The Journal of Experimental Medicine
Avanti Polar Lipids
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Published 7 November 2005. doi:10.1084/jem.20051027
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 9, 1235-1247
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ARTICLE

 Interaction of CagA with Crk plays an important role in Helicobacter pylori–induced loss of gastric epithelial cell adhesion

Masato Suzuki1, Hitomi Mimuro1, Toshihiko Suzuki1, Morag Park4, Tadashi Yamamoto2, and Chihiro Sasakawa1,3,5

1 Department of Microbiology and Immunology, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
2 Department of Cancer Biology, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
3 Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
4 Molecular Oncology Group, McGill University Hospital Center, McGill University, Montreal, Quebec H3A 1A1, Canada
5 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi-shi, Saitama 332-0012, Japan

CORRESPONDENCE Chihiro Sasakawa: sasakawa{at}ims.u-tokyo.ac.jp

CagA protein is a major virulence factor of Helicobacter pylori, which is delivered into gastric epithelial cells and elicits growth factor–like responses. Once within the cells, CagA is tyrosine phosphorylated by Src family kinases and targets host proteins required to induce the cell responses. We show that the phosphorylated CagA binds Crk adaptor proteins (Crk-II, Crk-I, and Crk-L) and that the interaction is important for the CagA-mediated host responses during H. pylori infection. H. pylori–induced scattering of gastric epithelial cells in culture was blocked by overexpression of dominant-negative Crk and by RNA interference–mediated knockdown of endogenous Crk. H. pylori infection of the gastric epithelium induced disruption of E-cadherin/catenin–containing adherens junctions, which was also dependent on CagA/Crk signaling. Furthermore, inhibition of the SoS1/H-Ras/Raf1, C3G/Rap1/B-Raf, or Dock180/Rac1/Wiskott-Aldrich syndrome protein family verprolin homologous protein pathway, all of which are involved downstream of Crk adaptors, greatly diminished the CagA-associated host responses. Thus, CagA targeting of Crk plays a central role in inducing the pleiotropic cell responses to H. pylori infection that cause several gastric diseases, including gastric cancer.

Abbreviations used: ADPRT, ADP-ribosyl transferase; AJ, adherens junction; CrkR, RNAi-resistant Crk; EGFR, epidermal growth factor; EL, E-cadherin–expressing L; ERK, extracellular signal–regulated kinase; FAK, focal adhesion kinase; FRNK, FAK-related nonkinase; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GST, glutathione S-transferase; HGF, hepatocyte growth factor; MAPK, mitogen-activated protein kinase; MDCK, Madin-Darby canine kidney; MEK, MAPK/ERK-kinase; MOI, multiplicity of infection; N-WASP, neural Wiskott- Aldrich syndrome protein; pAb, polyclonal antibody; PI3K, phosphatidylinositol 3–kinase; PRR, proline-rich region; pY, tyrosine phosphorylated; RNAi, RNA interference; RTK, receptor tyrosine kinase; SFK, Src family kinase; SH, Src homology; SHP-2, SH2-containing protein tyrosine phosphatase–2; siRNA, small interfering RNA; TCF, T cell factor; TJ, tight junction; WAVE, Wiskott- Aldrich syndrome protein family verprolin homologous protein; ZO-1, zonula occludens–1.


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