Cell membrane Complex Enzyme Eukaryotic cell or cell component Microbe-host cell complex Microorganism or its component Other Other -- ion Pathway or action Protein Protein or gene Protein or gene complex Protein or protein complex Bacterial membrane or virus envelope Cell membrane Cytoplasm Eukaryotic cell or cell component Extracellular Golgi Golgi membrane Intercellular Intracellular Mitochondria Nucleocapsid/Cytoplasm Organelle Organelle -- Cell membrane Organelle -- Endoplasmic reticulum Organelle -- ER Organelle -- Golgi Organelle -- Golgi membrane Organelle -- Nucleus Organelle -- Phagolysosome Organelle -- Phagosome Organelle -- Ribosome Other Phagolysosome Phagosome Chaperone Defense, immunity protein Enzyme Enzyme activator Enzyme inhibitor Genomic S segment Infection Ligand binding or carrier Motor Nucleic acid binding Other Signal transducer Toxicity Transcription factor binding Transcription regulation Transporter Unknown IC Inferred by Curator IDA Inferred from Direct Assay IEA Inferred from Electronic Annotation IEP Inferred from Expression Pattern IGI Inferred from Genetic Interaction IMP Inferred from Mutant Phenotype IPI Inferred from Physical Interaction ISS Inferred from Sequence or Structural Similarity NAS Non-traceable Author Statement ND No biological Data available RCA inferred from Reviewed Computational Analysis TAS Traceable Author Statement NR Not Recorded Warawa J, Kenny B Molecular microbiology Phosphoserine modification of the enteropathogenic Escherichia coli Tir molecule is required to trigger conformational changes in Tir and efficient pedestal elongation 2001 11886558 PubMed Hartland EL, Batchelor M, Delahay RM, Hale C, Matthews S, Dougan G, Knutton S, Connerton I, Frankel G Molecular microbiology Binding of intimin from enteropathogenic Escherichia coli to Tir and to host cells 1999 10216868 PubMed Kenny B Molecular microbiology Phosphorylation of tyrosine 474 of the enteropathogenic Escherichia coli (EPEC) Tir receptor molecule is essential for actin nucleating activity and is preceded by additional host modifications 1999 10096089 PubMed Warawa J, Finlay BB, Kenny B Infection and immunity Type III secretion-dependent hemolytic activity of enteropathogenic Escherichia coli 1999 10496946 PubMed Hartland EL, Daniell SJ, Delahay RM, Neves BC, Wallis T, Shaw RK, Hale C, Knutton S, Frankel G Molecular microbiology The type III protein translocation system of enteropathogenic Escherichia coli involves EspA-EspB protein interactions 2000 10760148 PubMed Taylor KA, Luther PW, Donnenberg MS Infection and immunity Expression of the EspB protein of enteropathogenic Escherichia coli within HeLa cells affects stress fibers and cellular morphology 1999 9864205 PubMed Cornick NA, Booher SL, Moon HW Infection and immunity Intimin facilitates colonization by Escherichia coli O157:H7 in adult ruminants 2002 11953416 PubMed http://www.genome.jp/kegg/pathway/map/map03070.html 2006 Neves BC, Shaw RK, Frankel G, Knutton S Infection and immunity Polymorphisms within EspA filaments of enteropathogenic and enterohemorrhagic Escherichia coli 2003 12654853 PubMed Garred O, Dubinina E, Polesskaya A, Olsnes S, Kozlov J, Sandvig K The Journal of biological chemistry Role of the disulfide bond in Shiga toxin A-chain for toxin entry into cells 199725 9111051 PubMed Sandvig K, van Deurs B Physiological reviews Endocytosis, intracellular transport, and cytotoxic action of Shiga toxin and ricin 1996 8874490 PubMed http://www.genome.jp/kegg/pathway/hsa/hsa04210.html 2006 Sandvig K Toxicon : official journal of the International Society on Toxinology Shiga toxins 2001 11595626 PubMed http://www.genome.jp/kegg/pathway/hsa/hsa04810.html 2006 http://www.genome.jp/kegg/pathway/hsa/hsa05130.html 2006 Sharma R, Tesfay S, Tomson FL, Kanteti RP, Viswanathan VK, Hecht G American journal of physiology. Gastrointestinal and liver physiology Balance of bacterial pro- and anti-inflammatory mediators dictates net effect of enteropathogenic Escherichia coli on intestinal epithelial cells 2006 16322091 PubMed http://www.genome.jp/kegg/pathway/hsa/hsa04620.html 2006 Abreu MT, Arnold ET, Thomas LS, Gonsky R, Zhou Y, Hu B, Arditi M The Journal of biological chemistry TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells 