The Helicobacter pylori Type IV Secretion System Encoded by the cag Pathogenicity Island: Architecture, Function, and Signaling

  • Steffen Backert
  • Rainer Haas
  • Markus Gerhard
  • Michael Naumann
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 413)


Various gram-negative pathogens express type IV secretion systems (T4SSs) which translocate bacterial virulence factors into host target cells to hijack cellular processes for their own benefit and causing disease. The pathology of Helicobacter pylori, the causative agent of chronic gastritis, peptic ulcer disease, and gastric cancer in humans, strongly depends on a T4SS encoded by the cag pathogenicity island (cagPAI). This T4SS represents a pilus-like structure and a membrane-spanning complex. T4SS assembly is achieved by various protein–protein interactions and several pilus-associated components (CagL, CagI, CagY, and CagA) that allow docking to the host cell integrin member α5β1 followed by delivery of its major effector protein, CagA, across the host cell membrane. In addition, recent studies have shown that H. pylori exploits human CEACAM receptors via the adhesin HopQ, encoded outside of the cagPAI, for bacterial adherence and translocation of CagA. Here, we review the composition and assembly of the H. pylori T4SS and its fundamental role in the infection process. We discuss major CagA-dependent and CagA-independent signaling events by the T4SS in vitro and in animal models in vivo, which include the induction of cytoskeletal rearrangements, membrane dynamics, disturbance of cell polarity as well as transcriptional responses involved in inflammation, cell proliferation, and anti-apoptosis. The contribution of these signaling cascades to H. pylori colonization, and pathogenesis is reviewed.


Helicobacter pylori Type IV secretion NF-κB HBP Adherens junction E-cadherin CagA Integrin CEACAM HtrA Occludin Claudin-8 TLR 



We thank Drs. Timothy Cover (Vanderbilt University, Nashville, USA), Hayley Newton (University of Melbourne, Australia), and Wolfgang Fischer (Pettenkofer Institute, Munich, Germany) for comments on the manuscript. We also thank Drs. Manfred Rohde (Helmholtz Centre for Infection Biology, Braunschweig, Germany) for the electron microscopic image in Fig. 2, Timothy Cover for the electron microscopic images in Fig. 3c/d, and Laurent Terradot (University of Lyon, France) for the CagA structure in Fig. 4. This work was supported by the German Science Foundation to S.B. (A04 in CRC-1181), to R.H. (B05 in CRC-914), and M.N. (A04 in CRC-854).


  1. Al-Ghoul L, Wessler S, Hundertmark T, Krüger S, Fischer W, Wunder C, Roessner A, Naumann M (2004) Analysis of the type IV secretion system-dependent cell motility of H. pylori-infected epithelial cells. Biochem Biophys Res Commun 322(3):860–866. PubMedCrossRefGoogle Scholar
  2. Allison CC, Kufer TA, Kremmer E, Kaparakis M, Ferrero RL (2009) H. pylori induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism. J Immunol 183(12):8099–8109. PubMedCrossRefGoogle Scholar
  3. Amieva M, Peek RM Jr (2016) Pathobiology of H. pylori-Induced Gastric Cancer. Gastroenterology 150(1):64–78. PubMedCrossRefGoogle Scholar
  4. Andrzejewska J, Lee SK, Olbermann P, Lotzing N, Katzowitsch E, Linz B, Achtman M, Kado CI, Suerbaum S, Josenhans C (2006) Characterization of the pilin ortholog of the H. pylori type IV cag pathogenicity apparatus, a surface-associated protein expressed during infection. J Bacteriol 188(16):5865–5877PubMedPubMedCentralCrossRefGoogle Scholar
  5. Aras RA, Fischer W, Perez-Perez GI, Crosatti M, Ando T, Haas R, Blaser MJ (2003) Plasticity of repetitive DNA sequences within a bacterial (Type IV) secretion system component. J Exp Med 198(9):1349–1360. PubMedPubMedCentralCrossRefGoogle Scholar
  6. Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y, Tsubokawa M, Tohyama Y, Maeda S, Omata M, Suzuki T, Sasakawa C (2000) H. pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med 191(4):593–602PubMedPubMedCentralCrossRefGoogle Scholar
  7. Ayyappan S, Prabhakar D, Sharma N (2013) Epidermal growth factor receptor (EGFR)-targeted therapies in esophagogastric cancer. Anticancer Res 33(10):4139–4155PubMedGoogle Scholar
  8. Backert S, Clyne M (2011) Pathogenesis of Helicobacter pylori Infection. Helicobacter 16:19–25Google Scholar
  9. Backert S, Clyne M, Tegtmeyer N (2011) Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Commun Signal 9:28.
  10. Backert S, Fronzes R, Waksman G (2008) VirB2 and VirB5 proteins: specialized adhesins in bacterial type-IV secretion systems? Trends Microbiol 16(9): 409–413.
  11. Backert S, Kwok T, König W (2005) Conjugative plasmid DNA transfer in Helicobacter pylori mediated by chromosomally encoded relaxase and TraG-like proteins. Microbiology 151(Pt 11):3493–3503Google Scholar
  12. Backert S, Moese S, Selbach M, Brinkmann V, Meyer TF (2001) Phosphorylation of tyrosine 972 of the Helicobacter pylori CagA protein is essential for induction of a scattering phenotype in gastric epithelial cells. Mol Microbiol 42(3):631–644Google Scholar
  13. Backert S, Tegtmeyer N (2017) Type IV secretion and signal transduction of Helicobacter pylori CagA through interactions with host cell receptors. Toxins 9(4):115Google Scholar
  14. Backert S, Von Nickisch-Rosenegk E, Meyer TF (1998) Potential role of two Helicobacter pylori relaxases in DNA transfer? Mol Microbiol 30(3):673–674Google Scholar
  15. Backert S, Meyer TF (2006) Type IV secretion systems and their effectors in bacterial pathogenesis. Curr Opin Microbiol 9(2):207–217.
  16. Backert S, Schmidt TP, Harrer A, Wessler S (2017) Exploiting the gastric epithelial barrier: Helicobacter pylori’s attack on tight and adherens junctions. Curr Top Microbiol Immunol 400:195–226.
  17. Backert S, Tegtmeyer N, Fischer W (2015) Composition, structure and function of the Helicobacter pylori cag pathogenicity island encoded type IV secretion system. Future Microbiol 10(6):955–965.
  18. Backert S, Tegtmeyer N, Selbach M (2010) The versatility of Helicobacter pylori CagA effector protein functions: the master key hypothesis. Helicobacter 15(3):163–176.
  19. Backert S, Ziska E, Brinkmann V, Zimny-Arndt U, Fauconnier A, Jungblut PR, Naumann M, Meyer TF (2000) Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol 2(2):155–164Google Scholar
  20. Banerjee A, Basu M, Blanchard TG, Chintalacharuvu SR, Guang W, Lillehoj EP, Czinn SJ (2016) Early molecular events in murine gastric epithelial cells mediated by H.pylori CagA. Helicobacter 21(5):395–404.
