The Versatility of Helicobacter pylori CagA Effector Protein Functions: The Master Key Hypothesis
Correction(s) for this article
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The Versatility of Helicobacter pylori CagA Effector Protein Functions: the Master Key Hypothesis
- Volume 15Issue 5Helicobacter
- pages: 483-483
- First Published online: September 7, 2010
Steffen Backert,
Nicole Tegtmeyer,
Matthias Selbach,
Steffen Backert
School of Biomolecular and Biomedical Sciences, University College Dublin, Ardmore House, Belfield Campus, Dublin-4, Ireland
Department Medical Microbiology, University of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany
Search for more papers by this authorNicole Tegtmeyer
School of Biomolecular and Biomedical Sciences, University College Dublin, Ardmore House, Belfield Campus, Dublin-4, Ireland
Search for more papers by this authorMatthias Selbach
Max Delbrueck Centre for Molecular Medicine, Robert Roessle-Str. 10, D-13125 Berlin, Germany
Search for more papers by this authorSteffen Backert,
Nicole Tegtmeyer,
Matthias Selbach,
Steffen Backert
School of Biomolecular and Biomedical Sciences, University College Dublin, Ardmore House, Belfield Campus, Dublin-4, Ireland
Department Medical Microbiology, University of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany
Search for more papers by this authorNicole Tegtmeyer
School of Biomolecular and Biomedical Sciences, University College Dublin, Ardmore House, Belfield Campus, Dublin-4, Ireland
Search for more papers by this authorMatthias Selbach
Max Delbrueck Centre for Molecular Medicine, Robert Roessle-Str. 10, D-13125 Berlin, Germany
Search for more papers by this authorReprint requests to: Steffen Backert, School of Biomolecular and Biomedical Science, University College Dublin, Belfield Campus, Science Center North, Office G09, Dublin-4, Ireland. E-mail: [email protected]
Abstract
Several bacterial pathogens inject virulence proteins into host target cells that are substrates of eukaryotic tyrosine kinases. One of the key examples is the Helicobacter pylori CagA effector protein which is translocated by a type-IV secretion system. Injected CagA becomes tyrosine-phosphorylated on EPIYA sequence motifs by Src and Abl family kinases. CagA then binds to and activates/inactivates multiple signaling proteins in a phosphorylation-dependent and phosphorylation-independent manner. A recent proteomic screen systematically identified eukaryotic binding partners of the EPIYA phosphorylation sites of CagA and similar sites in other bacterial effectors by high-resolution mass spectrometry. Individual phosphorylation sites recruited a surprisingly high number of interaction partners suggesting that each phosphorylation site can interfere with many downstream pathways. We now count 20 reported cellular binding partners of CagA, which represents the highest quantitiy among all yet known virulence-associated effector proteins in the microbial world. This complexity generates a highly remarkable and puzzling scenario. In addition, the first crystal structure of CagA provided us with new information on the function of this important virulence determinant. Here we review the recent advances in characterizing the multiple binding signaling activities of CagA. Injected CagA can act as a ‘master key’ that evolved the ability to highjack multiple host cell signalling cascades, which include the induction of membrane dynamics, actin-cytoskeletal rearrangements and the disruption of cell-to-cell junctions as well as proliferative, pro-inflammatory and anti-apoptotic nuclear responses. The discovery that different pathogens use this common strategy to subvert host cell functions suggests that more examples will emerge soon.
References
- 1 Graham DY, Yamaoka Y. Disease-specific Helicobacter pylori virulence factors: the unfulfilled promise. Helicobacter 2000; 5: 3–9.
- 2 Montecucco C, Rappuoli R. Living dangerously: How Helicobacter pylori survives in the human stomach. Nat Rev Mol Cell Biol 2001; 2: 457–66.
- 3 Viala J, Chaput C, Boneca IG, et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 2004; 5: 1166–74.
- 4 Peek RM Jr, Crabtree JE. Helicobacter infection and gastric neoplasia. J Pathol 2006; 208: 233–48.
- 5 Suerbaum S, Josenhans C. Helicobacter pylori evolution and phenotypic diversification in a changing host. Nat Rev Microbiol 2007; 5: 441–52.
