Dramatic increase in SHP2 binding activity of Helicobacter pylori Western CagA by EPIYA-C duplication: its implications in gastric carcinogenesis.
Infection with cagA-positive Helicobacter pylori is critically associated with the development of gastric cancer. The cagA-encoded CagA is delivered into gastric epithelial cells via type IV secretion, where it interacts with and thereby deregulates the pro-oncogenic phosphatase SHP2. East Asian CagA and Western CagA are two major CagA species produced by H. pylori circulating in East Asian countries and in the rest of the world, respectively. The SHP2 binding site of Western CagA, termed the EPIYA-C segment, variably duplicates and infection with H. pylori carrying Western CagA with multiple EPIYA-C segments is a distinct risk factor of gastric cancer. Here we show that duplication of EPIYA-C from one to two or more increases SHP2 binding of Western CagA by more than one hundredfold. Based on the decisive difference in SHP2 binding, Western CagA can be divided into two types: type I CagA carrying a single EPIYA-C segment and type II CagA carrying multiple EPIYA-C segments. Gastric epithelial cells expressing type II CagA acquire the ability to invade extracellular matrices, a malignant cellular trait associated with deregulated SHP2. A big leap in SHP2 binding activity may therefore provide molecular basis that makes type II Western CagA a distinct gastric cancer risk.
Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.
Lisa
L
Nagase
Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.
Takeru
T
Hayashi
CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.|Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan.
Toshiya
T
Senda
Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.
Masanori
M
Hatakeyama
D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D063646:Carcinogenesis / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D013270:Stomach / Q000382:microbiology / Q000473:pathology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11