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Helicobacter pylori-controlled c-Abl localization promotes cell migration and limits apoptosis
VerfasserPosselt, Gernot ; Wiesauer, Maria ; Chichirau, Bianca E. ; Engler, Daniela ; Krisch, Linda M. ; Gadermaier, Gabriele ; Briza, Peter ; Schneider, Sabine ; Boccellato, Francesco ; Meyer, Thomas F. ; Hauser-Kronberger, Cornelia ; Neureiter, Daniel ; Müller, Anne ; Wessler, Silja
Erschienen in
Cell Communication and Signaling, London, 2019, Jg. 17, H. 10, S. 1-15
ErschienenLondon : BMC, 2019
DokumenttypAufsatz in einer Zeitschrift
Schlagwörter (EN)C-Abl / Apoptosis / Cancer / Gastritis / Helicobacter pylori / Motility / HBP / PKC
URNurn:nbn:at:at-ubs:3-11288 Persistent Identifier (URN)
 Das Werk ist frei verfügbar
Helicobacter pylori-controlled c-Abl localization promotes cell migration and limits apoptosis [4.17 mb]
Zusammenfassung (Englisch)

Background: Deregulated c-Abl activity has been intensively studied in a variety of solid tumors and leukemia. The class-I carcinogen Helicobacter pylori (Hp) activates the non-receptor tyrosine kinase c-Abl to phosphorylate the oncoprotein cytotoxin-associated gene A (CagA). The role of c-Abl in CagA-dependent pathways is well established; however, the knowledge of CagA-independent c-Abl processes is scarce.

Methods: c-Abl phosphorylation and localization were analyzed by immunostaining and immunofluorescence. Interaction partners were identified by tandem-affinity purification. Cell elongation and migration were analyzed in transwell-filter experiments. Apoptosis and cell survival were examined by FACS analyses and MTT assays. In mice experiments and human biopsies, the involvement of c-Abl in Hp pathogenesis was investigated.

Results: Here, we investigated the activity and subcellular localization of c-Abl in vitro and in vivo and unraveled the contribution of c-Abl in CagA-dependent and -independent pathways to gastric Hp pathogenesis. We report a novel mechanism and identified strong c-Abl threonine 735 phosphorylation (pAblT735) mediated by the type-IV secretion system (T4SS) effector D-glycero--D-manno-heptose-1,7-bisphosphate (HBP) and protein kinase C (PKC) as a new c-Abl kinase. pAblT735 interacted with 143-3 proteins, which caused cytoplasmic retention of c-Abl, where it potentiated Hp-mediated cell elongation and migration. Further, the nuclear exclusion of pAblT735 attenuated caspase-8 and caspase-9-dependent apoptosis. Importantly, in human patients suffering from Hp-mediated gastritis c-Abl expression and pAblT735 phosphorylation were drastically enhanced as compared to type C gastritis patients or healthy individuals. Pharmacological inhibition using the selective c-Abl kinase inhibitor Gleevec confirmed that c-Abl plays an important role in Hp pathogenesis in a murine in vivo model.

Conclusions: In this study, we identified a novel regulatory mechanism in Hp-infected gastric epithelial cells by which Hp determines the subcellular localization of activated c-Abl to control Hp-mediated EMT-like processes while decreasing cell death.

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