- 6 Dubois A, Borén T. Helicobacter pylori is invasive and it may be a facultative intracellular organism. Cell Microbiol 2007; 9: 1108–16.
- 7 Boquet P, Ricci V, Galmiche A, et al. Gastric cell apoptosis and H. pylori: has the main function of VacA finally been identified? Trends Microbiol 2003; 11: 410–3.
- 8 Fujikawa A, Shirasaka D, Yamamoto S, et al. Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Nat Genet 2003; 33: 375–81.
- 9 Blaser MJ, Atherton JC. Helicobacter pylori persistence: biology and disease. J Clin Invest 2004; 113: 321–33.
- 10 Cover TL, Blanke SR. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol 2005; 3: 320–32.
- 11 Rieder G, Fischer W, Haas R. Interaction of Helicobacter pylori with host cells: function of secreted and translocated molecules. Curr Opin Microbiol 2005; 8: 67–73.
- 12 Covacci A, Telford JL, Del Giudice G, et al. Helicobacter pylori virulence and genetic geography. Science 1999; 284: 1328–33.
- 13 Backert S, Meyer TF. Type IV secretion systems and their effectors in bacterial pathogenesis. Curr Opin Microbiol 2006; 9: 207–17.
- 14 Mimuro H, Berg DE, Sasakawa C. Control of epithelial cell structure and developmental fate: lessons from Helicobacter pylori. Bioessays 2008; 30: 515–20.
- 15 Backert S, Selbach M. Role of type IV secretion in Helicobacter pylori pathogenesis. Cell Microbiol 2008; 10: 1573–81.
- 16 Rohde M, Püls J, Buhrdorf R, et al. A novel sheathed surface organelle of the Helicobacter pylori cag type IV secretion system. Mol Microbiol 2003; 49: 219–34.
- 17 Tanaka J, Suzuki T, Mimuro H, et al. Structural definition on the surface of Helicobacter pylori type IV secretion apparatus. Cell Microbiol 2003; 5: 395–404.
- 18 Kwok T, Zabler D, Urman S, et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 2007; 449: 862–6.
- 19 Fronzes R, Christie PJ, Waksman G. The structural biology of type IV secretion systems. Nat Rev Microbiol 2009; 7: 703–14.
- 20 Fischer W, Püls J, Buhrdorf R, et al. Systematic mutagenesis of the Helicobacter pylori cag pathogenicity island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol Microbiol 2001; 42: 1337–48.
- 21 Kutter S, Buhrdorf R, Haas J, et al. Protein subassemblies of the Helicobacter pylori Cag type IV secretion system revealed by localization and interaction studies. J Bacteriol 2008; 190: 2161–71.
- 22 Backert S, Fronzes R, Waksman G. VirB2 and VirB5 proteins: specialized adhesins in bacterial type-IV secretion systems? Trends Microbiol 2008; 16: 409–13.
- 23 Cover TL, Dooley CP, Blaser MJ. Characterization and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity. Infect Immun 1990; 58: 603–10.
- 24 Crabtree JE, Taylor JD, Wyatt JI, et al. Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration, and gastric pathology. Lancet 1991; 338: 332–5.
- 25 Covacci A, Censini S, Bugnoli M, et al. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci USA 1993; 90: 5791–5.
- 26 Watanabe T, Tada M, Nagai H, et al. Helicobacter pylori infection induces gastric cancer in mongolian gerbils. Gastroenterology 1998; 115: 642–8.
- 27 Wirth HP, Beins MH, Yang M, et al. Experimental infection of Mongolian gerbils with wild-type and mutant Helicobacter pylori strains. Infect Immun 1998; 66: 4856–66.
- 28 Peek RM Jr, Wirth HP, Moss SF, et al. Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils. Gastroenterology 2000; 118: 48–59.
- 29 Ogura K, Maeda S, Nakao M, et al. Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil. J Exp Med 2000; 192: 1601–10.
- 30 Rieder G, Merchant JL, Haas R. Helicobacter pylori cag-type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils. Gastroenterology 2005; 128: 1229–42.
- 31 Ohnishi N, Yuasa H, Tanaka S, et al. Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci USA 2008; 105: 1003–8.
