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.

  • Letter
  • Published:

Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity

Abstract

Helicobacter pylori cagA-positive strains are associated with gastritis, ulcerations and gastric adenocarcinoma1. CagA is delivered into gastric epithelial cells2 and, on tyrosine phosphorylation, specifically binds and activates the SHP2 oncoprotein3,4,5,6,7, thereby inducing the formation of an elongated cell shape known as the ‘hummingbird’ phenotype2,3. In polarized epithelial cells, CagA also disrupts the tight junction and causes loss of apical–basolateral polarity8,9. We show here that H. pylori CagA specifically interacts with PAR1/MARK kinase, which has an essential role in epithelial cell polarity10,11. Association of CagA inhibits PAR1 kinase activity and prevents atypical protein kinase C (aPKC)-mediated PAR1 phosphorylation, which dissociates PAR1 from the membrane12,13, collectively causing junctional and polarity defects. Because of the multimeric nature of PAR1 (ref. 14), PAR1 also promotes CagA multimerization, which stabilizes the CagA–SHP2 interaction15. Furthermore, induction of the hummingbird phenotype by CagA-activated SHP2 requires simultaneous inhibition of PAR1 kinase activity by CagA. Thus, the CagA–PAR1 interaction not only elicits the junctional and polarity defects but also promotes the morphogenetic activity of CagA. Our findings revealed that PAR1 is a key target of H. pylori CagA in the disorganization of gastric epithelial architecture underlying mucosal damage, inflammation and carcinogenesis.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Disruption of the tight junction by CagA mutants.
Figure 2: Interaction of CagA with PAR1.
Figure 3: Inhibition of PAR1 kinase by CagA.
Figure 4: Role of PAR1 in the biological activities of CagA.

Similar content being viewed by others

References

  1. Peek, R. M. & Blaser, M. J. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nature Rev. Cancer 2, 28– 37 (2002)

    Article  CAS  Google Scholar 

  2. Segal, E. D., Cha, J., Lo, J., Falkow, S. & Tompkins, L. S. 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 (1999)

    Article  ADS  CAS  Google Scholar 

  3. Higashi, H. et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295, 683– 686 (2002)

    Article  ADS  CAS  Google Scholar 

  4. Higashi, H. 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 99, 14428– 14433 (2002)

    Article  ADS  CAS  Google Scholar 

  5. Hatakeyama, M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nature Rev. Cancer 4, 688– 694 (2004)

    Article  CAS  Google Scholar 

  6. Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genet. 34, 148– 150 (2003)

    Article  CAS  Google Scholar 

  7. Bentires-Alj, M. et al. Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 64, 8816– 8820 (2004)

    Article  CAS  Google Scholar 

  8. Amieva, M. R. et al. Disruption of the epithelial apical–junctional complex by Helicobacter pylori CagA. Science 300, 1430– 1434 (2003)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  10. Macara, I. G. Parsing the polarity code. Nature Rev. Mol. Cell Biol. 5, 220– 231 (2004)

    Article  CAS  Google Scholar 

  11. Suzuki, A. & Ohno, S. The PAR–aPKC system: lessons in polarity. J. Cell Sci. 119, 979– 987 (2006)

    Article  CAS  Google Scholar 

  12. Suzuki, A. et al. aPKC acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity. Curr. Biol. 14, 1425– 1435 (2004)

    Article  CAS  Google Scholar 

  13. Hurov, J. B., Watkins, J. L. & Piwnica-Worms, H. Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Curr. Biol. 14, 736– 741 (2004)

    Article  CAS  Google Scholar 

  14. Panneerselvam, S., Marx, A., Mandelkow, E. M. & Mandelkow, E. Structure of the catalytic and ubiquitin-associated domains of the protein kinase MARK/PAR-1. Structure 14, 173– 183 (2006)

    Article  CAS  Google Scholar 

  15. Ren, S., Higashi, H., Lu, H., Azuma, T. & Hatakeyama, M. Structural basis and functional consequence of Helicobacter pylori CagA multimerization in cells. J. Biol. Chem. 281, 32344– 32352 (2006)

    Article  CAS  Google Scholar 

  16. Shin, K., Fogg, V. C. & Margolis, B. Tight junctions and cell polarity. Annu. Rev. Cell Dev. Biol. 22, 207– 235 (2006)

    Article  CAS  Google Scholar 

  17. Noach, L. A., Rolf, T. M. & Tytgat, G. N. Electron microscopic study of association between Helicobacter pylori and gastric and duodenal mucosa. J. Clin. Pathol. 47, 699– 704 (1994)

    Article  CAS  Google Scholar 

  18. Higashi, H. et al. EPIYA motif is a membrane-targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells. J. Biol. Chem. 280, 23130– 23137 (2005)

    Article  CAS  Google Scholar 

  19. Drewes, G. et al. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89, 297– 308 (1997)

    Article  CAS  Google Scholar 

  20. Kemphues, K. J., Priess, J. R., Morton, D. G. & Cheng, N. S. Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311– 320 (1988)

    Article  CAS  Google Scholar 

  21. Watts, J. L. et al. par-6, a gene involved in the establishment of asymmetry in early C. elegans embryos, mediates the asymmetric localization of PAR-3. Development 122, 3133– 3140 (1996)

    CAS  PubMed  Google Scholar 

  22. Bohm, H., Brinkmann, V., Drab, M., Henske, A. & Kurzchalia, T. V. Mammalian homologues of C. elegans PAR-1 are asymmetrically localized in epithelial cells and may influence their polarity. Curr. Biol. 7, 603– 606 (1997)

    Article  CAS  Google Scholar 

  23. Cohen, D., Brennwald, P. J., Rodriguez-Boulan, E. & Müsch, A. Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton. J. Cell Biol. 164, 717– 727 (2004)

    Article  CAS  Google Scholar 

  24. Mimuro, H. et al. Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol. Cell 10, 745– 755 (2002)

    Article  CAS  Google Scholar 

  25. Churin, Y. et al. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J. Cell Biol. 161, 249– 255 (2003)

    Article  CAS  Google Scholar 

  26. Suzuki, M. et al. 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 (2005)

    Article  CAS  Google Scholar 

  27. Timm, T. et al. MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1. EMBO J. 22, 5090– 5101 (2003)

    Article  CAS  Google Scholar 

  28. Bilder, D. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 18, 1909– 1925 (2004)

    Article  CAS  Google Scholar 

  29. Lizcano, J. M. et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 23, 833– 843 (2004)

    Article  CAS  Google Scholar 

  30. Jenne, D. E. et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nature Genet. 18, 38– 43 (1998)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Blenis, A. Toker, A. Harada and G. Drewes for cDNAs, G. K. Ojakian for antibody and K. Kikuchi for help. I.S. was supported by the Iranian Ministry of Science. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and by a research grant from Takeda Science Foundation (M.H.).

Author Contributions I.S., H.H., C.O., M.U., N.M-K., Y.S., H.L., N.O. and T.A. performed biochemical and cell biological experiments and analysed data; T.A., A.S. and S.O. generated reagents and contributed to experimental design; and I.S. and M.H. designed experiments and wrote the paper. All authors discussed the results and commented on the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Masanori Hatakeyama.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-13, Supplementary Table 1 and additional references. (PDF 4882 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saadat, I., Higashi, H., Obuse, C. et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447, 330–333 (2007). https://doi.org/10.1038/nature05765

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05765

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing