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 K01116 PLCG1; phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11] K01428 ureC; urease subunit alpha [EC:3.5.1.5] K02144 ATPeV1H; V-type H+-transporting ATPase subunit H K02145 ATPeV1A, ATP6A; V-type H+-transporting ATPase subunit A [EC:7.1.2.2] K02146 ATPeV0D, ATP6D; V-type H+-transporting ATPase subunit d K02147 ATPeV1B, ATP6B; V-type H+-transporting ATPase subunit B K02148 ATPeV1C, ATP6C; V-type H+-transporting ATPase subunit C K02149 ATPeV1D, ATP6M; V-type H+-transporting ATPase subunit D K02150 ATPeV1E, ATP6E; V-type H+-transporting ATPase subunit E K02151 ATPeV1F, ATP6S14; V-type H+-transporting ATPase subunit F K02152 ATPeV1G, ATP6G; V-type H+-transporting ATPase subunit G K02153 ATPeV0E, ATP6H; V-type H+-transporting ATPase subunit e K02154 ATPeV0A, ATP6N; V-type H+-transporting ATPase subunit a K02155 ATPeV0C, ATP6L; V-type H+-transporting ATPase 16kDa proteolipid subunit K02187 CASP3; caspase 3 [EC:3.4.22.56] K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit K03191 ureI; acid-activated urea channel K03196 virB11, lvhB11; type IV secretion system protein VirB11 [EC:7.4.2.8] K03661 ATPeV0B, ATP6F; V-type H+-transporting ATPase 21kDa proteolipid subunit K03662 ATPeVS1, ATP6S1; V-type H+-transporting ATPase S1 subunit K04175 CXCR1, IL8RA, CD181; C-X-C chemokine receptor type 1 K04361 EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1] K04392 RAC1; Ras-related C3 botulinum toxin substrate 1 K04393 CDC42; cell division control protein 42 K04409 PAK1; p21-activated kinase 1 [EC:2.7.11.1] K04430 MAP2K4, MKK4; mitogen-activated protein kinase kinase 4 [EC:2.7.12.2] K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24] K04441 P38; p38 MAP kinase [EC:2.7.11.24] K04448 JUN; transcription factor AP-1 K04466 MAP3K14, NIK; mitogen-activated protein kinase kinase kinase 14 [EC:2.7.11.25] K04467 IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10] K04734 NFKBIA; NF-kappa-B inhibitor alpha K04735 RELA; transcription factor p65 K05050 CXCR2, IL8RB, CD182; C-X-C chemokine receptor type 2 K05099 MET, HGFR; proto-oncogene tyrosine-protein kinase Met [EC:2.7.10.1] K05505 CXCL1_2_3, GRO; C-X-C motif chemokine 1/2/3 K05701 TJP1, ZO1; tight junction protein 1 K05704 SRC; tyrosine-protein kinase Src [EC:2.7.10.2] K05728 CSK; C-terminal Src kinase [EC:2.7.10.4] K05737 GIT1; G protein-coupled receptor kinase interactor 1 K05854 LYN; tyrosine-protein kinase Lyn [EC:2.7.10.2] K05859 PLCG2; phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11] K06059 ADAM17, TACE, CD156b; disintegrin and metalloproteinase domain-containing protein 17 [EC:3.4.24.86] K06089 F11R, JAM1, CD321; junctional adhesion molecule 1 K06704 ADAM10, CD156c; disintegrin and metalloproteinase domain-containing protein 10 [EC:3.4.24.81] K06735 JAM2, CD322; junctional adhesion molecule 2 K06785 JAM3; junctional adhesion molecule 3 K06786 JAM4, JCAM; junctional adhesion molecule 4 K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10] K07210 IKBKG, IKKG, NEMO; inhibitor of nuclear factor kappa-B kinase subunit gamma K07293 PTPN11, SHP2; tyrosine-protein phosphatase non-receptor type 11 [EC:3.1.3.48] K08114 PTPRZ; receptor-type tyrosine-protein phosphatase zeta [EC:3.1.3.48] K08303 prtC, trhP; U32 family peptidase [EC:3.4.-.-] K08523 HBEGF; heparin-binding EGF-like growth factor K08727 NOD1, CARD4; nucleotide-binding oligomerization domain-containing protein 1 K10030 IL8, CXCL8; interleukin 8 K11028 vacA; vacuolating cytotoxin K12086 cag1; cag pathogenicity island protein 1 K12087 cag2; cag pathogenicity island protein 2 K12088 cag3; cag pathogenicity island protein 3 K12089 cag4; cag pathogenicity island protein 4 K12090 cag5; cag pathogenicity island protein 5 K12091 cag6; cag pathogenicity island protein 6 K12092 cag7; cag pathogenicity island protein 7 K12093 cag8; cag pathogenicity island protein 8 K12094 cag9; cag pathogenicity island protein 9 K12095 cag10; cag pathogenicity island protein 10 K12096 cag11; cag pathogenicity island protein 11 K12097 cag12; cag pathogenicity island protein 12 K12098 cag13; cag pathogenicity island protein 13 K12099 cag14; cag pathogenicity island protein 14 K12100 cag15; cag pathogenicity island protein 15 K12101 cag16; cag pathogenicity island protein 16 K12102 cag17; cag pathogenicity island protein 17 K12103 cag18; cag pathogenicity island protein 18 K12104 cag19; cag pathogenicity island protein 19 K12105 cag20; cag pathogenicity island protein 20 K12106 cag21; cag pathogenicity island protein 21 K12107 cag22; cag pathogenicity island protein 22 K12108 cag23; cag pathogenicity island protein 23 [EC:7.4.2.8] K12109 cag24; cag pathogenicity island protein 24 K12110 cag25; cag pathogenicity island protein 25 K12499 CCL5; C-C motif chemokine 5 K14048 ureAB; urease subunit gamma/beta [EC:3.5.1.5] K15842 cagA; cytotoxicity-associated immunodominant antigen K15843 hopC, alpA; outer membrane protein HopC/AlpA K15844 hopB, alpB; outer membrane protein HopB/AlpB K15845 hopZ; outer membrane protein HopZ K15846 hpaA; neuraminyllactose-binding hemagglutinin K15847 babA; outer membrane protein BabA K15848 sabA; 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 ///