Helicobacter pylori CagA -- a bacterial intruder conspiring gastric carcinogenesis.
Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is delivered from the bacterium into the cytoplasm of the bacterium-attached gastric epithelial cell via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, translocated CagA functions as a scaffolding adaptor that interacts with a number of host proteins involved in cell signaling in both tyrosine phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, of which gain-of-function mutations have recently been found in human malignancies. Through the complex formation, SHP-2 is catalytically activated and induces morphological transformation that is associated with increased cell motility. In addition to the perturbation of intracellular signaling, CagA disrupts the apical junctional complex that regulates the cell-cell contact and maintains the integrity of the epithelial structure. These CagA activities may collectively cause cellular dysfunctions that promote accumulation of multiple genetic changes involved in malignant transformation. Further elucidation of host cell signaling targeted by CagA should provide a new paradigm for 'bacterial carcinogenesis' and also give insights into general understanding of inflammation-mediated cancers. Clinically, detailed studies on the relationship between structural diversity and degree of pathogenic activity of CagA should make it possible to identify a high-risk group for gastric carcinoma among H. pylori-infected populations through cagA genotyping.
Hatakeyama
Masanori
M
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. mhata@igm.hokudai.ac.jp
D000230:Adenocarcinoma / Q000382:microbiology*; D000942:Antigens, Bacterial / Q000502:physiology*; D001426:Bacterial Proteins / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D005753:Gastric Mucosa / Q000382:microbiology; D016481:Helicobacter Infections / Q000382:microbiology*; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000382:microbiology*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D047908:Intracellular Signaling Peptides and Proteins; C080866:cagA protein, Helicobacter pylori; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases