セッション情報 The 2nd JSGE International Topic Conference

3)Gastric Cancer;From the View of Helicobacter pylori-related Inflammation

タイトル IT3-2:

Interaction of Helicobacter pylori with Gastric Epithelial Cells and Induction of Oncogenic Signal Transduction

演者 Backert Steffen(Department of Biology, Friedrich Alexander University Erlangen-Nuremberg, Institute of Microbiology, Germany)
共同演者
抄録 Infection with Helicobacter pylori can induce gastric pathologies ranging from chronic gastritis to peptic ulcers and even cancer. Highly virulent isolates harbour a pathogenicity island in their chromosome encoding components of a type IV secretion system(T4SS). This T4SS forms extracellular pilus structures for the injection of virulence factors from the bacterium into host target cells such as the CagA oncoprotein. Injected CagA mimics a host cell protein to hijack normal intracellular signalling cascades. One of the downstream targets of CagA is the actin-binding protein cortactin, which acts as a classical actin nucleation promoting factor. Here we present an entirely novel function of cortactin in cell scattering and elongation using H. pylori as a model system. We show that H. pylori infection targets cortactin by two independent signalling cascades leading to tyrosine dephosphorylation and serine phosphorylation of cortactin at three distinct residues, respectively. Depending on the phosphorylation status, cortactin changes both its subcellular localization and its ability to bind and activate downstream signaling factors. Upon infection, a novel interaction partner of cortactin was identified as focal adhesion kinase(FAK). This interaction profoundly stimulates the kinase activity of FAK in vivo and in vitro, and requires the SH3 domain and phosphorylation of cortactin at serine residue 405 and to less extent at serine 418, as well as a novel proline-rich sequence in FAK. Thus, the interaction of cortactin with FAK proceeds directly via a classical SH3>PxxP-motif interaction. It appears that H. pylori targets cortactin to trap FAK in target cells and interferes with normal cell adhesion processes, which are important for cell elongation and scattering during infection. Taken together, our study unravels a new pathway leading to FAK activation and gives new insights into cortactin’s function and regulation at the molecular level.
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