  21. Barden S, Lange S, Tegtmeyer N, Conradi J, Sewald N, Backert S, Niemann HH (2013) A helical RGD motif promoting cell adhesion: crystal structures of the Helicobacter pylori type IV secretion system pilus protein CagL. Structure 21(11):1931–1941.
  22. Barden S, Niemann HH (2015) Adhesion of several cell lines to H. pylori CagL is mediated by integrin alphaVbeta6 via an RGDLXXL motif. J Mol Biol 427:1304–1315.
  23. Barrozo RM, Cooke CL, Hansen LM, Gaddy JA, Johnson EM, Cariaga TA, Suarez G, Peek RM Jr, Cover TL, Solnick JV (2013) Functional plasticity in the type IV secretion system of H. pylori. PLoS Pathog 9:e1003189.
  24. Barrozo RM, Hansen LM, Lam AM, Skoog EC, Martin ME, Cai LP, Lin Y, Latoscha A, Suerbaum S, Canfield DR, Solnick JV (2016) CagY is an immune-sensitive regulator of the H. pylori type IV secretion system. Gastroenterology 151(6):1164–1175.
  25. Basak C, Pathak SK, Bhattacharyya A, Pathak S, Basu J, Kundu M (2005) The secreted peptidyl prolyl cis, trans-isomerase HP0175 of H. pylori induces apoptosis of gastric epithelial cells in a TLR4- and apoptosis signal-regulating kinase 1-dependent manner. J Immunol 174(9):5672–5680Google Scholar
  26. Bauer B, Bartfeld S, Meyer TF (2009) H. pylori selectively blocks EGFR endocytosis via the non-receptor kinase c-Abl and CagA. Cell Microbiol 11(1):156–169.
  27. Bauer B, Pang E, Holland C, Kessler M, Bartfeld S, Meyer TF (2012) The H.pylori virulence effector CagA abrogates human β-defensin 3 expression via inactivation of EGFR signaling. Cell Host Microbe 11(6):576–586Google Scholar
  28. Bebb JR, Leach L, Zaitoun A, Hand N, Letley DP, Thomas R, Atherton JC (2006) Effects of Helicobacter pylori on the cadherin-catenin complex. J Clin Pathol 59(12):1261–1266Google Scholar
  29. Belogolova E, Bauer B, Pompaiah M, Asakura H, Brinkman V, Ertl C, Bartfeld S, Nechitaylo TY, Haas R, Machuy N, Salama N, Churin Y, Meyer TF (2013) H. pylori outer membrane protein HopQ identified as a novel T4SS-associated virulence factor. Cell Microbiol 15(11):1896–1912.
  30. Bergé C, Terradot L (2017) Structural insights into H. pylori cag protein interactions with host cell factors. Curr Top Microbiol Immunol 400:129–147.
  31. Bönig T, Olbermann P, Bats SH, Fischer W, Josenhans C (2016) Systematic site-directed mutagenesis of the H. pylori CagL protein of the Cag type IV secretion system identifies novel functional domains. Sci Rep 6:38101.
  32. Bonsor DA, Weiss E, Iosub-Amir A, Reingewertz TH, Haas R, Friedler A, Fischer W, Sundberg EJ (2013) Characterization of the translocation-competent complex between the H. pylori oncogenic protein CagA and the accessory protein CagF. J Biol Chem 288(46):32897–32909.
  33. Bonsor DA, Pham KT, Beadenkopf R, Diederichs K, Haas R, Fischer W, Sundberg EJ (2015) Integrin engagement by the helical RGD motif of the H. pylori CagL protein is regulated by pH-induced displacement of a neighboring helix. J Biol Chem 290(20):12929–12940.
  34. Boquet P, Ricci V (2012) Intoxication strategy of H. pylori VacA toxin. Trends Microbiol 20(4):165–174.
  35. Bradley CA, Salto-Tellez M, Laurent-Puig P, Bardelli A, Rolfo C, Tabernero J, Khawaja HA, Lawler M, Johnston PG, Van Schaeybroeck S, Consortium ME (2017) Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat Rev Clin Oncol
  36. Brisslert M, Enarsson K, Lundin S, Karlsson A, Kusters JG, Svennerholm AM, Backert S, Quiding-Järbrink M (2005) Helicobacter pylori induce neutrophil transendothelial migration: role of the bacterial HP-NAP. FEMS Microbiol Lett 249(1):95–103Google Scholar
  37. Cao X, Tsukamoto T, Nozaki K, Mizoshita T, Ogasawara N, Takenaka Y, Kaminishi M, Tatematsu M (2004) Beta-catenin gene alteration in glandular stomach adenocarcinomas in N-methyl-N-nitrosourea-treated and H. pylori-infected Mongolian gerbils. Cancer Sci 95(6):487–490Google Scholar
  38. Chandran Darbari V, Waksman G (2015) Structural biology of bacterial type IV secretion systems. Annu Rev Biochem 84:603–629.
  39. Chaturvedi R, Asim M, Piazuelo MB, Yan F, Barry DP, Sierra JC, Delgado AG, Hill S, Casero RA, Jr, Bravo LE, Correa P, Polk DB, Washington MK, Rose KL, Schey KL, Morgan DR, Peek RM, Jr, Wilson KT (2014) Activation of EGFR and ERBB2 by H. pylori results in survival of gastric epithelial cells with DNA damage. Gastroenterology 146(7):1739–1751, e1714.
  40. Christie PJ, Whitaker N, González-Rivera C (2014) Mechanism and structure of the bacterial type IV secretion systems. Biochim Biophys Acta 1843(8):1578–1591.
  41. Churin Y, Al-Ghoul L, Kepp O, Meyer TF, Birchmeier W, Naumann M (2003) H. pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol 161(2):249–255.
  42. Conradi J, Huber S, Gaus K, Mertink F, Royo GS, Strijowski U, Backert S, Sewald N (2012) Cyclic RGD peptides interfere with binding of the Helicobacter pylori protein CagL to integrins alphaVbeta3 and alpha5beta1. Amino Acids 43(1):219–232.
  43. Costa AM, Ferreira RM, Pinto-Ribeiro I, Sougleri IS, Oliveira MJ, Carreto L, Santos MA, Sgouras DN, Carneiro F, Leite M, Figueiredo C (2016) H. pylori activates matrix metalloproteinase 10 in gastric epithelial cells via EGFR and ERK-mediated pathways. J Infect Dis 213(11):1767–1776.
  44. Couturier MR, Tasca E, Montecucco C, Stein M (2006) Interaction with CagF is required for translocation of CagA into the host via the H. pylori type IV secretion system. Infect Immun 74(1):273–281Google Scholar
  45. Covacci A, Rappuoli R (2000) Tyrosine-phosphorylated bacterial proteins: Trojan horses for the host cell. J Exp Med 191(4):587–592Google Scholar
  46. Covacci A, Telford JL, Del Giudice G, Parsonnet J, Rappuoli R (1999) H. pylori virulence and genetic geography. Science 284(5418):1328–1333Google Scholar
  47. Coyle WJ, Sedlack RE, Nemec R, Peterson R, Duntemann T, Murphy M, Lawson JM (1999) Eradication of H. pylori normalizes elevated mucosal levels of epidermal growth factor and its receptor. Am J Gastroenterol 94(10):2885–2889.
