SHP2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein

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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???
• Professor???
• 2002/10/01

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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 worlds population

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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

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How H. pylori survives in human stomach
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The secretion system of H. pylori injects CagA
into the host cell
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SH2 protein tyrosine phosphatase 2 (SHP-2)

• Cytoplasmic tyrosine phosphatase
• SH2src homology 2 domains
• binding to protein
• PTPprotein tyrosine phosphatase
• catalysis of protein tyrosine
  phosphorylation

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Results and discussion
WTwild type PRphosphorylation
resistance HAhemagglutinin tag Potential
tyrosine phosphorylation siteGlu-Pro-Ile-Tyr-Ala
(EPIYA)
Expression of CagA
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Hummingbird phenotype (growth-factor-like
phenotype)Hepatocyte growth factor
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Interaction between CagA and SHP-2
IPimmunoprecipitate
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MycMyc tag ?PD-Mycdel PTP domain ?SH2-Mycdel
SH2 domain
Interaction between CagA and SHP-2
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Model for activation and inhibition of SHP2
Activation of SHP-2 by CagA
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Role of SHP-2 induce hummingbird phenotype
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MyrMembrane-localization signal sequence
(myristoylation signal sequence of v-Src)
Role of SHP-2 induce hummingbird phenotype
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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 CagASHP-2 complex abolished
  the CagA-dependent cellular response.
• SHP-2 lack membrane-targeting signal sequence
  incapable induce cellular morphological change

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Thanks