- 32 Jiménez-Soto LF, Kutter S, Sewald X, et al. Helicobacter pylori type IV secretion apparatus exploits beta1 integrin in a novel RGD-independent manner. PLoS Pathog 2009; 5: e1000684.
- 33 Wessler S, Backert S. Molecular mechanisms of epithelial-barrier disruption by Helicobacter pylori. Trends Microbiol 2008; 16: 397–405.
- 34 Couturier MR, Tasca E, Montecucco C, et al. Interaction with CagF is required for translocation of CagA into the host via the Helicobacter pylori type IV secretion system. Infect Immun 2006; 74: 273–81.
- 35 Pattis I, Weiss E, Laugks R, et al. The Helicobacter pylori CagF protein is a type IV secretion chaperone-like molecule that binds close to the C-terminal secretion signal of the CagA effector protein. Microbiology 2007; 153: 2896–909.
- 36 Covacci A, Rappuoli R. Tyrosine-phosphorylated bacterial proteins: Trojan horses for the host cell. J Exp Med 2000; 191: 587–92.
- 37 Backert S, Moese S, Selbach M, et al. Phosphorylation of tyrosine 972 of the Helicobacter pylori CagA protein is essential for induction of a scattering phenotype in gastric epithelial cells. Mol Microbiol 2001; 42: 631–44.
- 38 Stein M, Bagnoli F, Halenbeck R, et al. c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol 2002; 43: 971–80.
- 39 Higashi H, Tsutsumi R, Muto S, et al. SHP2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 2002; 295: 683–6.
- 40 Asahi M, Tanaka Y, Izumi T, et al. Helicobacter pylori CagA containing ITAM-like sequences localized to lipid rafts negatively regulates VacA-induced signaling in vivo. Helicobacter 2003; 8: 1–14.
- 41 Hatakeyama M. SagA of CagA in Helicobacter pylori pathogenesis. Curr Opin Microbiol 2008; 11: 30–7.
- 42
Brandt S,
Kwok T,
Hartig R, et al.
NF-κB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein.
Proc Natl Acad Sci USA
2005; 102: 9300–5.
10.1073/pnas.0409873102 Google Scholar
- 43 Xia Y, Yamaoka Y, Zhu Q, et al. A comprehensive sequence and disease correlation analyses for the C-terminal region of CagA protein of Helicobacter pylori. PLoS ONE 2009; 4: e7736.
- 44 Reyes-Leon A, Atherton JC, Argent RH, et al. Heterogeneity in the activity of Mexican Helicobacter pylori strains in gastric epithelial cells and its association with diversity in the cagA gene. J Infect Immun 2007; 75: 3445–54.
- 45 Tomb JF, White O, Kerlavage AR, et al. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 1997; 388: 539–47.
- 46 Baltrus DA, Amieva MR, Covacci A, et al. The complete genome sequence of Helicobacter pylori strain G27. J Bacteriol 2009; 191: 447–8.
- 47 Panayotopoulou EG, Sgouras DN, Papadakos K, et al. Strategy to characterize the number and type of repeating EPIYA phosphorylation motifs in the carboxyl terminus of CagA protein in Helicobacter pylori clinical isolates. J Clin Microbiol 2007; 45: 488–95.
- 48 Jones KR, Joo YM, Jang S, et al. Polymorphism in the CagA EPIYA motif impacts development of gastric cancer. J Clin Microbiol 2009; 47: 959–68.
- 49 Argent RH, Zhang Y, Atherton JC. Simple method for determination of the number of Helicobacter pylori CagA variable-region EPIYA tyrosine phosphorylation motifs by PCR. J Clin Microbiol 2005; 43: 791–5.
- 50 Oh JD, Kling-Bäckhed H, Giannakis M, et al. The complete genome sequence of a chronic atrophic gastritis Helicobacter pylori strain: evolution during disease progression. Proc Natl Acad Sci USA 2006; 103: 9999–10004.
- 51 Alm RA, Ling LS, Moir DT, et al. Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature 1999; 397: 176–80.
- 52 Truong BX, Mai VT, Tanaka H, et al. Diverse characteristics of the CagA gene of Helicobacter pylori strains collected from patients from southern vietnam with gastric cancer and peptic ulcer. J Clin Microbiol 2009; 47: 4021–8.
