ENTRY ko05120 Pathway NAME Epithelial cell signaling in Helicobacter pylori infection DESCRIPTION Two major virulence factors of H. pylori are the vacuolating cytotoxin (VacA) and the cag type-IV secretion system (T4SS) and its translocated effector protein, cytotoxin-associated antigen A (CagA). VacA binds to lipid rafts and glycosylphosphatidylinositol-anchored proteins (GPI-APs) of the target cell membrane. After insertion into the plasma membrane, VacA channels are endocytosed and eventually reach late endosomal compartments, increasing their permeability to anions with enhancement of the electrogenic vacuolar ATPase (v-ATPase) proton pump. In the presence of weak bases, osmotically active acidotropic ions will accumulate in the endosomes. This leads to water influx and vesicle swelling, an essential step in vacuole formation. In addition, it is reported that the VacA cleavage product binds to the tyrosine phosphatase receptor zeta (Ptprz) on epithelial cells and the induced signaling leads to the phosphorylation of the G protein-coupled receptor kinase-interactor 1 (Git1) and induces ulcerogenesis in mice. The other virulence factor cag T4SS mediates the translocation of the effector protein CagA, which is subsequently phosphorylated by a Src kinase. Phosphorylated CagA interacts with the protein tyrosine phosphatase SHP-2, thus stimulating its phosphatase activity. Activated SHP-2 is able to induce MAPK signalling through Ras/Raf-dependent and -independent mechanisms. Deregulation of this pathway by CagA may lead to abnormal proliferation and movement of gastric epithelial cells. CLASS Human Diseases; Infectious disease: bacterial PATHWAY_MAP ko05120 Epithelial cell signaling in Helicobacter pylori infection MODULE M00564 Helicobacter pylori pathogenicity signature, cagA pathogenicity island [PATH:ko05120] DISEASE H00320 Helicobacter pylori infection ORTHOLOGY K15842 cytotoxicity-associated immunodominant antigen K12086 cag pathogenicity island protein 1 K12087 cag pathogenicity island protein 2 K12088 cag pathogenicity island protein 3 K12089 cag pathogenicity island protein 4 K12090 cag pathogenicity island protein 5 K03196 type IV secretion system protein VirB11 [EC:7.4.2.8] K12091 cag pathogenicity island protein 6 K12092 cag pathogenicity island protein 7 K12093 cag pathogenicity island protein 8 K12094 cag pathogenicity island protein 9 K12095 cag pathogenicity island protein 10 K12096 cag pathogenicity island protein 11 K12097 cag pathogenicity island protein 12 K12098 cag pathogenicity island protein 13 K12099 cag pathogenicity island protein 14 K12100 cag pathogenicity island protein 15 K12101 cag pathogenicity island protein 16 K12102 cag pathogenicity island protein 17 K12103 cag pathogenicity island protein 18 K12104 cag pathogenicity island protein 19 K12105 cag pathogenicity island protein 20 K12106 cag pathogenicity island protein 21 K12107 cag pathogenicity island protein 22 K12108 cag pathogenicity island protein 23 [EC:7.4.2.8] K12109 cag pathogenicity island protein 24 K12110 cag pathogenicity island protein 25 K07293 tyrosine-protein phosphatase non-receptor type 11 [EC:3.1.3.48] K05099 proto-oncogene tyrosine-protein kinase Met [EC:2.7.10.1] K01116 phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11] K05859 phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11] K05701 tight junction protein 1 K06089 junctional adhesion molecule 1 K06735 junctional adhesion molecule 2 K06785 junctional adhesion molecule 3 K06786 junctional adhesion molecule 4 K06059 disintegrin and metalloproteinase domain-containing protein 17 [EC:3.4.24.86] K08523 heparin-binding EGF-like