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Identified virulence factors of Helicobacter: Type IV secretory protein


CagA (cytotoxin-associated antigen)  

Related genes: cagA;
Keywords: Type IV secretory protein;
Structure features:
Characterized by amino acid sequence polymorphism, primarily depending on the duplicaton of various numbers of a 34-amino-acid sequence located at the C-terminal region of the protein.
Glu-Pro-Ile-Tyr-Ala(EPIYA) motifs present in the C-terminal half of CagA is the tyrosine phosphorylation site.
Mechanism:
CagA injected by type IV secretion system into gastric epithelial cells and subsequently undergoes tyrosine phosphorylation by Src family kinase. The phosphorylated CagA specifically binds SHP-2 (Src homology 2 domain containing protein) phosphatase, activates the phosphatase activity, which, in turn might be responsible for dephosphorylation of several cellular proteins.
CagA interacts with hepatocyte growth factor/scatter factor (HGF/SF) receptor, c-MET. This interaction leads to deregulation of the motogenic response.
Non-phosphorylated CagA binds directly to Grb2 by its EPIYA motifs, and this interaction activates the stress-kinase pathway, resulting in the scatter phenotype.
Non-phosphorylated CagA associates with the epithelial tight-junction scaffolding protein, ZO-1, and the transmembrane protein junctional adhesion molecule (JAM) to induce the formation of an aberrant apical junction protein complex, which results in the loss of cell polarity, proliferation and differentiation..
CagA specifically interacts with PAR1 (partitioning-defective 1)/MARK (microtubule affinity-regulating kinase) kinase to disorganize gastric mucosal architecture underlying tissue damage and inflammation in vivo. Because normal epithelial architecture constrains cell proliferation, its disorganization by CagA may liberate cells from growth-inhibitory cues and thereby promote gastric carcinogenesis in conjunction with the phosphorylation dependent CagA activities..
H. pylori disrupts the polarity of epithelial cells to use the apical cell surface as a replicative niche. CagA's ability to disrupt host cell polarity is a key factor in enabling colonization of the apical cell surface by H. pylori.
References:
Segal ED, et al., 1999. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc. Natl. Acad. Sci. USA. 96(25):14559-14564.
Stein M, et al., 2000. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc. Natl. Acad. Sci. USA. 97(3):1263-1268.
Asahi M, et al., 2000. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J. Exp. Med. 191(4):593-602.
Odenbreit S, et al., 2000. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287(5457):1497-1500.
Backert S, et al., 2000. Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol. 2(2):155-164.
Higashi H, et al., 2002. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295(5555):683-686.
Selbach M, et al., 2002. Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J. Biol. Chem. 277(9):6775-6778.
Stein M, et al., 2002. c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol. Microbiol. 43(4):971-980.
Mimuro H, et al., 2002. Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol. Cell 10(4):745-755.
Hatakeyama M, 2003. Helicobacter pylori CagA--a potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins. Microbes Infect. 5(2):143-150.
Amieva MR, et al., 2003. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300(5624):1430-1434.
Saadat I, et al., 2007. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447(7142):330-333.
Tan S, et al., 2009. Helicobacter pylori usurps cell polarity to turn the cell surface into a replicative niche. PLoS Pathog. 5(5):e1000407.








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