  48. Cuadrado and Nebreda (2010) Mechanisms and functions of p38 MAPK signaling. Biochem J 429(3):403–411. PubMedCrossRefGoogle Scholar
  49. Delahay RM, Balkwill GD, Bunting KA, Edwards W, Atherton JC, Searle MS (2008) The highly repetitive region of the H. pylori CagY protein comprises tandem arrays of an alpha-helical repeat module. J Mol Biol 377(3):956–971. PubMedPubMedCentralCrossRefGoogle Scholar
  50. Ding SZ, Olekhnovich IN, Cover TL, Peek RM Jr, Smith MF Jr, Goldberg JB (2008) H. pylori and mitogen-activated protein kinases mediate activator protein-1 subcomponent protein expression and DNA-binding activity in gastric epithelial cells. FEMS Immunol Med Microbiol 53(3):385–394. PubMedPubMedCentralCrossRefGoogle Scholar
  51. Dubois A, Borén T (2007) H. pylori is invasive and it may be a facultative intracellular organism. Cell Microbiol 9(5):1108–1116. PubMedPubMedCentralCrossRefGoogle Scholar
  52. Fernandez-Gonzalez E, Backert S (2014) DNA transfer in the gastric pathogen Helicobacter pylori. J Gastroenterol 49(4):594–604. PubMedCrossRefGoogle Scholar
  53. Fischer W (2011) Assembly and molecular mode of action of the H. pylori cag type IV secretion apparatus. FEBS J 278(8):1203–1212. PubMedCrossRefGoogle Scholar
  54. Fischer W, Püls J, Buhrdorf R, Gebert B, Odenbreit S, Haas R (2001) Systematic mutagenesis of the H. pylori cag island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol Microbiol 42(5):1337–1348PubMedCrossRefGoogle Scholar
  55. Foegeding NJ, Caston RR, McClain MS, Ohi MD, Cover TL (2016) An overview of H. pylori VacA toxin biology. Toxins (Basel) 8(6) pii: E173.
  56. Franco AT1, Johnston E, Krishna U, Israel DA, Nagy TA, Wroblewski LE, Piazuelo MB, Correa P, Peek RM Jr (2008) Regulation of gastric carcinogenesis by H. pylori virulence factors. Cancer Res 68(2):379–387.
  57. Frick-Cheng AE, Pyburn TM, Voss BJ, McDonald WH, Ohi MD, Cover TL (2016) Molecular and structural analysis of the H. pylori cag type IV secretion system core complex. MBio 7(1):e02001–15.
  58. Fronzes R, Christie PJ, Waksman G (2009a) The structural biology of type IV secretion systems. Nat Rev Microbiol 7(10):703–714. PubMedCrossRefGoogle Scholar
  59. Fronzes R, Schäfer E, Wang L, Saibil HR, Orlova E, Waksman G (2009b) Structure of a type IV secretion system core complex. Science 323(5911):266–268. PubMedCrossRefGoogle Scholar
  60. Gaddy JA, Radin JN, Loh JT, Piazuelo MB, Kehl-Fie TE, Delgado AG, Ilca FT, Peek RM, Cover TL, Chazin WJ, Skaar EP, Scott Algood HM (2014) The host protein calprotectin modulates the H. pylori cag type IV secretion system via zinc sequestration. PLoS Pathog 10(10):e1004450. PubMedPubMedCentralCrossRefGoogle Scholar
  61. Gall A, Gaudet RG, Gray-Owen SD, Salama NR (2017) TIFA Signaling in gastric epithelial cells initiates the cag type 4 secretion system-dependent innate immune response to Helicobacter pylori infection. MBio 8(4) pii: e01168–17.
  62. Glowinski F, Holland C, Thiede B, Jungblut PR, Meyer TF (2014) Analysis of T4SS-induced signaling by H. pylori using quantitative phosphoproteomics. Front Microbiol 5:356.
  63. Gopal GJ, Pal J, Kumar A, Mukhopadhyay G (2015) C-terminal domain of CagX is responsible for its interaction with CagT protein of H. pylori type IV secretion system. Biochem Biophys Res Commun 456(1):98–103. PubMedCrossRefGoogle Scholar
  64. Grohmann E, Christie PJ, Waksman G, Backert S (2018) Type IV secretion in gram-negative and gram-positive bacteria. Mol Microbiol 107:455–471.
  65. Grove JI, Alandiyjany MN, Delahay RM (2013) Site-specific relaxase activity of a VirD2-like protein encoded within the tfs4 genomic island of Helicobacter pylori. J Biol Chem 288(37):26385–26396. PubMedPubMedCentralCrossRefGoogle Scholar
  66. Haley KP, Blanz EJ, Gaddy JA (2014) High resolution electron microscopy of the H. pylori cag type IV secretion system pili produced in varying conditions of iron availability. J Vis Exp (93):e52122.
  67. Hammond CE, Beeson C, Suarez G, Peek RMJr, Backert S, Smolka AJ (2015) Helicobacter pylori virulence factors affecting gastric proton pump expression and acid secretion. Am J Physiol Gastrointest Liver Physiol. 309(3):G193–201.
  68. Harrer A, Boehm M, Backert S, Tegtmeyer N (2017) Overexpression of serine protease HtrA enhances disruption of adherens junctions, paracellular transmigration and type IV secretion of CagA by Helicobacter pylori. Gut Pathog 9:40.
  69. Hare S, Fischer W, Williams R, Terradot L, Bayliss R, Haas R, Waksman G (2007) Identification, structure and mode of action of a new regulator of the H. pylori HP0525 ATPase. EMBO J 26:4926–4934. PubMedPubMedCentralCrossRefGoogle Scholar
  70. Hartung ML, Gruber DC, Koch KN, Grüter L, Rehrauer H, Tegtmeyer N, Backert S, Müller A. (2015) H. pylori-induced DNA strand breaks are introduced by nucleotide excision repair endonucleases and promote NF-κB target gene expression. Cell Rep 13(1):70–79.
  71. Hayakawa Y, Hirata Y, Kinoshita H, Sakitani K, Nakagawa H, Nakata W, Takahashi R, Sakamoto K, Maeda S, Koike K (2013) Differential roles of ASK1 and TAK1 in H. pylori-induced cellular responses. Infect Immun 81(12):4551–4560. PubMedPubMedCentralCrossRefGoogle Scholar
  72. Hayashi T, Senda M, Morohashi H, Higashi H, Horio M, Kashiba Y, Nagase L, Sasaya D, Shimizu T, Venugopalan N, Kumeta H, Noda NN, Inagaki F, Senda T, Hatakeyama M (2012) Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of H. pylori oncogenic effector CagA. Cell Host Microbe 12(1):20–33. PubMedCrossRefGoogle Scholar
  73. Hecht JR, Bang YJ, Qin SK, Chung HC, Xu JM, Park JO, Jeziorski K, Shparyk Y, Hoff PM, Sobrero A, Salman P, Li J, Protsenko SA, Wainberg ZA, Buyse M, Afenjar K, Houe V, Garcia A, Kaneko T, Huang Y, Khan-Wasti S, Santillana S, Press MF, Slamon D (2016) Lapatinib in combination with capecitabine plus oxaliplatin in human EGFR2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC–A randomized phase III trial. J Clin Oncol 34(5):443–451. PubMedCrossRefGoogle Scholar
  74. Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, Hatakeyama M (2002) SHP-2 tyrosine phosphatase as an intracellular target of H. pylori CagA protein. Science 295(5555):683–686.