20027 11923281 PubMed Neal MD, Leaphart C, Levy R, Prince J, Billiar TR, Watkins S, Li J, Cetin S, Ford H, Schreiber A, Hackam DJ Journal of immunology (Baltimore, Md. : 1950) Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier 20061 16493066 PubMed Miyamoto Y, Iimura M, Kaper JB, Torres AG, Kagnoff MF Cellular microbiology Role of Shiga toxin versus H7 flagellin in enterohaemorrhagic Escherichia coli signalling of human colon epithelium in vivo 2006 16611235 PubMed Zhou X, Giron JA, Torres AG, Crawford JA, Negrete E, Vogel SN, Kaper JB Infection and immunity Flagellin of enteropathogenic Escherichia coli stimulates interleukin-8 production in T84 cells 2003 12654834 PubMed http://www.genome.jp/kegg/pathway/map/map02040.html 2006 Pathogenic E. coli Function: . This is to elucidate the pathogenic Escherichia coli infection of host cells such as intestinal epithelial cells. Flagellar assembly Function: . Flagella are filamentous appendages required for bacterial chemotaxis and motility. The flagella of EPEC mediate adhesionto epithelial cells.(KEGG_map02040)(Zhou et al., 2003) Flagellin Function: . Flagellae are composed of a structural repeating protein called flagellin. It is found that flagellin of EPEC stimulatesIL-8 production in a dose-dependent manner in T84 epithelial cells and also results in activation of the kinases Erk-1 and -2 and Jnk1 and -2. These results suggest that flagellinplays an important role in the gut inflammatory response during EPEC infection.(Zhou et al., 2003) TLR5 Function: . Host cell Toll-like receptor (TLR) 5 is the receptor for bacterial flagellin. TLR5 is expressed in native human epithelial cells and in many cultured intestinal epithelial lines, including HT-29 cells.(Miyamoto et al., 2006) TLR4 Function: . Host cell TLR4 is a Toll like receptor. Intact TLR4 signaling is critical for in the phagocytosis of bacteria by epithelial cells.(Neal et al., 2006) MD-2 Function: . MD-2 is TLR4's co-receptor. It is required for LPS signaling through cell surface receptors.(Neal et al., 2006)(Abreu et al., 2002) MD-2 associated with TLR4 Function: . MD-2 is TLR4's co-receptor. Both are required for LPS signaling through cell surface receptors.(Neal et al., 2006)(Abreu et al., 2002) Toll-like receptor signaling pathway Function: . See the KEGG information of the human Toll-like receptor signaling pathway.(KEGG_hsa04620) Inflammation Function: . EPEC-induced inflammation is a balance between pro- and anti-inflammatory proteins; extracellular factors, including flagellin and an unidentified TTSS-independent, >50-kDa protein, trigger inflammation while intracellular TTSS-dependent factors, including EspB, attenuate this response. EPEC infection activates the nuclear transcription factor NF-{kappa}B, which in turn promotes the expression of proinflammatory cytokines such as interleukin (IL)-8(Sharma et al., 2006) EspG Function: . EspG is one of the LEE-encoded effector protein of E. coli Type III secretion system. It is secreted into eukaryotic cell cytoplasm. EspG is a conserved protein encoded by the locus of enterocyte effacement (LEE) of attaching and effacing (A/E) pathogens, including enteropathogenic and enterohemorrhagic Escherichia coli.(Sharma et al., 2006) EspG2 Function: . EspG2 is one of the LEE-encoded effector protein of E. coli Type III secretion system. It is secreted into eukaryotic cell cytoplasm.(Sharma et al., 2006) TUBA Function: . alpha tubulin. See database records. TUBB Function: . tubulin, beta 3. See database records. Association of EspG, EspG2, TUBA and TUBB Function: . EspG, EspG2, TUBA and TUBB function together to disrupt microtubule network.(KEGG_hsa05130) GEF-H1 Function: . rho/rac guanine nucleotide exchange factor (GEF) 2. See database records. Rho Function: . ras homolog gene family, member A. See database records. ROCK Function: . Rho-associated, coiled-coil containing protein kinase 1 [EC:2.7.11.-]. See database records. Regulation of actin cytoskeleton Function: . Regulation of actin cytoskeleton - Homo sapiens (human)(KEGG_hsa04810) Stess fiber formation Function: . Stress fiber forms.(KEGG_hsa05130) EspFU Function: . EspFU is one of the LEE-encoded effector protein of E. coli Type III secretion system. It is secreted into eukaryotic cell cytoplasm.