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, , January 25, 2002 Speaker ：林智健 Professor ：吳夙欽 2002/10/01

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 Introduction

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

How H. pylori survives in human stomach

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

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

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

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

Interaction between CagA and SHP-2 IP ： immunoprecipitate

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

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

Role of SHP-2 induce hummingbird phenotype

Myr ： Membrane-localization signal sequence (myristoylation signal sequence of v-Src)

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

Thanks