title: Epithelial cell ADAM17 activation by Helicobacter pylori: role of ADAM17 C-terminus and Threonine-735 phosphorylation.
abstract: Helicobacter pylori transactivates the epidermal growth factor receptor (EGFR) on gastric epithelial cells via a signalling cascade involving a disintegrin and metalloprotease 17 (ADAM17) cleavage of membrane bound heparin binding-epidermal growth factor (HB-EGF). The effects of H. pylori on ADAM17 C-terminus in epithelial cells have been examined. Total cellular ADAM17 and surface expression of ADAM17 were significantly increased by H. pylori in AGS gastric epithelial cells. These changes were associated with ADAM17 C-terminal phosphorylation at T375 and S791. AGS cells lacking the ADAM17 C-terminal domain induced significantly attenuated cleavage of HB-EGF and were also unable to upregulate HB-EGF and EGFR transcripts to the same extent as cells expressing full length ADAM17. In mitotic unstimulated AGS and ADAM17 over-expressing AGS cells, ADAM17 was highly T735 phosphorylated indicating ADAM17 T735 phosphorylation is modified during the cell cycle. In conclusion, H. pylori induced ADAM17 C-terminal T735 and/or S791 phosphorylation in gastric epithelial cells are likely to be an important trigger inducing ADAM17 activation and shedding of HB-EGF leading to EGFR transactivation. ADAM17 over-expression in gastric cancer represents a potential target for therapeutic intervention.
authors.affiliation: Leeds Institute, Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Urszula L
authors.initials: UL
authors.lastname: McClurg
authors.affiliation: Leeds Institute, Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Danjo
authors.affiliation: Leeds Institute, Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Harry O
authors.initials: HO
authors.lastname: King
authors.affiliation: Leeds Institute, Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Gina B
authors.initials: GB
authors.lastname: Scott
authors.affiliation: Leeds Institute, Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Robinson
authors.affiliation: Leeds Institute, Biomedical and Clinical Sciences, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK. Electronic address: j.crabtree@leeds.ac.uk.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Crabtree
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000276:immunology / Q000502:physiology*; D016480:Helicobacter pylori / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D010766:Phosphorylation / Q000276:immunology; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics; D013912:Threonine / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D013912:Threonine; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: ADAM 17; EGFR; HB-EGF; Helicobacter pylori; Phosphorylation; TNF-α