  75. Hirata Y, Ohmae T, Shibata W, Maeda S, Ogura K, Yoshida H, Kawabe T, Omata M (2006) MyD88 and TNF receptor-associated factor 6 are critical signal transducers in H. pylori-infected human epithelial cells. J Immunol 176(6):3796–3803PubMedCrossRefGoogle Scholar
  76. Howlett M, Giraud AS, Lescesen H, Jackson CB, Kalantzis A, Van Driel IR, Robb L, Van der Hoek M, Ernst M, Minamoto T, Boussioutas A, Oshima H, Oshima M, Judd LM (2009) The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development. Gastroenterology 136:967–977.
  77. Hsu KW, Hsieh RH, Huang KH, Fen-Yau Li A, Chi CW, Wang TY, Tseng MJ, Wu KJ, Yeh TS (2012) Activation of the notch1/STAT3/twist signaling axis promotes gastric cancer progression. Carcinogenesis 33(8):1459–1467. PubMedCrossRefGoogle Scholar
  78. Huang JY, Sweeney EG, Sigal M, Zhang HC, Remington SJ, Cantrell MA, Kuo CJ, Guillemin K, Amieva MR (2015) Chemodetection and destruction of host urea allows H. pylori to locate the epithelium. Cell Host Microbe 18(2):147–156. PubMedPubMedCentralCrossRefGoogle Scholar
  79. Javaheri A, Kruse T, Moonens K, Mejias-Luque R, Debraekeleer A, Asche CI, Tegtmeyer N, Kalali B, Bach NC, Sieber SA, Hill DJ, Koniger V, Hauck CR, Moskalenko R, Haas R, Busch DH, Klaile E, Slevogt H, Schmidt A, Backert S, Remaut H, Singer BB, Gerhard M (2016) Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs. Nat Microbiol 2:16189. PubMedCrossRefGoogle Scholar
  80. Jiménez-Soto LF, Kutter S, Sewald X, Ertl C, Rohde M, Pirch T, Jung K, Retta SF, Terradot L, Fischer W, Haas R (2009) H.pylori type IV secretion apparatus exploits beta1 integrin in a novel RGD-independent manner. PLoS Pathog 5(12):e1000684. PubMedPubMedCentralCrossRefGoogle Scholar
  81. Jiménez-Soto LF, Clausen S, Sprenger A, Ertl C, Haas R (2013) Dynamics of the Cag-type IV secretion system of H. pylori as studied by bacterial co-infections. Cell Microbiol 15(11):1924–1937. PubMedGoogle Scholar
  82. Johnson EM, Gaddy JA, Voss BJ, Hennig EE, Cover TL (2014) Genes required for assembly of pili associated with the H. pylori cag type IV secretion system. Infect Immun 82(8):3457–3470. PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kaplan-Türköz B, Jiménez-Soto LF, Ertl C, Remaut H, Louche A, Tosi T, Haas R, Terradot L (2012) Structural insights into H. pylori oncoprotein CagA interaction with β1 integrin. Proc Natl Acad Sci 109(36):14640–14645.
  84. Karin K, Zq Liu, Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9(2):240–246PubMedCrossRefGoogle Scholar
  85. Kawakami H, Okamoto I (2016) MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy. Gastric Cancer 19(3):687–695. PubMedCrossRefGoogle Scholar
  86. Keates S, Keates AC, Warny M, Peek RM Jr, Murray PG, Kelly CP (1999) Differential activation of mitogen-activated protein kinases in AGS gastric epithelial cells by cag+ and cag- H. pylori. J Immunol 163(10):5552–5559PubMedGoogle Scholar
  87. Keates S, Sougioultzis S, Keates AC, Zhao D, Peek RM Jr, Shaw LM, Kelly CP (2001) cag+ H. pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells. J Biol Chem 276:48127–48134. PubMedCrossRefGoogle Scholar
  88. Kim MH, Yoo HS, Chang HJ, Hong MH, Kim HD, Chung IJ, Shin BA, Cho MJ, Ahn BW, Jung YD (2005) Urokinase plasminogen activator receptor is upregulated by H. pylori in human gastric cancer AGS cells via ERK, JNK, and AP-1. Biochem Biophys Res Commun 333(3):874–880. PubMedCrossRefGoogle Scholar
  89. Koch KN, Hartung ML, Urban S, Kyburz A, Bahlmann AS, Lind J, Backert S, Taube C, Müller A (2015) Helicobacter urease-induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma. J Clin Invest 125(8):3297–3302. PubMedPubMedCentralCrossRefGoogle Scholar
  90. Kong Y, Ma LQ, Bai PS, Da R, Sun H, Ma JQ, Zhao RM, Chen NZ, Nan KJ (2013) H. pylori promotes invasion and metastasis of gastric cancer cells through activation of AP-1 and up-regulation of CACUL1. Int J Biochem Cell Biol 45(11):2666–2678.
  91. Koniger V, Holsten L, Harrison U, Busch B, Loell E, Bonsor DA, Roth A, Kengmo-Tchoupa A, Smith SI, Mueller S, Sundberg EJ, Zimmermann W, Fischer W, Hauck CR, Haas R (2016) H. pylori exploits human CEACAMs via HopQ for adherence and translocation of CagA. Nat Microbiol 2:16188.
