Helicobacter exploits integrin for type IV secretion and kinase activation

Kwok T, Zabler D, Urman S, Rohde M, Hartig R, Wessler S, Misselwitz R, Berger J, Sewald N, Koenig W, Backert S (2007)
NATURE 449(7164): 862-866.

Journal Article | Published | English

No fulltext has been uploaded

; ; ; ; ; ; ; ; ; ;
Integrins are important mammalian receptors involved in normal cellular functions as well as pathogenesis of chronic inflammation and cancer. We propose that integrins are exploited by the gastric pathogen and type-1 carcinogen Helicobacter pylori for injection of the bacterial oncoprotein cytotoxin-associated gene A (CagA) into gastric epithelial cells. Virulent H. pylori express a type-IV secretion pilus that injects CagA into the host cell; CagA then becomes tyrosine-phosphorylated by Src family kinases. However, the identity of the host cell receptor involved in this process has remained unknown. Here we show that the H. pylori CagL protein is a specialized adhesin that is targeted to the pilus surface, where it binds to and activates integrin alpha(5)beta(1) receptor on gastric epithelial cells through an arginine-glycine-aspartate motif. This interaction triggers CagA delivery into target cells as well as activation of focal adhesion kinase and Src. Our findings provide insights into the role of integrins in H.-pylori-induced pathogenesis. CagL may be exploited as a new molecular tool for our further understanding of integrin signalling.
Publishing Year

Cite this

Kwok T, Zabler D, Urman S, et al. Helicobacter exploits integrin for type IV secretion and kinase activation. NATURE. 2007;449(7164):862-866.
Kwok, T., Zabler, D., Urman, S., Rohde, M., Hartig, R., Wessler, S., Misselwitz, R., et al. (2007). Helicobacter exploits integrin for type IV secretion and kinase activation. NATURE, 449(7164), 862-866.
Kwok, T., Zabler, D., Urman, S., Rohde, M., Hartig, R., Wessler, S., Misselwitz, R., Berger, J., Sewald, N., Koenig, W., et al. (2007). Helicobacter exploits integrin for type IV secretion and kinase activation. NATURE 449, 862-866.
Kwok, T., et al., 2007. Helicobacter exploits integrin for type IV secretion and kinase activation. NATURE, 449(7164), p 862-866.
T. Kwok, et al., “Helicobacter exploits integrin for type IV secretion and kinase activation”, NATURE, vol. 449, 2007, pp. 862-866.
Kwok, T., Zabler, D., Urman, S., Rohde, M., Hartig, R., Wessler, S., Misselwitz, R., Berger, J., Sewald, N., Koenig, W., Backert, S.: Helicobacter exploits integrin for type IV secretion and kinase activation. NATURE. 449, 862-866 (2007).
Kwok, Terry, Zabler, Dana, Urman, Sylwia, Rohde, Manfred, Hartig, Roland, Wessler, Silja, Misselwitz, Rolf, Berger, Juergen, Sewald, Norbert, Koenig, Wolfgang, and Backert, Steffen. “Helicobacter exploits integrin for type IV secretion and kinase activation”. NATURE 449.7164 (2007): 862-866.
This data publication is cited in the following publications:
This publication cites the following data publications:

217 Citations in Europe PMC

Data provided by Europe PubMed Central.

Dynamic interplay between adhesion surfaces in carcinomas: Cell-cell and cell-matrix crosstalk.
Smith YE, Vellanki SH, Hopkins AM., World J Biol Chem 7(1), 2016
PMID: 26981196
Molecular and Structural Analysis of the Helicobacter pylori cag Type IV Secretion System Core Complex.
Frick-Cheng AE, Pyburn TM, Voss BJ, McDonald WH, Ohi MD, Cover TL., MBio 7(1), 2016
PMID: 26758182
H. pylori-Induced DNA Strand Breaks Are Introduced by Nucleotide Excision Repair Endonucleases and Promote NF-κB Target Gene Expression.
Hartung ML, Gruber DC, Koch KN, Gruter L, Rehrauer H, Tegtmeyer N, Backert S, Muller A., Cell Rep 13(1), 2015
PMID: 26411687
Helicobacter pylori virulence factors in development of gastric carcinoma.
Wang MY, Liu XF, Gao XZ., Future Microbiol 10(9), 2015
PMID: 26346770
CagA of Helicobacter pylori interacts with and inhibits the serine-threonine kinase PRK2.
Mishra JP, Cohen D, Zamperone A, Nesic D, Muesch A, Stein M., Cell. Microbiol. 17(11), 2015
PMID: 26041307
Crystal structure of CagL from Helicobacter pylori K74 strain.
Choi JM, Choi YH, Sudhanva MS, Devakumar S, Lee KH, Cha JH, Lee SH., Biochem. Biophys. Res. Commun. 460(4), 2015
PMID: 25839651
Epithelial cell ADAM17 activation by Helicobacter pylori: role of ADAM17 C-terminus and Threonine-735 phosphorylation.
McClurg UL, Danjo K, King HO, Scott GB, Robinson PA, Crabtree JE., Microbes Infect. 17(3), 2015
PMID: 25499189
Clinical relevance of cagL gene and virulence genotypes with disease outcomes in a Helicobacter pylori infected population from Iran.
Yadegar A, Mobarez AM, Alebouyeh M, Mirzaei T, Kwok T, Zali MR., World J. Microbiol. Biotechnol. 30(9), 2014
PMID: 24854336
Helicobacter pylori CagA tertiary structure reveals functional insights.
Backert S, Tegtmeyer N., Cell Host Microbe 12(1), 2012
PMID: 22817982

