4.7 Article

Helicobacter pylori-controlled c-Abl localization promotes cell migration and limits apoptosis

期刊

CELL COMMUNICATION AND SIGNALING
卷 17, 期 -, 页码 -

出版社

BMC
DOI: 10.1186/s12964-019-0323-9

关键词

C-Abl; Apoptosis; Cancer; Gastritis; Helicobacter pylori; Motility; HBP; PKC

资金

  1. EMBO Short-Term Fellowship [7427]
  2. Austrian Science Fund (FWF) [P_24315, W_1213]
  3. Deutsche Forschungsgesellschaft (DFG) [2843]
  4. Austrian Science Fund (FWF) [W1213] Funding Source: Austrian Science Fund (FWF)
  5. Austrian Science Fund (FWF) [P 24315] Funding Source: researchfish

向作者/读者索取更多资源

BackgroundDeregulated 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.Methodsc-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.ResultsHere, 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 (pAbl(T735)) 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. pAbl(T735) interacted with 14-3-3 proteins, which caused cytoplasmic retention of c-Abl, where it potentiated Hp-mediated cell elongation and migration. Further, the nuclear exclusion of pAbl(T735) attenuated caspase-8 and caspase-9-dependent apoptosis. Importantly, in human patients suffering from Hp-mediated gastritis c-Abl expression and pAbl(T735) 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.ConclusionsIn 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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