  92. Kumar N, Shariq M, Kumar A, Kumari R, Subbarao N, Tyagi RK, Mukhopadhyay G (2017) Analyzing the role of CagV, a VirB8 homolog of the type IV secretion system of Helicobacter pylori. FEBS Open Bio 7(7):915–933. PubMedPubMedCentralCrossRefGoogle Scholar
  93. Kumari R, Shariq M, Kumar N, Mukhopadhyay G (2017) Biochemical characterization of the H. pylori cag-type IV secretion system unique component CagU. FEBS Lett 591(3):500–512. PubMedCrossRefGoogle Scholar
  94. Kutter S, Buhrdorf R, Schneider-Brachert W, Haas R, Fischer W (2008) Protein subassemblies of the H. pylori cag type IV secretion system revealed by localization and interaction studies. J Bacteriol 190(6):2161–2171. PubMedPubMedCentralCrossRefGoogle Scholar
  95. Kwok T, Zabler D, Urman S, Rohde M, Hartig R, Wessler S, Misselwitz R, Berger J, Sewald N, König W, Backert S (2007) Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 449(7164):862–866. PubMedCrossRefGoogle Scholar
  96. Lee IO, Kim JH, Choi YJ, Pillinger MH, Kim SY, Blaser MJ, Lee YC (2010) H. pylori CagA phosphorylation status determines the gp130-activated SHP2/ERK and JAK/STAT signal transduction pathways in gastric epithelial cells. J Biol Chem 285(21):16042–16050. PubMedPubMedCentralCrossRefGoogle Scholar
  97. Lee KS, Kalantzis A, Jackson CB, O’Connor L, Murata-Kamiya N, Hatakeyama M, Judd LM, Giraud AS, Menheniott TR (2012) Helicobacter pylori CagA triggers expression of the bactericidal lectin REG3γ via gastric STAT3 activation. PLoS One 7(2):e30786. PubMedPubMedCentralCrossRefGoogle Scholar
  98. Lim MCC, Maubach G, Sokolova O, Feige MH, Diezko R, Buchbinder J, Backert S, Schlüter D, Lavrik IN, Naumann M (2017) Pathogen-induced ubiquitin editing enzyme A20 bifunctionally shuts off NF-κB and caspase 8-dependent apoptotic cell death. Cell Death Differ. PubMedCentralGoogle Scholar
  99. Lind J, Backert S, Pfleiderer K, Berg DE, Yamaoka Y, Sticht H, Tegtmeyer N (2014) Systematic analysis of phosphotyrosine antibodies recognizing single phosphorylated EPIYA-motifs in CagA of Western-type Helicobacter pylori strains. PLoS One 9(5):e96488. PubMedPubMedCentralCrossRefGoogle Scholar
  100. Lind J, Backert S, Hoffmann R, Eichler J, Yamaoka Y, Perez-Perez GI, Torres J, Sticht H, Tegtmeyer N (2016) Systematic analysis of phosphotyrosine antibodies recognizing single phosphorylated EPIYA-motifs in CagA of East Asian-type Helicobacter pylori strains. BMC Microbiol 16(1):201. PubMedPubMedCentralCrossRefGoogle Scholar
  101. Liu G, McDaniel TK, Falkow S, Karlin S (1999) Sequence anomalies in the Cag7 gene of the H. pylori pathogenicity island. Proc Natl Acad Sci USA 96(12):7011–7016Google Scholar
  102. Loh JT, Torres VJ, Algood HM, McClain MS, Cover TL (2008) Helicobacter pylori HopQ outer membrane protein attenuates bacterial adherence to gastric epithelial cells. FEMS Microbiol Lett 289(1):53–58PubMedPubMedCentralCrossRefGoogle Scholar
  103. Low HH, Gubellini F, Rivera-Calzada A, Braun N, Connery S, Dujeancourt A, Lu F, Redzej A, Fronzes R, Orlova EV, Waksman G (2014) Structure of a type IV secretion system. Nature 508(7497):550–553. PubMedPubMedCentralCrossRefGoogle Scholar
  104. Lu H, Wu JY, Kudo T, Ohno T, Graham DY, Yamaoka Y (2005) Regulation of interleukin-6 promoter activation in gastric epithelial cells infected with H. pylori. Mol Biol Cell 16(10):4954–4966. PubMedPubMedCentralCrossRefGoogle Scholar
  105. Lv G, Zhu H, Zhou F, Lin Z, Lin G, Li C (2014) AMP-activated protein kinase activation protects gastric epithelial cells from H. pylori-induced apoptosis. Biochem Biophys Res Commun 453(1):13–18. PubMedCrossRefGoogle Scholar
  106. Miao L, Liu K, Xie M, Xing Y, Xi T (2014) miR-375 inhibits H. pylori-induced gastric carcinogenesis by blocking JAK2-STAT3 signaling. Cancer Immunol Immunother 63:699–711. PubMedCrossRefGoogle Scholar
  107. Milivojevic M, Dangeard AS, Kasper CA, Tschon T, Emmenlauer M, Pique C, Schnupf P, Guignot J, Arrieumerlou C, Philpott DJ (2017) ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria. PLOS Pathog 13(2):e1006224Google Scholar
  108. Mimuro H, Suzuki T, Rieder G, Suzuki M, Nagai T, Fujita Y, Nagamatsu K, Ishijima N, Koyasu S, Haas R, Sasakawa C (2007) H. pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach. Cell Host Microbe 2(4):250–263. PubMedCrossRefGoogle Scholar
  109. Moese S, Selbach M, Zimny-Arndt U, Jungblut PR, Meyer TF, Backert S (2001) Identification of a tyrosine-phosphorylated 35 kDa carboxy-terminal fragment (p35CagA) of the Helicobacter pylori CagA protein in phagocytic cells: processing or breakage? Proteomics 1(4):618–629Google Scholar
  110. Moodley Y, Linz B (2009) H. pylori sequences reflect past human migrations. Genome Dyn 6:62–74. PubMedCrossRefGoogle Scholar
  111. Mueller D, Tegtmeyer N, Brandt S, Yamaoka Y, De Poire E, Sgouras D, Wessler S, Torres J, Smolka A, Backert S (2012) c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J Clin Invest 122(4):1553–1566. PubMedPubMedCentralCrossRefGoogle Scholar
  112. Murata-Kamiya N, Kikuchi K, Hayashi T, Higashi H, Hatakeyama M (2010) H. pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of CagA. Cell Host Microbe 7(5):399–411. PubMedCrossRefGoogle Scholar
  113. Murata-Kamiya N, Kurashima Y, Teishikata Y, Yamahashi Y, Saito Y, Higashi H, Aburatani H, Akiyama T, Peek RM Jr, Azuma T, Hatakeyama M (2007) H. pylori CagA interacts with E-cadherin and deregulates catenin that promotes intestinal transdifferentiation in cells. Oncogene 26(32):4617–4626. PubMedCrossRefGoogle Scholar
  114. Musti AM, Treier M, Bohmann D (1997) Reduced ubiquitin-dependent degradation of c-Jun after phosphorylation by MAP kinases. Science 275(5298):400–402PubMedCrossRefGoogle Scholar
  115. Naumann M, Sokolova O, Tegtmeyer N, Backert S (2017) Helicobacter pylori: a paradigm pathogen for subverting host cell signal transmission. Trends Microbiol 25(4):316–328. PubMedCrossRefGoogle Scholar
  116. Naumann M, Wessler S, Bartsch C, Wieland B, Covacci A, Haas R, Meyer TF (1999) Activation of activator protein 1 and stress response kinases in epithelial cells colonized by H. pylori encoding the cag pathogenicity island. J Biol Chem 274(44):31655–31662PubMedCrossRefGoogle Scholar
  117. Neumann M, Naumann M (2007) Beyond IκBs: alternative regulation of NF-κB activity. FASEB J 21(11):2642–2654. PubMedCrossRefGoogle Scholar
  118. Noto JM, Gaddy JA, Lee JY, Piazuelo MB, Friedman DB, Colvin DC, Romero-Gallo J, Tan S, Morgan DR, Wilson KT, Bravo LE, Correa P, Cover TL, Amieva MR, Peek RM Jr (2013) Iron deficiency accelerates H. pylori-induced carcinogenesis in rodents and humans. J Clin Invest 123(1):479–492. PubMedCrossRefGoogle Scholar
  119. Odenbreit S, Püls J, Sedlmaier B, Gerland E, Haas R (2000) Translocation of H. pylori CagA into gastric epithelial cells by type IV secretion. Science 287(5457):1497–1500PubMedCrossRefGoogle Scholar
  120. Odenbreit S, Swoboda K, Barwig I, Ruhl S, Borén T, Koletzko S, Haas R (2009) Outer membrane protein expression profile in H. pylori clinical isolates. Infect Immun 77(9):3782–3790. PubMedPubMedCentralCrossRefGoogle Scholar
  121. Ogden SR, Wroblewski LE, Weydig C, Romero-Gallo J, O’Brien DP, Israel DA, Krishna US, Fingleton B, Reynolds AB, Wessler S, Peek RM Jr (2008) p120 and Kaiso regulate Helicobacter pylori-induced expression of matrix metalloproteinase-7. Mol Biol Cell 19(10):4110–4121. PubMedPubMedCentralCrossRefGoogle Scholar
  122. Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M, Matsui A, Higashi H, Musashi M, Iwabuchi K, Suzuki M, Yamada G, Azuma T, Hatakeyama M (2008) Transgenic expression of H. pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci USA 105(3):1003–1008.
