Abstract
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.
Highlights
Infection with cagA-positive Helicobacter pylori is critically associated with the development of gastric cancer
We previously reported that an increase in the number of EPIYA-C segments enhances complex formation of Western CagA with the pro-oncogenic phosphatase SHP2 in gastric epithelial cells[8,9]
We first constructed an E. coli expression vector for the N-terminal GST-fused and C-terminal His-tagged Western CagA protein, which contains a variable number of functional EPIYA-C segments (1, 2, 3, 5, or 8), from the pGEX6P2 vector carrying an ampicillin-resistance gene (Fig. 1a)
Summary
Infection with cagA-positive Helicobacter pylori is critically associated with the development of gastric cancer. 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. The robust increase in SHP2 binding activity of CagA by EPIYA-C duplication was associated with the marked enhancement of cell invasion phenotype into the extracellular matrix, a malignant cellular trait associated with SHP2 deregulation[21,22,23,24]. These observations provide a molecular basis underlying the clinico-epidemiological observation that Western CagA with multiple EPIYA-C segments is a distinct risk factor for the development of gastric cancer
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