The Role of Helicobacter pylori CagA in Gastric Carcinogenesis

Article

Abstract

Gastric carcinoma is the second most common cause of cancer-related deaths in the world, accounting for more than 400,000 deaths each year. Infection with cagA-positive Helicobacter pylori plays a pivotal role in the development of gastric adenocarcinoma. The cagA gene product CagA is directly delivered into gastric epithelial cells via the type IV secretion system. Following membrane localization and subsequent tyrosine phosphorylation by Src family kinases, CagA interacts with a variety of host cell proteins that are involved in the regulation of cell growth and motility in both phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SH2 domain-containing tyrosine phosphatase SHP-2, gain-of-function mutations of which have recently been found in human malignancies. CagA binds to and activates SHP-2 in a tyrosine phosphorylation-dependent manner, thereby provoking abnormal activation of Erk MAP kinase while inducing elevated cell motility. Perturbation of SHP-2 and other signaling molecules by H pylori CagA may predispose cells to accumulate multiple genetic and epigenetic changes that promote multistep gastric carcinogenesis. Intriguingly, the structural polymorphism of CagA accounts for the differences in pathophysiological activity of individual CagA proteins, raising the possibility of subclassification of H pylori strains into benign and malignant strains.

Key words

Helicobacter pylori CagA Gastric carcinoma SHP-2 Tyrosine phosphorylation 

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Copyright information

© The Japanese Society of Hematology 2006

Authors and Affiliations

  1. 1.Division of Molecular Oncology, Institute for Genetic MedicineHokkaido UniversitySapporoJapan

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