  123. Okines A, Cunningham D, Chau I (2011) Targeting the human EGFR family in esophagogastric cancer. Nat Rev Clin Oncol 8(8):492–503. PubMedCrossRefGoogle Scholar
  124. Olbermann P, Josenhans C, Moodley Y, Uhr M, Stamer C, Vauterin M, Suerbaum S, Achtman M, Linz B (2010) A global overview of the genetic and functional diversity in the H. pylori cag pathogenicity island. PLoS Genet 6(8):e1001069. PubMedPubMedCentralCrossRefGoogle Scholar
  125. Oliveira MJ, Costa AC, Costa AM, Henriques L, Suriano G, Atherton JC, Machado JC, Carneiro F, Seruca R, Mareel M, Leroy A, Figueiredo C (2006) H. pylori induces gastric epithelial cell invasion in a c-Met and type IV secretion system-dependent manner. J Biol Chem 281(46):34888–34896. PubMedCrossRefGoogle Scholar
  126. Oliveira MJ, Costa AM, Costa AC, Ferreira RM, Sampaio P, Machado JC, Seruca R, Mareel M, Figueiredo C (2009) CagA associates with c-Met, E-cadherin, and p120-catenin in a multiproteic complex that suppresses H. pylori-induced cell-invasive phenotype. J Infect Dis 200(5):745–755. PubMedCrossRefGoogle Scholar
  127. Oyarzabal OA, Rad R, Backert S (2007) Conjugative transfer of chromosomally encoded antibiotic resistance from Helicobacter pylori to Campylobacter jejuni. J Clin Microbiol 45(2):402–408PubMedCrossRefGoogle Scholar
  128. Pachathundikandi SK, Müller A, Backert S (2016) Inflammasome activation by Helicobacter pylori and its implications for persistence and immunity. Curr Top Microbiol Immunol 397:117–131. PubMedGoogle Scholar
  129. Parsonnet J, Friedman GD, Orentreich N, Vogelman H (1997) Risk for gastric cancer in people with CagA positive or CagA negative H. pylori infection. Gut 40(3):297–301Google Scholar
  130. Pattis I, Weiss E, Laugks R, Haas R, Fischer W (2007) The H. pylori CagF protein is a type IV chaperone-like molecule that binds close to the C-terminal secretion signal of the CagA effector protein. Microbiology 153(Pt 9):2896–2909. PubMedCrossRefGoogle Scholar
  131. Pham KT, Weiss E, Jiménez Soto LF, Breithaupt U, Haas R, Fischer W (2012) CagI is an essential component of the H. pylori Cag type IV secretion system and forms a complex with CagL. PLoS One 7(4):e35341. PubMedPubMedCentralCrossRefGoogle Scholar
  132. Pinto-Santini DM, Salama NR (2009) Cag3 is a novel essential component of the H. pylori Cag type IV secretion system outer membrane subcomplex. J Bacteriol 191(23):7343–7352. PubMedPubMedCentralCrossRefGoogle Scholar
  133. Pomorski T, Meyer TF, Naumann M (2001) H. pylori-induced prostaglandin E(2) synthesis involves activation of cytosolic phospholipase A(2) in epithelial cells. J Biol Chem 276(1):804–810. PubMedCrossRefGoogle Scholar
  134. Poppe M, Feller SM, Römer G, Wessler S (2007) Phosphorylation of H. pylori CagA by c-Abl leads to cell motility. Oncogene 26(24):3462–3472. PubMedCrossRefGoogle Scholar
  135. Rath S, Das L, Kokate SB, Pratheek BM, Chattopadhyay S, Goswami C, Chattopadhyay R, Crowe SE, Bhattacharyya A (2015) Regulation of Noxa-mediated apoptosis in H. pylori-infected gastric epithelial cells. FASEB J 29(3):796–806. PubMedCrossRefGoogle Scholar
  136. Rieke C, Papendieck A, Sokolova O, Naumann M (2011) H. pylori-induced tyrosine phosphorylation of IKKβ contributes to NF-κB activation. Biol Chem 392(4):387–393. PubMedCrossRefGoogle Scholar
  137. Rohde M, Püls J, Buhrdorf R, Fischer W, Haas R (2003) A novel sheathed surface organelle of the H. pylori cag type IV secretion system. Mol Microbiol 49(1):219–234PubMedCrossRefGoogle Scholar
  138. Rohrer S, Holsten L, Weiss E, Benghezal M, Fischer W, Haas R (2012) Multiple pathways of plasmid DNA transfer in Helicobacter pylori. PLoS ONE 7(9):e45623. PubMedPubMedCentralCrossRefGoogle Scholar
  139. Roskoski R Jr (2014) The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 79:34–74. PubMedCrossRefGoogle Scholar
  140. Saadat I, Higashi H, Obuse C, Umeda M, Murata-Kamiya N, Saito Y, Lu H, Ohnishi N, Azuma T, Suzuki A, Ohno S, Hatakeyama M (2007) H. pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447(7142):330–333.
  141. Saha A, Backert S, Hammond CE, Gooz M, Smolka AJ (2010) Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H. K-ATPase alpha subunit. Gastroenterology 139(1):239–248. PubMedGoogle Scholar
  142. Saju P, Murata-Kamiya N, Hayashi T, Senda Y, Nagase L, Noda S, Matsusaka K, Funata S, Kunita A, Urabe M, Seto Y, Fukayama M, Kaneda A, Hatakeyama M (2016) Host SHP1 phosphatase antagonizes H. pylori CagA and can be downregulated by Epstein-Barr virus. Nature Microbiol 1:16026. CrossRefGoogle Scholar
  143. Salama NR, Hartung ML, Müller A (2013) Life in the human stomach: persistence strategies of the bacterial pathogen H. pylori. Nat Rev Microbiol 11(6):385–399. PubMedPubMedCentralCrossRefGoogle Scholar
  144. Sause WE, Keilberg D, Aboulhouda S, Ottemann KM (2017) The H. pylori autotransporter ImaA tempers the bacterium’s interaction with alpha5beta1 integrin. Infect Immun 85(1):pii: e00450-16.
