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SHP-2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein

SHP-2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein. Hideaki Higashi, Ryouhei Tsutsumi, Syuichi Muto,Toshiro Sugiyama, Takeshi Azuma, Masahiro Asaka, Masanori Hatakeyama Science , Vol. 295, 683-686, January 25, 2002 Speaker ：林智健 Professor ：吳夙欽

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SHP-2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein

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  1. SHP-2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein Hideaki Higashi, Ryouhei Tsutsumi, Syuichi Muto,Toshiro Sugiyama, Takeshi Azuma, Masahiro Asaka, Masanori Hatakeyama Science, Vol. 295, 683-686, January 25, 2002 Speaker：林智健 Professor：吳夙欽 2002/10/01

  2. Introduction Helicobacter pylori (H. pylori) • Gram-negative bacterium • Cause chronic gastritis and gastroduodenal ulcers • Associate with the gastric cancer and MALT lymphoma • Infection half of the world’s population

  3. Cytotoxin associated gene A (CagA) • 128 ~ 145 kDa protein • Signal the nucleus to release I L-8 • Inject into host cell by type IV secretion system • Tyrosine phosphorylation in host cell • High immunogenicity

  4. How H. pylori survives in human stomach

  5. The secretion system of H. pylori injects CagA into the host cell

  6. SH2 protein tyrosine phosphatase 2 (SHP-2) • Cytoplasmic tyrosine phosphatase • SH2：src homology 2 domains binding to protein • PTP：protein tyrosine phosphatase catalysis of protein tyrosine phosphorylation

  7. Results and discussion WT：wild type PR：phosphorylation resistance HA：hemagglutinin tag Potential tyrosine phosphorylation site：Glu-Pro-Ile-Tyr-Ala (EPIYA) Expression of CagA

  8. Hummingbird phenotype (growth-factor-like phenotype)Hepatocyte growth factor

  9. Interaction between CagA and SHP-2 IP：immunoprecipitate

  10. Myc：Myc tag ∆PD-Myc：del PTP domain ∆SH2-Myc：del SH2 domain Interaction between CagA and SHP-2

  11. Model for activation and inhibition of SHP2 Activation of SHP-2 by CagA

  12. Role of SHP-2 induce hummingbird phenotype

  13. Myr：Membrane-localization signal sequence (myristoylation signal sequence of v-Src) Role of SHP-2 induce hummingbird phenotype

  14. Conclusion • Wild-Type CagA induce a growth factor-like response (hummingbird phenotype) but tyrosine-phosphorylation resistance CagA • CagA formed a physical complex with SH2 domain of SHP-2 protein • Disruption of the CagA–SHP-2 complex abolished the CagA-dependent cellular response. • SHP-2 lack membrane-targeting signal sequence incapable induce cellular morphological change

  15. Thanks

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