title: Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion.
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.
authors.affiliation: Department of Microbiology and Immunology, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hitomi
authors.initials: H
authors.lastname: Mimuro
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Suzuki
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sasakawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism / Q000502:physiology*; D001426:Bacterial Proteins / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D004285:Dogs; D066246:ErbB Receptors / Q000502:physiology; D005753:Gastric Mucosa / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori / Q000276:immunology*; D006801:Humans; D010641:Phenotype; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013274:Stomach Neoplasms / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C485285:CRK protein, human; C098587:GAB1 protein, human; D010750:Phosphoproteins; D050737:Proto-Oncogene Proteins c-crk; C114864:WASF1 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; C080866:cagA protein, Helicobacter pylori; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met