  145. Schmidt TP, Perna AM, Fugmann T, Böhm M, Hiss Jan, Haller S, Götz C, Tegtmeyer N, Hoy B, Rau TT, Neri D, Backert S, Schneider G, Wessler S (2016) Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA. Sci Rep 6:23264. PubMedPubMedCentralCrossRefGoogle Scholar
  146. Schweitzer K, Sokolova O, Bozko P, Naumann M (2010) H. pylori induces NF-ĸB independent of CagA. EMBO Rep 11(1):10–11. PubMedPubMedCentralCrossRefGoogle Scholar
  147. Segal ED, Cha J, Lo J, Falkow S, Tompkins LS (1999) Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by H. pylori. Proc Natl Acad Sci USA 96(25):14559–14564Google Scholar
  148. Selbach M, Moese S, Hauck CR, Meyer TF, Backert S (2002) Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J Biol Chem 277(9):6775–6778. PubMedCrossRefGoogle Scholar
  149. Selbach M, Paul FE, Brandt S, Guye P, Daumke O, Backert S, Dehio C, Mann M (2009) Host cell interactome of tyrosine-phosphorylated bacterial proteins. Cell Host Microbe 5(4):397–403PubMedCrossRefGoogle Scholar
  150. Senda Y, Murata-Kamiya N, Hatakeyama M (2016) C-terminal Src kinase-mediated EPIYA phosphorylation of Pragmin creates a feed-forward C-terminal Src kinase activation loop that promotes cell motility. Cancer Sci 107(7):972–980. PubMedPubMedCentralCrossRefGoogle Scholar
  151. Shaffer CL, Gaddy JA, Loh JT, Johnson EM, Hill S, Hennig EE, McClain MS, McDonald WH, Cover TL (2011) H. pylori exploits a unique repertoire of type IV secretion system components for pilus assembly at the bacteria-host cell interface. PLoS Pathog 7(9):e1002237. PubMedPubMedCentralCrossRefGoogle Scholar
  152. Shanks AM, El-Omar EM (2009) H. pylori infection, host genetics and gastric cancer. J Dig Dis 10(3):157–164. PubMedCrossRefGoogle Scholar
  153. Shariq M, Kumar N, Kumari R, Kumar A, Subbarao N, Mukhopadhyay G (2015) Biochemical analysis of CagE: a VirB4 homologue of H. pylori Cag-T4SS. PLoS One 10(11):e0142606. PubMedPubMedCentralCrossRefGoogle Scholar
  154. Sierra JC, Asim M, Verriere TG, Piazuelo MB, Suarez G, Romero-Gallo J, Delgado AG, Wroblewski LE, Barry DP, Peek RM Jr, Gobert AP, Wilson KT (2017) Epidermal growth factor receptor inhibition downregulates H. pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut pii: gutjnl-2016-312888Google Scholar
  155. Skaug B, Chen J, Du F, He J, Ma A, Chen ZJ (2011) Direct, noncatalytic mechanism of IKK inhibition by A20. Mol Cell 44(4):559–571. PubMedPubMedCentralCrossRefGoogle Scholar
  156. Smart J, Fouillen A, Casu B, Nanci A, Baron C (2017) Cag-delta (Cag3) protein from the H. pylori 26695 cag type IV secretion system forms ring-like supramolecular assemblies. FEMS Microbiol Lett 364(1): pii: fnw280.
  157. Snider JL, Allison C, Bellaire BH, Ferrero RL, Cardelli JA (2008) The beta1 integrin activates JNK independent of CagA, and JNK activation is required for H. pylori CagA-induced motility of gastric cancer cells. J Biol Chem 283(20):13952–13963. PubMedPubMedCentralCrossRefGoogle Scholar
  158. Sokolova O, Borgmann M, Schweitzer K, Rothkötter HJ, Naumann M (2013) H. pylori induces type 4 secretion system-dependent, but CagA-independent activation of IκBs and NF-κB/RelA at early time points. Int J Med Microbiol 303(8):548–552. PubMedCrossRefGoogle Scholar
  159. Sokolova O, Bozko PM, Naumann M (2008) H. pylori suppresses glycogen synthase kinase 3beta to promote beta-catenin activity. J Biol Chem 283(43):29367–29374. PubMedPubMedCentralCrossRefGoogle Scholar
  160. Sokolova O, Maubach G, Naumann M (2014) MEKK3 and TAK1 synergize to activate IKK complex in H. pylori infection. Biochim Biophys Acta 1843(4):715–724. PubMedCrossRefGoogle Scholar
  161. Stein M, Rappuoli R, Covacci A (2000) Tyrosine phosphorylation of the H. pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci USA 97(3):1263–1268Google Scholar
  162. Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A (2002) c-Src/Lyn kinases activate H. pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol 43(4):971–980PubMedCrossRefGoogle Scholar
  163. Stein SC, Faber E, Bats SH, Murillo T, Speidel Y, Coombs N, Josenhans C (2017) Helicobacter pylori modulates host cell responses by CagT4SS-dependent translocation of an intermediate metabolite of LPS inner core heptose biosynthesis. PLoS Pathog 13(7):e1006514. PubMedPubMedCentralCrossRefGoogle Scholar
  164. Tammer I, Brandt S, Hartig R, König W, Backert S (2007) Activation of Abl by Helicobacter pylori: a novel kinase for CagA and crucial mediator of host cell scattering. Gastroenterology 132(4):1309–1319. PubMedCrossRefGoogle Scholar
  165. Tanaka J, Suzuki T, Mimuro H, Sasakawa C (2003) Structural definition on the surface of H. pylori type IV secretion apparatus. Cell Microbiol 5(6):395–404PubMedCrossRefGoogle Scholar
  166. Tanos B, Pendergast AM (2006) Abl tyrosine kinase regulates endocytosis of the epidermal growth factor receptor. J Biol Chem 281(43):32714–32723. PubMedCrossRefGoogle Scholar
  167. Tegtmeyer N, Hartig R, Delahay RM, Rohde M, Brandt S, Conradi J, Takahashi S, Smolka AJ, Sewald N, Backert S (2010) A small fibronectin-mimicking protein from bacteria induces cell spreading and focal adhesion formation. J Biol Chem 285(30):23515–23526.
  168. Tegtmeyer N, Wessler S, Backert S (2011a) Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. FEBS J 278(8):1190–1202.
  169. Tegtmeyer N, Zabler D, Schmidt D, Hartig R, Brandt S, Backert S (2009) Importance of EGF receptor, HER2/Neu and Erk1/2 kinase signaling for host cell elongation and scattering induced by the Helicobacter pylori CagA protein: antagonistic effects of the vacuolating cytotoxin VacA. Cell Microbiol 11(3):488–505. PubMedCrossRefGoogle Scholar
  170. Tegtmeyer N, Wessler S, Necchi V, Rohde M, Harrer A, Rau TT, Asche CI, Boehm M, Loessner M, Figueiredo C, Naumann M, Palmisano R, Solcia E, Ricci V, Backert S (2017) A unique basolateral type IV secretion model for the CagA oncoprotein of Helicobacter pylori. Cell Host Microbe 22(4):552–560.e5.
