title: CagA phosphorylation-dependent MMP-9 expression in gastric epithelial cells.
abstract: BACKGROUND
  Infection of cagA-positive Helicobacter pylori is associated with increased expression of MMPs in gastric epithelial cells. The role of phosphorylated CagA in the induction of MMP-9, a protease-degrading basement membrane, in gastric epithelial cells has not been clearly defined yet. The aim of this study is to analyze whether the presence of CagA and its phosphorylation status play a role in increased expression of MMP-9 in gastric epithelial cells.
  
  
  METHODS
  Induction of MMP-9 secretion was analyzed in gastric epithelial AGS cells harboring CagA with or without EPIYA motif, which is injected by H. pylori or ectopically expressed. In addition, signaling pathways involved in the CagA-dependent MMP-9 production have been studied.
  
  
  RESULTS
  The 147C strain of H. pylori expressing tyrosine-phosphorylated CagA (EPIYA present) induced higher MMP-9 secretion by AGS cells than the 147A strain expressing non-tyrosine-phosphorylated CagA (EPIYA absent). In addition, in bacteria-free CagA-inducible AGS cells, expression of wild-type CagA induced more MMP-9 secretion than phosphorylation-resistant CagA. Inhibition of CagA phosphorylation by the Src family kinase inhibitor PP1 downregulated CagA-mediated MMP-9 secretion. Knockdown of SHP-2 phosphatase dramatically reduced MMP-9 secretion. ERK inhibitors, PD98059 and U0126, and NF-κB pathway inhibitors, sulfasalazine and N-acetyl-l-cysteine, also inhibited MMP-9 expression.
  
  
  CONCLUSIONS
  These results support a model whereby the EPIYA motif of CagA is phosphorylated by Src family kinases in gastric epithelial cells, which initiates activation of SHP-2. In addition, they suggest that the resultant activation of ERK pathway along with CagA-dependent NF-κB activation is critical for the induction of MMP-9 secretion.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Nam
authors.forename: Eunju
authors.initials: E
authors.lastname: Ryu
authors.forename: Doyeon
authors.initials: D
authors.lastname: Lee
authors.forename: Hyun Jae
authors.initials: HJ
authors.lastname: Shim
authors.forename: Yong Chan
authors.initials: YC
authors.lastname: Lee
authors.forename: Seung-Taek
authors.initials: ST
authors.lastname: Lee
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000201:enzymology* / Q000382:microbiology*; D005753:Gastric Mucosa / Q000382:microbiology / Q000473:pathology*; D015870:Gene Expression; D016480:Helicobacter pylori / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori; D019061:src-Family Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D020780:Matrix Metalloproteinase 9