growth factor K04361 epidermal growth factor receptor [EC:2.7.10.1] K10030 interleukin 8 K04175 C-X-C chemokine receptor type 1 K05050 C-X-C chemokine receptor type 2 K06704 disintegrin and metalloproteinase domain-containing protein 10 [EC:3.4.24.81] K05704 tyrosine-protein kinase Src [EC:2.7.10.2] K05854 tyrosine-protein kinase Lyn [EC:2.7.10.2] K05728 c-src tyrosine kinase [EC:2.7.10.2] K04392 Ras-related C3 botulinum toxin substrate 1 K04393 cell division control protein 42 K04441 p38 MAP kinase [EC:2.7.11.24] K04409 p21-activated kinase 1 [EC:2.7.11.1] K04430 mitogen-activated protein kinase kinase 4 [EC:2.7.12.2] K04440 mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24] K04448 transcription factor AP-1 K04466 mitogen-activated protein kinase kinase kinase 14 [EC:2.7.11.25] K04467 inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10] K07209 inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10] K07210 inhibitor of nuclear factor kappa-B kinase subunit gamma K04734 NF-kappa-B inhibitor alpha K02580 nuclear factor NF-kappa-B p105 subunit K04735 transcription factor p65 K08727 nucleotide-binding oligomerization domain-containing protein 1 K05505 C-X-C motif chemokine 1/2/3 K12499 C-C motif chemokine 5 K11028 vacuolating cytotoxin K08114 receptor-type tyrosine-protein phosphatase zeta [EC:3.1.3.48] K05737 G protein-coupled receptor kinase interactor 1 K02187 caspase 3 [EC:3.4.22.56] K02145 V-type H+-transporting ATPase subunit A [EC:7.1.2.2] K02147 V-type H+-transporting ATPase subunit B K02148 V-type H+-transporting ATPase subunit C K02149 V-type H+-transporting ATPase subunit D K02150 V-type H+-transporting ATPase subunit E K02151 V-type H+-transporting ATPase subunit F K02152 V-type H+-transporting ATPase subunit G K02153 V-type H+-transporting ATPase subunit e K02154 V-type H+-transporting ATPase subunit a K02146 V-type H+-transporting ATPase subunit d K02144 V-type H+-transporting ATPase subunit H K03662 V-type H+-transporting ATPase S1 subunit K02155 V-type H+-transporting ATPase 16kDa proteolipid subunit K03661 V-type H+-transporting ATPase 21kDa proteolipid subunit K03191 acid-activated urea channel K14048 urease subunit gamma/beta [EC:3.5.1.5] K01428 urease subunit alpha [EC:3.5.1.5] K08303 U32 family peptidase [EC:3.4.-.-] K15843 outer membrane protein HopC/AlpA K15844 outer membrane protein HopB/AlpB K15845 outer membrane protein HopZ K15846 neuraminyllactose-binding hemagglutinin K15847 outer membrane protein BabA K15848 outer membrane protein SabA COMPOUND C00014 Ammonia C00080 H+ C00086 Urea C00698 Cl- C01342 NH4+ G00242 Sialyl Lewis x antigen G00263 Lewis b antigen REFERENCE PMID:14700549 AUTHORS Naumann M, Crabtree JE. TITLE Helicobacter pylori-induced epithelial cell signalling in gastric carcinogenesis. JOURNAL Trends Microbiol 12:29-36 (2004) DOI:10.1016/j.tim.2003.11.005 REFERENCE PMID:15694859 AUTHORS Rieder G, Fischer W, Haas R. TITLE Interaction of Helicobacter pylori with host cells: function of secreted and translocated molecules. JOURNAL Curr Opin Microbiol 8:67-73 (2005) DOI:10.1016/j.mib.2004.12.004 REFERENCE PMID:11389469 AUTHORS Montecucco C, Rappuoli R. TITLE Living dangerously: how Helicobacter pylori survives in the human stomach. JOURNAL Nat Rev Mol Cell Biol 2:457-66 (2001) DOI:10.1038/35073084 REFERENCE PMID:12197905 AUTHORS Gerhard M, Rad R, Prinz C, Naumann M. TITLE Pathogenesis of Helicobacter pylori infection. JOURNAL Helicobacter 7 Suppl 1:17-23 (2002) DOI:10.1046/j.1523-5378.7.s1.3.x REL_PATHWAY ko00190 Oxidative phosphorylation ko03070 Bacterial secretion system ko04010 MAPK signaling pathway ko04210 Apoptosis ko04530 Tight junction ///