title: Helicobacter pylori Induces Serine Phosphorylation of EGFR via Novel TAK1-p38 Activation Pathway in an HB-EGF-Independent Manner.
abstract: BACKGROUND
  The interaction of Helicobacter pylori with gastric epithelial cells can result in the activation of transcription factor NF-κB via TGF-β-activated kinase 1 (TAK1). In this study, we have demonstrated the role of H. pylori in the activation of EGFR via TAK1-mediated phosphorylation of p38.
  
  
  METHODS
  Gastric epithelial AGS or MKN-45 cells were co-cultured with wild-type or cagA(-) H. pylori strains. H. pylori was added to the cells, and the activation of EGFR, p65 (NF-κB) subunit, p38, ERK, and TAK1 was examined by Western blotting. Infected cells were pretreated with or without ligands, chemical inhibitors, anti-HB-EGF antibody, and siRNAs to evaluate the effects on phosphorylation of various EGFR residues. Fluorescence microscopy and flow cytometry were performed to detect the internalization of EGFR.
  
  
  RESULTS
  Incubating cells with wild-type and CagA(-) H. pylori strains resulted in the rapid and transient phosphorylation of serine residues of EGFR. RNAi experiments using siRNA against TAK1 and p38 pathways blocked the phosphorylation of serine residue. Immunofluorescence and flow cytometry revealed that EGFR was internalized in H. pylori-infected cells after EGFR phosphorylation in a p38-dependent manner. In contrast, pretreatment with gefitinib and anti-HB-EGF antibody did not block both the phosphorylation and internalization of EGFR.
  
  
  CONCLUSIONS
  Helicobacter pylori induces internalization of EGFR via novel TAK1-p38-serine activation pathway which is independent of HB-EGF. The interaction between TAK1 and EGFR in H. pylori-infected cells might open new dimensions in understanding H. pylori-associated gastric carcinogenesis.
authors.affiliation: Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.|Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University of Health Sciences, Jeddah, Saudi Arabia.|Department of Biological and Biomedical Sciences, Faculty of Health Sciences, Aga Khan University, Karachi, Pakistan.
authors.forename: Syed Faisal
authors.initials: SF
authors.lastname: Zaidi
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.|Center for Aging and Associated Diseases, Zewail City of Science and Technology, Giza, Egypt.
authors.forename: Alaa
authors.initials: A
authors.lastname: Refaat
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Jibran
authors.initials: J
authors.lastname: Sualeh Muhammad
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Myoung-Sook
authors.initials: MS
authors.lastname: Shin
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.affiliation: Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sugiyama
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D018920:Coculture Techniques; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D016480:Helicobacter pylori / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012694:Serine / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases; D012694:Serine; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C512478:EGFR protein, human
keywords: Epidermal growth factor receptor; HB-EGF; Helicobacter pylori; TAK1; p38; transactivation