- 53 Naito M, Yamazaki T, Tsutsumi R, et al. Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology 2006; 130: 1181–90.
- 54 Schmidt HM, Goh KL, Fock KM, et al. Distinct cagA EPIYA motifs are associated with ethnic diversity in Malaysia and Singapore. Helicobacter 2009; 14: 256–63.
- 55 Aras RA, Lee Y, Kim SK, et al. Natural variation in populations of persistently colonizing bacteria affect human host cell phenotype. J Infect Dis 2003; 188: 486–96.
- 56
Kim SY,
Lee YC,
Kim HK, et al.
Helicobacter pylori CagA transfection of gastric epithelial cells induces interleukin-8.
Cell Microbiol
2006; 8: 97–106.
10.1111/j.1462-5822.2005.00603.x Google Scholar
- 57 Basso D, Zambon CF, Letley DP, et al. Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 2008; 135: 91–9.
- 58 Miura M, Ohnishi N, Tanaka S, et al. Differential oncogenic potential of geographically distinct Helicobacter pylori CagA isoforms in mice. Int J Cancer 2009; 125: 2497–504.
- 59 Tammer I, Brandt S, Hartig R, et al. Activation of Abl by Helicobacter pylori: a novel kinase for CagA and crucial mediator of host cell scattering. Gastroenterology 2007; 132: 1309–19.
- 60 Backert S, Müller EC, Jungblut PR, et al. Tyrosine phosphorylation patterns and size modification of the Helicobacter pylori CagA protein after translocation into gastric epithelial cells. Proteomics 2001; 1: 608–17.
- 61 Ishikawa S, Ohta T, Hatakeyama M. Stability of Helicobacter pylori CagA oncoprotein in human gastric epithelial cells. FEBS Lett 2009; 583: 2414–8.
- 62 Ren S, Higashi H, Lu H, et al. Structural basis and functional consequence of Helicobacter pylori CagA multimerization in cells. J Biol Chem 2006; 281: 32344–52.
- 63 Higashi H, Yokoyama K, Fujii Y, et al. EPIYA motif is a membrane-targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells. J Biol Chem 2005; 280: 23130–7.
- 64 Mimuro H, Suzuki T, Tanaka J, et al. Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol Cell 2002; 10: 745–55.
- 65 Selbach M, Moese S, Hauck CR, et al. Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J Biol Chem 2002; 277: 6775–8.
- 66 Poppe M, Feller SM, Römer G, et al. Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility. Oncogene 2007; 26: 3462–72.
- 67 Selbach M, Moese S, Hurwitz R, et al. The Helicobacter pylori CagA protein induces cortactin dephosphorylation and actin rearrangement by c-Src inactivation. EMBO J 2003; 22: 515–28.
- 68 Tsutsumi R, Higashi H, Higuchi M, et al. Attenuation of Helicobacter pylori CagA x SHP2 signaling by interaction between CagA and C-terminal Src kinase. J Biol Chem 2003; 278: 3664–70.
- 69 Suzuki M, Mimuro H, Suzuki T, et al. Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J Exp Med 2005; 202: 1235–47.
- 70 Selbach M, Paul FE, Brandt S, et al. Host cell interactome of tyrosine-phosphorylated bacterial proteins. Cell Host Microbe 2009; 5: 397–403.
- 71 Segal ED, Cha J, Lo J, et al. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci USA 1999; 96: 14559–64.
- 72 Moese S, Selbach M, Kwok T, et al. Helicobacter pylori induces AGS cell motility and elongation via independent signaling pathways. Infect Immun 2004; 72: 3646–9.
- 73 Bourzac KM, Botham CM, Guillemin K. Helicobacter pylori CagA induces AGS cell elongation through a cell retraction defect that is independent of Cdc42, Rac1, and Arp2/3. Infect Immun 2007; 75: 1203–13.
- 74
Moese S,
Selbach M,
Brinkmann V, et al.
The Helicobacter pylori CagA protein disrupts matrix adhesion of gastric epithelial cells by dephosphorylation of vinculin.
Cell Microbiol
2007; 9: 1148–61.
