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

CagA Protein Hideaki Higashi, Ryouhei Tsutsumi, Syuichi Muto,Toshiro Sugiyama, T

akeshi Azuma, Masahiro Asaka, Masanori Hatakeyama

Science, Vol. 295, 683-686, 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 gastrod

uodenal ulcers• Associate with the gastric cancer a

nd MALT lymphoma• Infection half of the world’s populati

on

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

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