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

ABSTRACT 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, Sep 29, 2015
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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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    ABSTRACT: H. pylori is a major etiological agent in the development of various gastro-duodenal diseases. Its persistence in gastric mucosa is determined by the interaction between various host, microbial and environmental factors. The bacteria colonizes the gastric epithelium and induces activation of various chemokine mediators, including NFKB, the master regulator of inflammation. H. pylori infection is also associated with an increase in expression of cell cycle regulators thereby leading to mucosal cell hyper proliferation. Thus, H. pylori-associated infections manifest activation of key host response events, which inadvertently could lead to the establishment of chronic infection and neoplastic progression. This article reviews and elaborates the current knowledge in H. pylori induced activation of various host signaling pathways that could promote cancer development. Special focus is placed on the inflammatory and proliferative responses that could serve as suitable biomarkers of infection, since a sustained cell proliferation in an environment rich in inflammatory cells is characteristic in H. pylori-associated gastric malignancies. Here, the role of ERK and WNT signaling in H. pylori-induced activation of inflammatory and proliferative responses respectively is discussed in detail. An in depth analysis of the underlying signaling pathways and interacting partners causing alterations in these crucial host responses could contribute to the development of successful therapeutic strategies for the prevention, management and treatment of H. pylori infection.
    Microbiology 02/2015; 161(6). DOI:10.1099/mic.0.000066 · 2.56 Impact Factor
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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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    ABSTRACT: Short linear motifs (SLiMs) are functional stretches of protein sequence that are of crucial importance for numerous biological processes by mediating protein-protein interactions. These motifs often comprise peptides of less than 10 amino acids that modulate protein-protein interactions. While well-characterized in eukaryotic intracellular signaling, their role in prokaryotic signaling is less well-understood. We surveyed the distribution of known motifs in prokaryotic extracellular and virulence proteins across a range of bacterial species and conducted searches for novel motifs in virulence proteins. Many known motifs in virulence effector proteins mimic eukaryotic motifs and enable the pathogen to control the intracellular processes of their hosts. Novel motifs were detected by finding those that had evolved independently in three or more unrelated virulence proteins. The search returned several significantly over-represented linear motifs of which some were known motifs and others are novel candidates with potential roles in bacterial pathogenesis. A putative C-terminal G[AG].$ motif found in type IV secretion system proteins was among the most significant detected. A KK$ motif that has been previously identified in a plasminogen-binding protein, was demonstrated to be enriched across a number of adhesion and lipoproteins. While there is some potential to develop peptide drugs against bacterial infection based on bacterial peptides that mimic host components, this could have unwanted effects on host signaling. Thus, novel SLiMs in virulence factors that do not mimic host components but are crucial for bacterial pathogenesis, such as the type IV secretion system, may be more useful to develop as leads for anti-microbial peptides or drugs.
    Frontiers in Microbiology 01/2014; 5:4. DOI:10.3389/fmicb.2014.00004 · 3.99 Impact Factor
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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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    ABSTRACT: Background and Aims:The Helicobacter pylori CagA gene is a major virulence factor that plays an important role in gastric pathologies. The size variation of CagA gene, which is dependent on the 3’ repeat region, contains one or more Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs and CagA multimerization (CM) motifs. Four segments flanking the EPIYA motifs, EPIYA −A, −B, −C, or −D, were reported to play a crucial role in the pathogenesis of H. pylori infection. The aim was to determine the roles of EPIYA segments and CM motifs in gastroduodenal pathogenesis in an Iraqi population.Patients and Methods:Gastric biopsies were collected from 210 patients with gastritis, duodenal ulcer (DU), gastric ulcer (GU), and gastric cancer (GC). The EPIYA motif genotyping was determined by polymerase chain reaction and sequencing. The differences in age, gender, and CagA EPIYA motifs of H. pylori between GC, DU, GU and gastritis patients were analyzed using a χ2 -test.ResultsA total of 22 (45.8%) strains had three copies of EPIYA (ABC type), 2 (4.16%) had four copies (ABCC type), 6 (12.7%) had five copies (ABCCC type), 13 (27.08%) had two copies (AB type), 3 (6.25%) had the BC, and 2 (4.17%) had AC motif. The alignment of the deduced protein sequences confirmed that there were no East Asian type EPIYA-D sequences in Iraqi strains. A significant association was found between increase in number of EPIYA-C motifs and GU (P ≤ 0.01) compared with gastritis.Conclusions:The structure of the 3’ region of the CagA gene in Iraqi strains was Western type with a variable number of EPIYA-C and CM motifs. A significant association was found between increase in number of EPIYA-C motifs and GU compared with gastritis indicating predictive association with the severity of the disease. The GenBank accession numbers for the partial CagA nucleotide sequences determined in this study are JX164093-JX164112.
    Saudi Journal of Gastroenterology 03/2013; 19(2):69-74. DOI:10.4103/1319-3767.108474 · 1.12 Impact Factor
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