Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation

• DOI: 10.1074/jbc.m309964200
• Publication Date: 2004-04-16T19:53:15Z
• Authors: Hideaki Higashi; Akihiro Nakaya; Ryouhei Tsutsumi; Kazuyuki Yokoyama; Yumiko Fujii; Susumu Ishikawa; Megumi Higuchi; Atsushi Takahashi; Yo Kurashima; Yasuhiro Teishikata; Shinya Tanaka; Takeshi Azuma; Masanori Hatakeyama
• Keywords: CagA; GRB2

The CagA protein of <i>Helicobacter pylori</i>, which is injected from the bacteria into bacteria-attached gastric epithelial cells, associated with carcinoma. tyrosine-phosphorylated by Src family kinases, binds SH2 domain-containing SHP-2 phosphatase in a tyrosine phosphorylation-dependent manner, and deregulates its enzymatic activity. We established AGS human cells that inducibly express wild-type or phosphorylation-resistant CagA, residues constituting EPIYA motifs were substituted alanines. Upon induction, but not mutant elicited strong elongation cell shape, termed "hummingbird" phenotype. Time-lapse video microscopic analysis revealed CagA-expressing exhibited marked increase motility successive rounds elongation-contraction processes. Inhibition phosphorylation an kinase inhibitor, PP2, knockdown expression small interference RNA (siRNA) abolished CagA-mediated hummingbird morphogenetic activity also required Erk MAPK was independent Ras Grb2. In prolonged duration activation response to serum stimulation. Conversely, inhibition siRNA sustained activation. Thus, acts as positive regulator cells. These results indicate involved Ras-independent modification signals necessary for CagA. Our work therefore suggests key role pathological <i>H. pylori</i> virulence factor