreasing cell death.

Important publications:

  • Posselt et al., 2019, Cell Commun Signal
  • Müller et al., 2012, J Clin Invest
  • Poppe et al., 2007, Oncogene
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