Abstract
Gastric carcinoma is the second most common cause of cancer-related deaths in the world, accounting for more than 400,000 deaths each year. Infection with cagA-positive Helicobacter pylori plays a pivotal role in the development of gastric adenocarcinoma. The cagA gene product CagA is directly delivered into gastric epithelial cells via the type IV secretion system. Following membrane localization and subsequent tyrosine phosphorylation by Src family kinases, CagA interacts with a variety of host cell proteins that are involved in the regulation of cell growth and motility in both phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SH2 domain-containing tyrosine phosphatase SHP-2, gain-of-function mutations of which have recently been found in human malignancies. CagA binds to and activates SHP-2 in a tyrosine phosphorylation-dependent manner, thereby provoking abnormal activation of Erk MAP kinase while inducing elevated cell motility. Perturbation of SHP-2 and other signaling molecules by H pylori CagA may predispose cells to accumulate multiple genetic and epigenetic changes that promote multistep gastric carcinogenesis. Intriguingly, the structural polymorphism of CagA accounts for the differences in pathophysiological activity of individual CagA proteins, raising the possibility of subclassification of H pylori strains into benign and malignant strains.
Similar content being viewed by others
References
Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000: the global picture. Eur J Cancer. 2001;37:S4-S66.
Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402–405.
Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991; 325:1132–1136.
Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori and the risk of gastric carcinoma. N Engl J Med. 1991;325:1127–1131.
Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784–789.
Covacci A, Censini S, Bugnoli M, et al. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci U S A. 1993;90:5791–5795.
Tummuru MK, Cover TL, Blaser MJ. Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect Immun. 1993;61:1799–1809.
Censini S, Lange C, Xiang Z, et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci U S A. 1996;93:14648–14653.
Akopyants NS, Clifton SW, Kersulyte D, et al. Analyses of the cag pathogenicity island of Helicobacter pylori. Mol Microbiol. 1998;28:37–53.
Blaser MJ, Perez-Perez GI, Kleanthous H, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res. 1995;55:2111–2115.
Kuipers EJ, Perez-Perez GI, Meuwissen SG, Blaser MJ. Helicobacter pylori and atrophic gastritis: importance of the cagA status. J Natl Cancer Inst. 1995;87:1777–1780.
Parsonnet J, Friedman GD, Orentreich N, Vogelman H. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut. 1997;40:297–301.
Segal ED, Cha J, Lo J, Falkow S, Tompkins LS. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci U S A. 1999;96:14559–14564.
Asahi M, Azuma T, Ito S, et al. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med. 2000;191:593–602.
Backert S, Ziska E, Brinkmann V, et al. Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol. 2000;2:155–164.
Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science. 2000;287:1497–1500.
Stein M, Rappuoli R, Covacci A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci U S A. 2000;97:1263–1268.
Selbach M, Moese S, Hauck CR, Meyer TF, Backert S. Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J Biol Chem. 2002;277:6775–6778.
Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A. c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol. 2002;43:971–980.
Higashi H, Tsutsumi R, Muto S, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science. 2002;295:683–686.
Higashi H, Tsutsumi R, Fujita A, et al. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci U S A. 2002;99:14428–14433.
Higashi H,Yokoyama K, Fujii Y, et al. EPIYA motif is a membrane targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells. J Biol Chem. 2005;280:23130–23137.
Yamazaki S, Yamakawa A, Ito Y, et al. The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. J Infect Dis. 2003;187:334–337.
Hof P, Pluskey S, Dhe-Paganon S, Ech MJ, Shoelson SE. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998;92:441–450.
Naito M, Yamazaki T, Tsutsumi R, et al. Influence of EPIYA- repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology. 2006;130:1181–1190.
Neel BG, Gu H, Pao L. The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28:284–293.
Higashi H, Nakaya A, Tsutsumi R, et al. Helicobacter pylori CagA provokes Ras-independent morphogenetic response through targeting SHP-2. J Biol Chem. 2004;279:17205–17216.
Higuchi M, Tsutsumi R, Higashi H, Hatakeyama M. Conditional gene silencing utilizing the lac repressor reveals a role of SHP-2 in cagA-positive Helicobacter pylori pathogenicity. Cancer Sci. 2004;95:442–447.
Tsutsumi R, Takahashi A, Azuma T, Higashi H, Hatakeyama M. FAK is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. Mol Cell Biol. 2006;26:261–276.
Roovers K, Assoian RK. Integrating the MAP kinase signal into the G1 phase cell cycle machinery. Bioessays. 2000;22:818–826.
Tsutsumi R, Higashi H, Higuchi M, Okada M, Hatakeyama M. Attenuation of Helicobacter pylori CagA-SHP-2 signaling by interaction between CagA and C-terminal Src Kinase. J Biol Chem. 2003;278:3664–3670.
Hatakeyama M. Oncogenic mechanisms of Helicobacter pylori CagA protein. Nat Rev Cancer. 2004;4:688–694.
Hatakeyama M. Helicobacter pylori CagA: a potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins. Microbes Infect. 2003;5:143–150.
Mimuro H, Suzuki T,Tanaka J,Asahi M, Haas R, Sasakawa C. Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol Cell. 2002;10:745–755.
Churin Y, Al-Ghoul L, Kepp O, Meyer TF, Birchmeier W, Naumann M. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol. 2003;161:249–255.
Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 2003;300:1430–1434.
Bagnoli F, Buti L,Tompkins L, Covacci A, Amieva MR. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci U S A. 2005;102:16339–16344.
Franco AT, Israel DA, Washington MK, et al. Activation of β- catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci U S A. 2005;102:10646–10651.
Hirata Y, Maeda S, Mitsuno Y, et al. Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation. Gastroenterology. 2002;123:1962–1971.
Brandt S, Kwok T, Hartig R, Konig W, Backert S. NF-κB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc Natl Acad Sci U S A. 2005; 102:9300–9305.
Yokoyama K, Higashi H, Ishikawa S, et al. Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc Natl Acad Sci U S A. 2005;102:9661–9666.
Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34:148–150.
Bentires-Alj M, Paez JG, David FS, et al. Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 2004;64:8816–8820.
Correa P. Human gastric pathogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52:6735- 6740.
Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306:1568–1571.
Azuma T, Yamazaki S, Yamakawa A, et al. Association between diversity in the Src homology 2 domain-containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer. J Infect Dis. 2004;189:820–827.
Azuma T, Ohtani M, Yamazaki Y, Higashi H, Hatakeyama M. Meta-analysis of the relationship between CagA seropositivity and gastric cancer. Gastroenterology. 2004;126:1926–1927.
Argent RH, Kidd M, Owen RJ,Thomas RJ, Limb MC,Atherton JC. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. Gastroenterology. 2004;127:514–523.
Goto Y, Ando T, Yamamoto K, et al. Association between serum pepsinogens and polymorphisms of PTPN11 encoding SHP-2 among Helicobacter pylori seropositive Japanese. Int J Cancer. 2006;118:203–208.
Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA. 2004;291:187–194.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Hatakeyama, M. The Role of Helicobacter pylori CagA in Gastric Carcinogenesis. Int J Hematol 84, 301–308 (2006). https://doi.org/10.1532/IJH97.06166
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1532/IJH97.06166