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http://purl.uniprot.org/citations/30704478http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/30704478http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.org/dc/terms/identifier"doi:10.1186/s12964-019-0323-9"xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Meyer T.F."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Schneider S."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Muller A."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Wessler S."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Briza P."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Gadermaier G."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Posselt G."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Hauser-Kronberger C."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Engler D."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Neureiter D."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Boccellato F."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Chichirau B.E."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Krisch L.M."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/author"Wiesauer M."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/date"2019"xsd:gYear
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/name"Cell Commun Signal"xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/pages"10"xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/title"Helicobacter pylori-controlled c-Abl localization promotes cell migration and limits apoptosis."xsd:string
http://purl.uniprot.org/citations/30704478http://purl.uniprot.org/core/volume"17"xsd:string
http://purl.uniprot.org/citations/30704478http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/30704478
http://purl.uniprot.org/citations/30704478http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/30704478
http://purl.uniprot.org/uniprot/#_A0A023PX70-mappedCitation-30704478http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/30704478
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