(KEGG_hsa05130) Eae Function: . Eae is a host outer membrane protein. Nck Function: . NCK adaptor protein 1. See database records. N-WASP Function: . Wiskott-Aldrich syndrome (eczema-thrombocytopenia) Arp2/3 Function: . actin related protein 2/3 complex, subunit 5, 16kDa. See database records. F-Actin Function: . actin-like protein. See database records. EspH Function: . EspH is one of the LEE-encoded effector protein of E. coli Type III secretion system. It is secreted into eukaryotic cell cytoplasm. Retraction of filopodium Function: . Filopodium retracts.(KEGG_hsa05130) Map Function: . Map is one of the LEE-encoded effector protein of E. coli Type III secretion system. It is secreted into eukaryotic cell cytoplasm.(KEGG_hsa05130) Filopodium formation Function: . Filopodium forms(KEGG_hsa05130) EspF Function: . EspF is one of the LEE-encoded effector protein of E. coli Type III secretion system. It is secreted into eukaryotic cell cytoplasm. Mitochondrial dysfunction Function: . Mitochondria have disordered functions.(KEGG_hsa05130) Apoptosis Function: . Apoptosis - Homo sapiens (human). See KEGG apoptosis pathway record.(KEGG_hsa04210) EspFU Function: . EspFU is one of the LEE-encoded effector protein of E. coli Type III secretion system. It is secreted into eukaryotic cell cytoplasm. Outer membrane proteins Function: . Host outer membrane proteins.(KEGG_hsa05130) OCLN Function: . occludin. See database records. Ezrin Function: . villin 2 (ezrin). See database records. CLDN1 Function: . claudin 1. See database records. Redistribution Function: . OCLN, Ezrin, and CLDN1 are redistributed.(KEGG_hsa05130) Disruption of tight junctions Function: . Tight junctions are disrupted. PRKCA Function: . protein kinase C, alpha [EC:2.7.11.13]. See database records. Cadherin Function: . cadherin 1, type 1, E-cadherin (epithelial). See database records. Beta-Catenin Function: . catenin (cadherin-associated protein), beta 1, 88kDa. See database records. Disruption of adherens junctions Function: . Adherens junctions are disrupted. Disruption of barrier function, increase in monolayer permeability Function: . Barrier function is disrupted with increased monolayer permeabiility.(KEGG_hsa05130) Cytoskeleton rearrangement Function: . Cytoskeleton structure has been rearranged.(KEGG_hsa05130) Shiga Toxin secretion by bacterial cells Function: Transporter. Shiga Toxin secretion by bacterial cells.(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Shiga Toxin (Subunit A - Subunit B) Function: Enzyme inhibitor. The Shiga Toxin is composed of a single catalytic subunit A that is associated with a pentameric ring formed by subunit B. Shiga toxin is released out of bacterial cell.(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Subunit B - Receptor Gb3 interaction on host cell surface Function: Enzyme inhibitor. The B subunit binds globotriaosyl ceramide (Gb3) glycolipid receptor on cell surfaces.(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Endocytosis of Shiga Toxin Subunit B Function: Enzyme inhibitor. Following binding, toxin uptake occurs by endocytosis.(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Shiga Toxin inside endosomes Function: Enzyme inhibitor. Shiga Toxin containing endosomes are being transported to the Trans-Golgi Network (TGN).(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Nicking of Shiga Toxin Subunit A by Furin in Trans-Golgi Network Function: Enzyme. Followed by transport to the Trans-Golgi Network and endoplasmic reticulum (ER), the A subunit is cleaved by protease Furin in the Trans-Golgi Network(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Nicking of Shiga Toxin Subunit A by Furin in Golgi Function: Enzyme. Followed by transport to the Golgi apparatus and endoplasmic reticulum (ER), the A subunit is cleaved by furin in the endosomes/Golgi apparatus.(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Release of Shiga Toxin fragment A1 from fragment A2 in ER. Function: Enzyme. The Shiga Toxin fragment A1 enzymatically active part released from the A2 fragment in the ER.(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Toxin A1 cleaves the N-glycosidic bond in 28S rRNA Function: Nucleic acid binding. In ribosome, the A1 fragment cleaves the N-glycosidic bond, removing one adenine from adenosine in position 4324 from the 5' terminus in 28S rRNA of the 60S ribosomal subunit.