10.1111/j.1462-5822.2006.00856.x Google Scholar
- 75 Higashi H, Nakaya A, Tsutsumi R, et al. Helicobacter pylori CagA induces Ras-independent morphogenetic response through SHP2 recruitment and activation. J Biol Chem 2004; 279: 17205–16.
- 76 Tsutsumi R, Takahashi A, Azuma T, et al. Focal adhesion kinase is a substrate and downstream effector of SHP2 complexed with Helicobacter pylori CagA. Mol Cell Biol 2006; 26: 261–76.
- 77 Selbach M, Moese S, Backert S, et al. The Helicobacter pylori CagA protein induces tyrosine dephosphorylation of ezrin. Proteomics 2004; 4: 2961–8.
- 78
Selbach M,
Backert S.
Cortactin: An Achilles’ heel of the actin cytoskeleton targeted by pathogens.
Trends Microbiol
2005; 13: 181–9.
10.1016/j.tim.2005.02.007 Google Scholar
- 79 Brandt S, Shafikhani S, Balachandran P, et al. Use of a novel coinfection system reveals a role for Rac1, H-Ras, and CrkII phosphorylation in Helicobacter pylori-induced host cell actin cytoskeletal rearrangements. FEMS Immunol Med Microbiol 2007; 50: 190–205.
- 80 Hirata Y, Maeda S, Mitsuno Y, et al. Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation. Gastroenterology 2002; 123: 1962–71.
- 81 Botham CM, Wandler AM, Guillemin K. A transgenic Drosophila model demonstrates that the Helicobacter pylori CagA protein functions as a eukaryotic Gab adaptor. PLoS Pathog 2008; 4: e1000064.
- 82 Guillemin K, Salama NR, Tompkins LS, et al. Cag pathogenicity island-specific responses of gastric epithelial cells to Helicobacter pylori infection. Proc Natl Acad Sci USA 2002; 99: 15136–41.
- 83 El-Etr SH, Mueller A, Tompkins LS, et al. Phosphorylation-independent effects of CagA during interaction between Helicobacter pylori and T84 polarized monolayers. J Infect Dis 2004; 190: 1516–23.
- 84 Pillinger MH, Marjanovic N, Kim SY, et al. Helicobacter pylori stimulates gastric epithelial cell MMP-1 secretion via CagA-dependent and -independent ERK activation. J Biol Chem 2007; 282: 18722–31.
- 85 Mimuro H, Suzuki T, Nagai S, et al. Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach. Cell Host Microbe 2007; 2: 250–63.
- 86 Chang YJ, Wu MS, Lin JT, et al. Mechanisms for Helicobacter pylori CagA-induced cyclin D1 expression that affect cell cycle. Cell Microbiol 2006; 8: 1740–52.
- 87 Amieva MR, Vogelmann R, Covacci A, et al. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 2003; 300: 1430–4.
- 88 Bagnoli F, Buti L, Tompkins L, et al. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci USA 2005; 102: 16339–44.
- 89 Murata-Kamiya N, Kurashima Y, Teishikata Y, et al. Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene 2007; 26: 4617–26.
- 90 Franco AT, Israel DA, Washington MK, et al. Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci USA 2005; 102: 10646–51.
- 91 Oliveira MJ, Costa AM, Costa AC, et al. E-cadherin, and p120-catenin in a multiproteic complex that suppresses Helicobacter pylori-induced cell-invasive phenotype. J Infect Dis 2009; 200: 745–55.
- 92 Churin Y, Al-Ghoul L, Kepp O, et al. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol 2003; 161: 249–55.
- 93 Suzuki M, Mimuro H, Kiga K, et al. Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation. Cell Host Microbe 2009; 5: 23–34.
- 94 Snider JL, Cardelli JA. Helicobacter pylori induces cancer cell motility independent of the c-Met receptor. J Carcinog 2009; 8: 7.
- 95 Saadat I, Higashi H, Obuse C, et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 2007; 447: 330–3.
- 96 Zeaiter Z, Cohen D, Müsch A, et al. Analysis of detergent-resistant membranes of Helicobacter pylori infected gastric adenocarcinoma cells reveals a role for MARK2/Par1b in CagA-mediated disruption of cellular polarity. Cell Microbiol 2008; 10: 781–94.
