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

Authors :
Gernot Posselt
Maria Wiesauer
Bianca E. Chichirau
Daniela Engler
Linda M. Krisch
Gabriele Gadermaier
Peter Briza
Sabine Schneider
Francesco Boccellato
Thomas F. Meyer
Cornelia Hauser-Kronberger
Daniel Neureiter
Anne Müller
Silja Wessler
Source :
Cell Communication and Signaling, Vol 17, Iss 1, Pp 1-15 (2019)
Publication Year :
2019
Publisher :
BMC, 2019.

Abstract

Abstract 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-β-D-manno-heptose-1,7-bisphosphate (βHBP) and protein kinase C (PKC) as a new c-Abl kinase. pAblT735 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 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.

Details

Language :
English
ISSN :
1478811X
Volume :
17
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cell Communication and Signaling
Publication Type :
Academic Journal
Accession number :
edsdoj.768ac5aecb44bf99a2dbdc8afe6c606
Document Type :
article
Full Text :
https://doi.org/10.1186/s12964-019-0323-9