Disturbance of cell signaling by H. pylori CagA
| Project/Area Number |
16017201
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
HIGASHI Hideaki Hokkaido Univ., Inst. for Genetic Med., Asso., Prof, 病原性大腸菌, 助教授 (20311227)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2005: ¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 2004: ¥7,400,000 (Direct Cost: ¥7,400,000)
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| Keywords | Helicobacter pylori / gastric cancer / tyrosine phosphorylation / phosphatase / infection / transcriptional factor / 癌 / シグナル伝達 / 微生物 / ヘリコバクター・ピロリ |
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| Research Abstract |
1. Membrane association of CagA is important for the pathogenic action of CagA in gastric epithelial cells and requires the EPIYA motif but is independent of EPIYA tyrosine phosphorylation.
2. The activated SHP-2 with CagA directly dephosphorylates phospho-tyrosine residues of FAK, which are the activating phosphorylation sites. Accordingly, FAK activation is abolished in cells, and the inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA.
3. Induction of cell morphological change with CagA is due to the Ras-independent modification of Erk signals.
4. By screening of CagA-responsive genes using DNA microarray, we identified NFAT. CagA induced nuclear translocation and transcriptional activity of NFAT depending on calcineurin/PLCg pathway. Furthermore, H. pylori VacA toxin counteracted the ability of CagA to activate NFAT.
5. Using a series of EPIYA-repeat variants of CagA that represent reported variations in clinical isolates of H. pylori, we show that EPIYA-repeat polymorphism, which is due to differences of both number and order of EPIYA segment, influences the phosphorylation-dependent CagA biological activity.
6. We identified CagA multimerization motif that is composed of 16 amino acid residues and mediates an intermolecular interaction between CagA molecules. The CagA multimerization is necessary to express CagA biological activity that relates with cell morphogenetic activity and stimulation of cell motility.
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Report
(3 results)
Research Products
(38 results)
