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PMID: 16275761 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of experimental medicine ·Vol. 202 ·No. 9 ·2005-11-07 ·Pages 1235-47

Suzuki M, Mimuro H, Suzuki T, Park M, Yamamoto T, Sasakawa C

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing/physiology Animals Antigens, Bacterial/metabolism,physiology Bacterial Proteins/metabolism,physiology Cell Adhesion/immunology Cell Communication/immunology Cell Line, Tumor Dogs ErbB Receptors/physiology Gastric Mucosa/immunology,microbiology,pathology Helicobacter Infections/metabolism Helicobacter pylori/immunology Humans Phenotype Phosphoproteins/physiology Phosphorylation Proto-Oncogene Proteins c-crk/metabolism,physiology Proto-Oncogene Proteins c-met/physiology Signal Transduction/immunology Stomach Neoplasms/immunology,microbiology,pathology Wiskott-Aldrich Syndrome Protein Family/physiology
Chemicals
Adaptor Proteins, Signal Transducing Antigens, Bacterial Bacterial Proteins CRK protein, human GAB1 protein, human Phosphoproteins Proto-Oncogene Proteins c-crk WASF1 protein, human Wiskott-Aldrich Syndrome Protein Family cagA protein, Helicobacter pylori ErbB Receptors Proto-Oncogene Proteins c-met
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Suzuki Masato
Department of Microbiology and Immunology, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Japan.
Mimuro Hitomi
Suzuki Toshihiko
Park Morag
Yamamoto Tadashi
Sasakawa Chihiro
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20051027
Published
2005-11-07
Pages
1235-47
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2213224
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20051027 PMC Full Text View journal details
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