Structural basis and functional consequence of Helicobacter pylori CagA multimerization in cells
Shumei Ren1, Hideaki Higashi, Huaisheng Lu
1Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
The Journal of Biological Chemistry
|September 7, 2006
Summary
Helicobacter pylori CagA protein multimerization, independent of phosphorylation, is essential for binding and deregulating SHP-2 phosphatase. Inhibiting CagA multimerization may prevent gastric cancer development.
Area of Science:
- Microbiology
- Cell Biology
- Oncology
Background:
- Helicobacter pylori CagA-positive strains are linked to gastric adenocarcinoma.
- CagA protein is delivered into gastric epithelial cells, localizing to the plasma membrane.
- Tyrosine phosphorylation of CagA at EPIYA repeats is crucial for its function.
Purpose of the Study:
- To investigate the role of CagA multimerization in its interaction with SHP-2 phosphatase.
- To identify the molecular mechanisms underlying CagA multimerization.
- To explore the potential of targeting CagA multimerization for cancer therapy.
Main Methods:
- Site-directed mutagenesis of CagA to create phosphorylation-resistant mutants.
- Analysis of CagA multimerization using various CagA mutants.
- Investigation of CagA-SHP-2 complex formation and SHP-2 deregulation.
Main Results:
- CagA multimerization occurs independently of tyrosine phosphorylation.
- A conserved motif (FPLXRXXXVXDLSKVG) mediates CagA multimerization.
- Phosphorylation-resistant, multimerizing CagA inhibits wild-type CagA-SHP-2 interaction and abolishes the hummingbird phenotype.
Conclusions:
- CagA multimerization is a prerequisite for CagA-SHP-2 interaction and SHP-2 deregulation.
- SHP-2 binds to preformed, tyrosine-phosphorylated CagA multimers.
- Inhibiting CagA multimerization could be a therapeutic strategy against CagA-driven gastric carcinogenesis.
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