Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility

Oncogene volume 26, pages 3462–3472 (2007)Cite this article

Abstract

Helicobacter pylori induces a strong motogenic response in infected gastric epithelial host cells, which is enhanced by translocation of the pathogenic factor cytotoxin-associated gene A (CagA) into host cells via a specialized type IV secretion system. Once injected into the cytosol CagA is rapidly tyrosine phosphorylated by Src family kinases followed by Src inactivation. Hence, it remained unknown why CagA is constantly phosphorylated in sustained H. pylori infections to induce cell migration, whereas other substrates of Src kinases are dephosphorylated. Here, we identify the non-receptor tyrosine kinase c-Abl as a crucial mediator of H. pylori-induced migration and novel CagA kinase in epithelial cells. Upon H. pylori infection c-Abl directly interacts with CagA and localizes in focal adhesion complexes and membrane ruffles, which are highly dynamic cytoskeletal structures necessary for cell motility. Selective inhibition of c-Abl kinase activity by STI571 or shRNA abrogates sustained CagA phosphorylation and epithelial cell migration, indicating a pivotal role of c-Abl in H. pylori infection and pathogenicity. These results implicate c-Abl as a novel molecular target for therapeutic intervention in H. pylori-related gastric diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 6
Figure 3
Figure 4
Figure 5
Figure 7
Figure 8

Similar content being viewed by others

References

  • Al Ghoul L, Wessler S, Hundertmark T, Kruger S, Fischer W, Wunder C et al. (2004). Analysis of the type IV secretion system-dependent cell motility of Helicobacter pylori-infected epithelial cells. Biochem Biophys Res Commun 322: 860–866.

    Article  CAS  Google Scholar 

  • Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S . (2003). Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300: 1430–1434.

    Article  CAS  Google Scholar 

  • Argent RH, Zhang Y, Atherton JC . (2005). Simple method for determination of the number of Helicobacter pylori CagA variable-region EPIYA tyrosine phosphorylation motifs by PCR. J Clin Microbiol 43: 791–795.

    Article  CAS  Google Scholar 

  • Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y et al. (2000). Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med 191: 593–602.

    Article  CAS  Google Scholar 

  • 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: 631–644.

    Article  CAS  Google Scholar 

  • Backert S, Ziska E, Brinkmann V, Zimny-Arndt U, Fauconnier A, Jungblut PR et al. (2000). Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol 2: 155–164.

    Article  CAS  Google Scholar 

  • Bagnoli F, Buti L, Tompkins L, Covacci A, Amieva MR . (2005). Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci USA 102: 16339–16344.

    Article  CAS  Google Scholar 

  • Barila D, Rufini A, Condo I, Ventura N, Dorey K, Superti-Furga G et al. (2003). Caspase-dependent cleavage of c-Abl contributes to apoptosis. Mol Cell Biol 23: 2790–2799.

    Article  CAS  Google Scholar 

  • Bauer B, Moese S, Bartfeld S, Meyer TF, Selbach M . (2005). Analysis of cell type-specific responses mediated by the type IV secretion system of Helicobacter pylori. Infect Immun 73: 4643–4652.

    Article  CAS  Google Scholar 

  • Churin Y, Al Ghoul L, Kepp O, Meyer TF, Birchmeier W, Naumann M . (2003). Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol 161: 249–255.

    Article  CAS  Google Scholar 

  • Corthesy-Theulaz I, Porta N, Pringault E, Racine L, Bogdanova A, Kraehenbuhl JP et al. (1996). Adhesion of Helicobacter pylori to polarized T84 human intestinal cell monolayers is pH dependent. Infect Immun 64: 3827–3832.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Echarri A, Pendergast AM . (2001). Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway. Curr Biol 11: 1759–1765.

    Article  CAS  Google Scholar 

  • Escalante M, Courtney J, Chin WG, Teng KK, Kim JI, Fajardo JE et al. (2000). Phosphorylation of c-Crk II on the negative regulatory Tyr222 mediates nerve growth factor-induced cell spreading and morphogenesis. J Biol Chem 275: 24787–24797.

    Article  CAS  Google Scholar 

  • Feller SM . (2001). Crk family adaptors-signalling complex formation and biological roles. Oncogene 20: 6348–6371.

    Article  CAS  Google Scholar 

  • Feller SM, Knudsen B, Hanafusa H . (1994a). c-Abl kinase regulates the protein binding activity of c-Crk. EMBO J 13: 2341–2351.

    Article  CAS  Google Scholar 

  • Feller SM, Ren R, Hanafusa H, Baltimore D . (1994b). SH2 and SH3 domains as molecular adhesives: the interactions of Crk and Abl. Trends Biochem Sci 19: 453–458.

    Article  CAS  Google Scholar 

  • Frasca F, Vigneri P, Vella V, Vigneri R, Wang JY . (2001). Tyrosine kinase inhibitor STI571 enhances thyroid cancer cell motile response to hepatocyte growth factor. Oncogene 20: 3845–3856.

    Article  CAS  Google Scholar 

  • Hantschel O, Superti-Furga G . (2004). Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol 5: 33–44.

    Article  CAS  Google Scholar 

  • Hatakeyama M . (2004). Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer 4: 688–694.

    Article  CAS  Google Scholar 

  • Hernandez SE, Krishnaswami M, Miller AL, Koleske AJ . (2004). How do Abl family kinases regulate cell shape and movement? Trends Cell Biol 14: 36–44.

    Article  CAS  Google Scholar 

  • Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M et al. (2002). SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295: 683–686.