  171. Tegtmeyer N, Wittelsberger R, Hartig R, Wessler S, Martinez-Quiles N, Backert S (2011b) Serine phosphorylation of cortactin controls focal adhesion kinase activity and cell scattering induced by Helicobacter pylori. Cell Host Microbe 9:520–531. PubMedCrossRefGoogle Scholar
  172. Tsang YH, Lamb A, Romero-Gallo J, Huang B, Ito K, Peek RM Jr, Ito Y, Chen LF (2010) H. pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation. Oncogene 29:5643–5650. PubMedPubMedCentralCrossRefGoogle Scholar
  173. Udhayakumar G, Jayanthi V, Devaraj N, Devaraj H (2011) Nuclear translocation of beta-catenin correlates with CD44 upregulation in H. pylori-infected gastric carcinoma. Mol Cell Biochem 357(1–2):283–293. PubMedCrossRefGoogle Scholar
  174. Varga MG, Shaffer CL, Sierra JC, Suarez G, Piazuelo MB, Whitaker ME, Romero-Gallo J, Krishna US, Delgado A, Gomez MA, Good JA, Almqvist F, Skaar EP, Correa P, Wilson KT, Hadjifrangiskou M, Peek RM (2016) Pathogenic H. pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system. Oncogene 35(48):6262–6269. PubMedPubMedCentralCrossRefGoogle Scholar
  175. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Mémet S, Huerre MR, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL (2004) Nod1 responds to peptidoglycan delivered by the H. pylori cag pathogenicity island. Nat Immunol 5:1166–1174. PubMedCrossRefGoogle Scholar
  176. Wallasch C, Crabtree JE, Bevec D, Robinson PA, Wagner H, Ullrich A (2002) H. pylori-stimulated EGF receptor transactivation requires metalloprotease cleavage of HB-EGF. Biochem Biophys Res Commun 295(3):695–701PubMedCrossRefGoogle Scholar
  177. Wan XK, Yuan SL, Wang YC, Tao HX, Jiang W, Guan ZY, Cao C, Liu CJ (2016) The upregulation of TRAF1 induced by H.pylori plays an antiapoptotic effect on the infected cells. Helicobacter 21:554–564. PubMedCrossRefGoogle Scholar
  178. Wang J, Goetsch L, Tucker L, Zhang Q, Gonzalez A, Vaidya KS, Oleksijew A, Song M, Sokolova I, Pestova E, Anderson M, Pappano WN, Ansell P, Bhathena A, Naumovski L, Corvaia N, Reilly EB (2016) Anti-c-Met monoclonal antibody ABT-700 breaks oncogene addiction in tumors with MET amplification. BMC Cancer 16:105. PubMedPubMedCentralCrossRefGoogle Scholar
  179. Watanabe T, Tada M, Nagai H, Sasaki S, Nakao M (1998) H. pylori infection induces gastric cancer in mongolian gerbils. Gastroenterology 115(3):642–648PubMedCrossRefGoogle Scholar
  180. Weydig C, Starzinski-Powitz A, Carra G, Löwer J, Wessler S (2007) CagA-independent disruption of adherence junction complexes involves Ecadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. Exp Cell Res 313(16):3459–3471Google Scholar
  181. Wessler S, Backert S (2011) Abl family of tyrosine kinases and microbial pathogenesis. Int Rev Cell Mol Biol 286:271–300.
  182. Wessler S, Backert S (2008) Molecular mechanisms of epithelial-barrier disruption by Helicobacter pylori. Trends Microbiol 16(8):397–405. PubMedCrossRefGoogle Scholar
  183. Wiedemann T, Hofbaur S, Tegtmeyer N, Huber S, Sewald N, Wessler S, Backert S, Rieder G (2012) Helicobacter pylori CagL dependent induction of gastrin expression via a novel alphavbeta5-integrin-integrin linked kinase signaling complex. Gut 61(7):986–996. PubMedCrossRefGoogle Scholar
  184. Wong BC, Wang WP, So WH, Shin VY, Wong WM, Fung FM, Liu ES, Hiu WM, Lam SK, Cho CH (2001) Epidermal growth factor and its receptor in chronic active gastritis and gastroduodenal ulcer before and after H. pylori eradication. Aliment Pharmacol Ther 15(9):1459–1465PubMedCrossRefGoogle Scholar
  185. Yamaoka Y, Graham DY (2014) H. pylori virulence and cancer pathogenesis. Future Oncol 10:1487–1500. PubMedPubMedCentralCrossRefGoogle Scholar
  186. Yamasaki E, Wada A, Kumatori A, Nakagawa I, Funao J, Nakayama M, Hisatsune J, Kimura M, Moss J, Hirayama T (2006) H. pylori vacuolating cytotoxin induces activation of the proapoptotic proteins Bax and Bak, leading to cytochrome-c release and cell death, independent of vacuolation. J Biol Chem 281(16):11250–11259. PubMedCrossRefGoogle Scholar
  187. Yong X, Tang B, Xiao YF, Xie R, Qin Y, Luo G, Hu CJ, Dong H, Yang SM (2016) H. pylori upregulates Nanog and Oct4 via Wnt/beta-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. Cancer Lett 374(2):292–303. PubMedCrossRefGoogle Scholar
  188. Zaidi SF, Refaat A, Zhou Y, Sualeh Muhammad J, Shin MS, Saiki I, Sakurai H, Sugiyama T (2015) H. pylori induces serine phosphorylation of EGFR via novel TAK1-p38 activation pathway in an HB-EGF-independent manner. Helicobacter 20(5):381–389. PubMedCrossRefGoogle Scholar
  189. Zhang J, Fan F, Zhao Y, Sun L, Liu Y, Keegan RM, Isupov MN, Wu Y (2017) Crystal structure of the type IV secretion system component CagX from H. pylori. Acta Crystallogr F Struct Biol Commun 73(Pt 3):167–173.
  190. Zhang YM, Noto JM, Hammond CE, Barth JL, Argraves WS, Backert S, Peek RMJr, Smolka AJ (2014) Helicobacter pylori-induced posttranscriptional regulation of H-K-ATPase α-subunit gene expression by miRNA. Am J Physiol Gastrointest Liver Physiol 306(7):G606–613.
  191. Zimmermann S, Pfannkuch L, Al-Zeer M, Bartfeld S, Koch M, Liu J, Rechner C, Soerensen M, Sokolova O, Zamyatina A, Kosma P, Maeurer AP, Glowinski F, Pleissner KP, Schmid M, Brinkmann V, Naumann M, Rother M, Machuy N, Meyer TF (2017) ALPK1 and TIFA dependent innate immune response triggered By The H. pylori type IV secretion system. Cell Rep 20(10):2384–2395.

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Steffen Backert
    • 1
  • Rainer Haas
    • 2
    • 4
  • Markus Gerhard
    • 3
    • 4
  • Michael Naumann
    • 5
  1. 1.Division of Microbiology, Department of BiologyFriedrich Alexander University Erlangen-NurembergErlangenGermany
  2. 2.Max von Pettenkofer-Institute for Hygiene and Medical MicrobiologyLudwig-Maximilians-UniversityMunichGermany
  3. 3.Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität MünchenMunichGermany
  4. 4.German Center for Infection Research (DZIF)MunichGermany
  5. 5.Institute of Experimental Internal MedicineOtto von Guericke UniversityMagdeburgGermany

Personalised recommendations