- 97 Umeda M, Murata-Kamiya N, Saito Y, et al. Helicobacter pylori CagA causes mitotic impairment and induces chromosomal instability. J Biol Chem 2009; 284: 22166–72.
- 98 Lu H, Murata-Kamiya N, Saito Y, et al. Role of partitioning-defective 1/microtubule affinity-regulating kinases in the morphogenetic activity of Helicobacter pylori CagA. J Biol Chem 2009; 284: 23024–36.
- 99 Crabtree JE, Xiang Z, Lindley IJ, et al. Induction of interleukin-8 secretion from gastric epithelial cells by a cagA negative isogenic mutant of Helicobacter pylori. J Clin Pathol 1995; 48: 967–9.
- 100 Sharma SA, Tummuru MK, Blaser MJ, et al. Activation of IL-8 gene expression by Helicobacter pylori is regulated by transcription factor nuclear factor-κB in gastric epithelial cells. J Immunol 1998; 160: 2401–7.
- 101 Censini S, Lange C, Xiang Z, et al. Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci USA 1996; 93: 14648–53.
- 102 Brandt S, Wessler S, Hartig R, et al. Helicobacter pylori activates protein kinase C delta to control Raf in MAP kinase signaling: role in AGS epithelial cell scattering and elongation. Cell Motil Cytoskeleton 2009; 66: 874–92.
- 103 Lamb A, Yang XD, Tsang YH, et al. Helicobacter pylori CagA activates NF-kappaB by targeting TAK1 for TRAF6-mediated Lys 63 ubiquitination. EMBO Rep 2009; 10: 1242–9.
- 104 Baek HY, Lim JW, Kim H. Interaction between the Helicobacter pylori CagA and alpha-Pix in gastric epithelial AGS cells. Ann N Y Acad Sci 2007; 1096: 18–23.
- 105 Oliveira MJ, Costa AC, Costa AM, et al. Helicobacter pylori induces gastric epithelial cell invasion in a c-Met and typeIV secretion system-dependent manner. J Biol Chem 2006; 281: 34888–96.
- 106 Nesić D, Miller MC, Quinkert ZT, et al. Helicobacter pylori CagA inhibits PAR1-MARK family kinases by mimicking host substrates. Nat Struct Mol Biol 2010; 17: 130–2.
- 107 Knighton DR, Zheng JH, Ten Eyck LF, et al. Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 1991; 253: 414–20.
- 108 Zheng J, Trafny EA, Knighton DR, et al. 2.2 A refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor. Acta Crystallogr D Biol Crystallogr 1993; 49: 362–5.
- 109 Russo AA, Jeffrey PD, Pavletich NP. Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat Struct Biol 1996; 3: 696–700.
- 110 Seet BT, Dikic I, Zhou MM, et al. Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol 2006; 7: 473–83.
- 111 Bhavsar AP, Guttman JA, Finlay BB. Manipulation of host-cell pathways by bacterial pathogens. Nature 2007; 449: 827–34.
- 112 Backert S, Selbach M. Tyrosine-phosphorylated bacterial effector proteins: the enemies within. Trends Microbiol 2005; 13: 476–84.
- 113 Higashi H, Tsutsumi R, Fujita A, et al. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci USA 2002; 99: 14428–33.
- 114 Yokoyama K, Higashi H, Ishikawa S, et al. Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc Natl Acad Sci USA 2005; 102: 9661–6.
- 115 Tegtmeyer N, Zabler D, Schmidt D, et al. Importance of EGF receptor, HER2/Neu and Erk1/2 kinase signalling for host cell elongation and scattering induced by the Helicobacter pylori CagA protein: antagonistic effects of the vacuolating cytotoxin VacA. Cell Microbiol 2009; 11: 488–505.
- 116 Oldani A, Cormont M, Hofman V, et al. Helicobacter pylori counteracts the apoptotic action of its VacA toxin by injecting the CagA protein into gastric epithelial cells. PLoS Pathog 2009; 5: e1000603.
- 117 Tan S, Tompkins LS, Amieva MR. Helicobacter pylori usurps cell polarity to turn the cell surface into a replicative niche. PLoS Pathog 2009; 5: e1000407.
