Helicobacter pylori activate epidermal growth factor receptor- and phosphatidylinositol 3-OH kinase-dependent Akt and glycogen synthase kinase 3beta phosphorylation.
The signalling pathways leading to the development of Helicobacter pylori-induced gastric cancer remain poorly understood. We tested the hypothesis that H. pylori infections involve the activation of Akt signalling in human gastric epithelial cancer cells. Immunoblot, immunofluorescence and kinase assays show that H. pylori infection of gastric epithelial cells induced phosphorylation of Akt at Ser 473 and Thr 308. Mutations in the H. pylori virulence factor OipA dramatically reduced phosphorylation of Ser 473, while the cag pathogenicity island mutants predominantly inhibited phosphorylation of Thr 308. As the downstream of Akt activation, H. pylori infection inactivated the inactivation of glycogen synthase kinase 3beta at Ser 9 by its phosphorylation. As the upstream of Akt activation, H. pylori infection activated epidermal growth factor receptor (EGFR) at Tyr 992, phosphatidylinositol 3-OH kinase (PI3K) p85 subunit and PI3K-dependent kinase 1 at Ser 241. Pharmacologic inhibitors of PI3K or mitogen-activated protein kinase kinase (MEK), Akt knock-down and EGFR knock-down showed that H. pylori infection induced the activation of EGFR-->PI3K-->PI3K-dependent kinase 1-->Akt-->extracellular signal-regulated kinase signalling pathways, the inactivation of glycogen synthase kinase 3beta and interleukin-8 production. The combined functions of cag pathogenicity island and OipA were necessary and sufficient for full activation of signalling at each level. We propose activation of these pathways as a novel mechanism for H. pylori-mediated carcinogenesis.
Tabassam
Fazal H
FH
Department of Medicine-Gastroenterology, Michael DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030, USA.
Graham
David Y
DY
Yamaoka
Yoshio
Y
D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D044404:Genomic Islands; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D016480:Helicobacter pylori / Q000276:immunology / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D016209:Interleukin-8 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D001425:Bacterial Outer Membrane Proteins; D066246:ErbB Receptors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D016209:Interleukin-8; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; C526444:OipA protein, Helicobacter pylori; C000605506:GSK3B protein, human
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