(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Inhibition of binding of aminoacyl - tRNA Function: Nucleic acid binding. In ribosome, inhibition of binding of aminoacyl-tRNA to the 60S ribosomal subunit.(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Blocking of protein synthesis and death of intoxicated cells Function: Other. This action blocks protein synthesis, resulting in death of intoxicated cells. The B subunit is capable of triggering apoptosis, mechanism not understood.(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Furin Function: Enzyme. Furin is a critical enzyme for the processing of Shiga Toxin (cleavage of Shiga toxin).(Sandvig, 2001)(Sandvig et al., 1996)(Garred et al., 1997) Cdc42 Function: . See database records. Type III Secretion System Function: Transporter. Many E.coli virulence proteins are secreted via the type III secretion apparatus (TTSS) across the envelope.(Neves et al., 2003)(KEGG_map03070) Intimin, EspA secretion via TTSS and EspA(n) polymerization Function: Transporter. Intimin (receptor), EspA (E.coli secreted protein) proteins are secreted via the type III secretion apparatus. EspA forms the filamentous extension to the TTSS and which interacts with host cells during early stages of attaching and effacing lesion formation.(Neves et al., 2003)(Cornick et al., 2002) EspA-containing filaments formation Function: Transporter. EspA protein polymerizes on the bacterial surface to form an extension (EspA-containing filaments) enabling the transfer of the Esp (proteins) directly into the host cell. See database records.(Neves et al., 2003) EspB, EspD translocation via TTSS-EspA(n) Function: Transporter. EspD and EspB proteins are translocated directly into the host plasma membrane and associated with infected host cell membrane.(Taylor et al., 1999) EspD(n)-A(n), D(n)-D(n), B(n)-D(n) Function: Other. The EspD may be involved in interaction with EspA-containing filaments. This may explain the observation that EspD is required for proper formation of the EspA-containing filaments. EspB may be both part of the translocation apparatus and a translocated effector.(Hartland et al., 2000) EspA(n)-EspF(n) Function: Other. The EspF may be involved in interaction with EspA to form needle like structure.(Warawa et al., 1999) Tir Function: Enzyme activator. Tir (translocated intimin receptor) is one of the LEE-encoded effector protein of E. coli Type III secretion system. The type III secretion and Esp translocon deliver Tir into the host cytoplasm.(Kenny, 1999)(Hartland et al., 1999) Tir-P formation by serine 434 phosphorylation Function: Other. Tir is associated with the host plasma membrane, where it is phosphorylated on serine 434 by the cAMP-dependent kinase, protein kinase A ( PKA) generating the partially modified Tir-P.(Warawa et al., 2001) Tir-PP formation by serine 463 phosphorylation Function: . It is possible that the PKA-mediated modification may function to expose another serine (463 Serine) modification site. Product is Tir-PP.(Warawa et al., 2001) TirM formation by tyrosine 474 phosphorylation Function: . The Tir-PP now becomes the substrate for an undefined tyrosine kinase, leading to the phosphorylation of tyrosine 474 generating the fully modified TirM (Tir-PPP).(Kenny, 1999) TirM - Host Membrane Function: . TirM spans the plasma membrane in a hairpin structure.(Hartland et al., 1999) TirM - Intimin Interaction Function: . Intimin, anchored in the outer membrane of bacterial cells, binds and clusters Tir in the host cell membrane.(Hartland et al., 1999) TirM(n) Clustering Function: . TirM clustering triggers changes in associated host cell cytoskeletal proteins.(Hartland et al., 1999) Pedestal Formation Function: . TirM clustering leads to the formation of pedestals underneath adherent bacteria.(Hartland et al., 1999) cAMP-PKA Function: Enzyme. cAMP-dependent kinase, protein kinase A ( PKA). cAMP-PKA Function: Enzyme. cAMP-dependent kinase, protein kinase A (PKA). Undefined Tyrosine Kinase Function: Enzyme. ECUTK is undefined Tyrosine Kinase. Host Membrane Function: Other. Host plasma membrane. Intimin Function: Other. Intimin (receptor).