Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA

Ryouhei Tsutsumi, Atsushi Takahashi, Takeshi Azuma, Hideaki Higashi, Masanori Hatakeyama

Research output: Contribution to journalArticlepeer-review

153 Citations (Scopus)

Abstract

Infection with cagA-pesitive Helicobacter pylori (H. pylori) is associated with atrophic gastritis, peptic ulcer, and gastric adenocarcinoma. The cagA gene product CagA is translocated from H. pylori into gastric epithelial cells and undergoes tyrosine phosphorylation by Src family kinases (SFKs). Tyrosine-phosphorylated CagA binds and activates SHP-2 phosphatase and the C-terminal Src kinase (Csk) while inducing an elongated cell shape termed the "hummingbird phenotype." Here we show that CagA reduces the level of focal adhesion kinase (FAK) tyrosine phosphorylation in gastric epithelial cells. The decrease in phosphorylated FAK is due to SHP-2-mediated dephosphorylation of FAK at the activating phosphorylation sites, not due to Csk-dependent inhibition of SFKs, which phosphorylate FAK. Coexpression of constitutively active FAK with CagA inhibits induction of the hummingbird phenotype, whereas expression of dominant-negative FAK elicits an elongated cell shape characteristic of the hummingbird phenotype. These results indicate that inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA. Impaired cell adhesion and increased motility by CagA may be involved in the development of gastric lesions associated with cagA-positive H. pylori infection.

Original languageEnglish
Pages (from-to)261-276
Number of pages16
JournalMolecular and cellular biology
Volume26
Issue number1
DOIs
Publication statusPublished - 2006 Jan
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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