    Article  CAS  Google Scholar 

  • Ito Y, Pandey P, Mishra N, Kumar S, Narula N, Kharbanda S et al. (2001). Targeting of the c-Abl tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced apoptosis. Mol Cell Biol 21: 6233–6242.

    Article  CAS  Google Scholar 

  • Kain KH, Klemke RL . (2001). Inhibition of cell migration by Abl family tyrosine kinases through uncoupling of Crk–CAS complexes. J Biol Chem 276: 16185–16192.

    Article  CAS  Google Scholar 

  • Lewis JM, Schwartz MA . (1998). Integrins regulate the association and phosphorylation of paxillin by c-Abl. J Biol Chem 273: 14225–14230.

    Article  CAS  Google Scholar 

  • Machuy N, Rajalingam K, Rudel T . (2004). Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis. Cell Death Differ 11: 290–300.

    Article  CAS  Google Scholar 

  • Mayer BJ, Hirai H, Sakai R . (1995). Evidence that SH2 domains promote processive phosphorylation by protein-tyrosine kinases. Curr Biol 5: 296–305.

    Article  CAS  Google Scholar 

  • Mimuro H, Suzuki T, Tanaka J, Asahi M, Haas R, Sasakawa C . (2002). Grb2 is a key mediator of helicobacter pylori CagA protein activities. Mol Cell 10: 745–755.

    Article  CAS  Google Scholar 

  • Moese S, Selbach M, Kwok T, Brinkmann V, Konig W, Meyer TF et al. (2004). Helicobacter pylori induces AGS cell motility and elongation via independent signaling pathways. Infect Immun 72: 3646–3649.

    Article  CAS  Google Scholar 

  • Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R . (2000). Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287: 1497–1500.

    Article  CAS  Google Scholar 

  • Plattner R, Kadlec L, DeMali KA, Kazlauskas A, Pendergast AM . (1999). c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev 13: 2400–2411.

    Article  CAS  Google Scholar 

  • Schmitt W, Haas R . (1994). Genetic analysis of the Helicobacter pylori vacuolating cytotoxin: structural similarities with the IgA protease type of exported protein. Mol Microbiol 12: 307–319.

    Article  CAS  Google Scholar 

  • 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 Helicobacter pylori. Proc Natl Acad Sci USA 96: 14559–14564.

    Article  CAS  Google Scholar 

  • Selbach M, Moese S, Backert S, Jungblut PR, Meyer TF . (2004). The Helicobacter pylori CagA protein induces tyrosine dephosphorylation of ezrin. Proteomics 4: 2961–2968.

    Article  CAS  Google Scholar 

  • 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: 6775–6778.

    Article  CAS  Google Scholar 

  • Selbach M, Moese S, Hurwitz R, Hauck CR, Meyer TF, Backert S . (2003). The Helicobacter pylori CagA protein induces cortactin dephosphorylation and actin rearrangement by c-Src inactivation. EMBO J 22: 515–528.

    Article  CAS  Google Scholar 

  • Srinivasan D, Plattner R . (2006). Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells. Cancer Res 66: 5648–5655.

    Article  CAS  Google Scholar 

  • Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A . (2002). c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol 43: 971–980.

    Article  CAS  Google Scholar 

  • Stein M, Rappuoli R, Covacci A . (2000). Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci USA 97: 1263–1268.

    Article  CAS  Google Scholar 

  • Suzuki M, Mimuro H, Suzuki T, Park M, Yamamoto T, Sasakawa C . (2005). Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J Exp Med 202: 1235–1247.

    Article  CAS  Google Scholar 

  • Tomb JF, White O, Kerlavage AR, Clayton RA, Sutton GG, Fleischmann RD et al. (1997). The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388: 539–547.

    Article  CAS  Google Scholar 

  • Van Etten RA . (2003). c-Abl regulation: a tail of two lipids. Curr Biol 13: R608–R610.

    Article  CAS  Google Scholar 

  • Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP et al. (2004). Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 5: 1166–1174.

    Article  CAS  Google Scholar 

  • Wessler S, Hocker M, Fischer W, Wang TC, Rosewicz S, Haas R et al. (2000). Helicobacter pylori activates the histidine decarboxylase promoter through a mitogen-activated protein kinase pathway independent of pathogenicity island-encoded virulence factors. J Biol Chem 275: 3629–3636.

    Article  CAS  Google Scholar 

  • WHO. (1994). Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum 61: 1–241.

  • Woodring PJ, Litwack ED, O'Leary DD, Lucero GR, Wang JY, Hunter T . (2002). Modulation of the F-actin cytoskeleton by c-Abl tyrosine kinase in cell spreading and neurite extension. J Cell Biol 156: 879–892.

    Article  CAS  Google Scholar 

  • Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY et al. (1999). p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399: 814–817.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Novartis for providing STI571, Philippe Soriano for SYF and SYF + Src cells and Steffen Backert for discussing unpublished results.

Author information

Authors and Affiliations

  1. Junior Research Group, Paul-Ehrlich Institute, Langen, Germany

    M Poppe, G Römer & S Wessler

  2. Cancer Research UK, Weatherall Institute of Molecular Medicine, Oxford, UK

    S M Feller

Authors
  1. M Poppe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S M Feller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Römer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Wessler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Wessler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Poppe, M., Feller, S., Römer, G. et al. Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility. Oncogene 26, 3462–3472 (2007). https://doi.org/10.1038/sj.onc.1210139

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210139

Keywords

This article is cited by

Search

Advanced search

Quick links