24 References

Data provided by Europe PubMed Central.

Integrin-regulated FAK-Src signaling in normal and cancer cells.
Mitra SK, Schlaepfer DD., Curr. Opin. Cell Biol. 18(5), 2006
PMID: 16919435
RGD and other recognition sequences for integrins.
Ruoslahti E., Annu. Rev. Cell Dev. Biol. 12(), 1996
PMID: 8970741

Binding and internalization of microorganisms by integrin receptors.
Isberg RR, Tran Van Nhieu G., Trends Microbiol. 2(1), 1994
PMID: 8162429
Bacterial pathogenesis: exploiting cellular adherence.
Boyle EC, Finlay BB., Curr. Opin. Cell Biol. 15(5), 2003
PMID: 14519399

Cascales, Nature Rev. Microbiol. 1(), 2003
Type IV secretion systems and their effectors in bacterial pathogenesis.
Backert S, Meyer TF., Curr. Opin. Microbiol. 9(2), 2006
PMID: 16529981

Amieva, Science 300(), 2004

Peek, Nature Rev. Cancer 2(), 2002
Tyrosine-phosphorylated bacterial proteins: Trojan horses for the host cell.
Covacci A, Rappuoli R., J. Exp. Med. 191(4), 2000
PMID: 10684850
The role of Helicobacter pylori CagA in gastric carcinogenesis.
Hatakeyama M., Int. J. Hematol. 84(4), 2006
PMID: 17118755
Beta 1 integrin-dependent and -independent polymerization of fibronectin.
Wennerberg K, Lohikangas L, Gullberg D, Pfaff M, Johansson S, Fassler R., J. Cell Biol. 132(1-2), 1996
PMID: 8567726
A novel sheathed surface organelle of the Helicobacter pylori cag type IV secretion system.
Rohde M, Puls J, Buhrdorf R, Fischer W, Haas R., Mol. Microbiol. 49(1), 2003
PMID: 12823823
Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation.
Mahdavi J, Sonden B, Hurtig M, Olfat FO, Forsberg L, Roche N, Angstrom J, Larsson T, Teneberg S, Karlsson KA, Altraja S, Wadstrom T, Kersulyte D, Berg DE, Dubois A, Petersson C, Magnusson KE, Norberg T, Lindh F, Lundskog BB, Arnqvist A, Hammarstrom L, Boren T., Science 297(5581), 2002
PMID: 12142529
Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.
Aspholm-Hurtig M, Dailide G, Lahmann M, Kalia A, Ilver D, Roche N, Vikstrom S, Sjostrom R, Linden S, Backstrom A, Lundberg C, Arnqvist A, Mahdavi J, Nilsson UJ, Velapatino B, Gilman RH, Gerhard M, Alarcon T, Lopez-Brea M, Nakazawa T, Fox JG, Correa P, Dominguez-Bello MG, Perez-Perez GI, Blaser MJ, Normark S, Carlstedt I, Oscarson S, Teneberg S, Berg DE, Boren T., Science 305(5683), 2004
PMID: 15273394
Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin.
Papini E, Satin B, Norais N, de Bernard M, Telford JL, Rappuoli R, Montecucco C., J. Clin. Invest. 102(4), 1998
PMID: 9710450
Specific entry of Helicobacter pylori into cultured gastric epithelial cells via a zipper-like mechanism.
Kwok T, Backert S, Schwarz H, Berger J, Meyer TF., Infect. Immun. 70(4), 2002
PMID: 11895977
Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo.
Selbach M, Moese S, Hauck CR, Meyer TF, Backert S., J. Biol. Chem. 277(9), 2002
PMID: 11788577
Integrin alpha5beta1 ligands: biological evaluation and conformational analysis.
Zimmermann D, Guthohrlein EW, Malesevic M, Sewald K, Wobbe L, Heggemann C, Sewald N., Chembiochem 6(2), 2005
PMID: 15645521


0 Marked Publications

Open Data PUB

Web of Science

View record in Web of Science®


PMID: 17943123
PubMed | Europe PMC

Search this title in

Google Scholar