Helicobacter pylori CagA Phosphorylation-Independent Function in Epithelial Proliferation and Inflammation

Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Cell host & microbe (Impact Factor: 12.33). 02/2009; 5(1):23-34. DOI: 10.1016/j.chom.2008.11.010
Source: PubMed


CagA, a major virulence factor of Helicobacter pylori (Hp), is delivered into gastric epithelial cells and exists in phosphorylated and nonphosphorylated forms. The biological activity of the phosphorylated form is well established; however, function(s) of the nonphosphorylated form remain elusive. Here, we report that a conserved motif in the C-terminal region of CagA, which is distinct from the EPIYA motifs used for phosphorylation and which we designate CRPIA (conserved repeat responsible for phosphorylation-independent activity), plays pivotal roles in Hp pathogenesis. The CRPIA motif in nonphosphorylated CagA was involved in interacting with activated Met, the hepatocyte growth factor receptor, leading to the sustained activation of phosphatidylinositol 3-kinase/Akt signaling in response to Hp infection. This in turn led to the activation of beta-catenin and NF-kappaB signaling, which promote proliferation and inflammation, respectively. Thus, nonphosphorylated CagA activity contributes to the epithelial proliferative and proinflammatory responses associated with development of chronic gastritis and gastric cancer.

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Available from: Masato Suzuki
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    • "Intriguingly, in vitro studies with cagA positive strains exhibited a pro-proliferative effect compared with the cagA negative strains (Smoot et al., 1999). This effect of CagA in cell proliferation, together with its contribution to inflammation, may explain in part the stronger association of cagA positive strains with gastric cancer (Cabral et al., 2007; Suzuki et al., 2009). "
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    • "∧ DE]((K[KR])|(RK))(([ ∧ DE][KR]) |(KR][ ∧ DE]))[ ∧ DE], [ ∧ DE]((K[RK])|(RK))(([ ∧ DE][KR])|([KR][ ∧ DE]))(([PKR]) |([ ∧ DE][DE])), (([PKR].{0,1}[ ∧ DE])|([PKR]))((K[RK])|(RK)) (([ ∧ DE][KR])|([KR][ ∧ DE]))[ ∧ DE] Nuclear localization signal (NLS) motifs Szurek et al., 2002; Deslandes et al., 2003; Dean, 2011; Dinkel et al., 2012 CagA, Tarp, AnkA, LspA E[PNS][IV]Y[AEG] Membrane targeting/phosphorylation motif Higashi et al., 2005; Suzuki et al., 2009; Hayashi et al., 2013 SspH2, "
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    • "The severity of disease outcome could be attributed to possession of the Cag pathogenicity island, which encodes a type IV secretion system that facilitates translocation of the CagA protein.[6] After the delivery, some CagA protein are rapidly tyrosine-phosphorylated on specific tyrosine residues within repeating Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs and interacts with various target molecules, such as phosphorylated, CagA binds to a cytoplasmic Src Homology 2 (SH2) domain of Src Homology 2 phosphatase (SHP-2).[2] Because CagA-SHP-2 complexes disrupt signal transduction pathways of the cell, the complexes may be involved in the development of atrophic gastritis and the transition from atrophy to intestinal metaplasia.[7] Unphosphorylated CagA on these dephosphorylation also contribute to the development of H. pylori associated gastric diseases, including GC. El-Etr, et al,[8] reported that a conserved motif in the C-terminal region of CagA, distinct from the EPIYA motifs designated CRPIA (conserved repeat responsible for phosphorylation-independent activity) or called CagA multimerization (CM) motifs play a vital role in H. pylori pathogenesis. "
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