Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis.
Infection with CagA-positive Helicobacter pylori is associated with the development of gastric adenocarcinoma. The CagA gene product CagA is injected directly from the bacterium into the bacterium-attached gastric epithelial cells via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, CagA functions as a scaffolding adaptor and interacts with a number of host proteins that regulate cell growth, cell motility and cell polarity in both CagA phosphorylation-dependent and phosphorylation-independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, gain-of-function mutations that of which have recently been found in a variety of human malignancies. The CagA-SHP-2 interaction is entirely dependent on CagA tyrosine phosphorylation and, through the complex formation, SHP-2 is catalytically activated and induces morphological transformation with elevated cell motility. Intriguingly, structural diversity of the tyrosine phosphorylation sites of CagA accounts for the differential activity of individual CagA to bind and activate SHP-2. Deregulation of SHP-2 and other intracellular signaling molecules by H. pylori CagA may predispose cells to accumulate multiple genetic and epigenetic changes involved in gastric carcinogenesis. Furthermore, the differential potential of individual CagA to disturb cellular functions indicates that H. pylori strains carrying biologically more active CagA are more virulent than those with less active CagA and are more closely associated with gastric carcinoma.
Hatakeyama
Masanori
M
Division of Molecular Oncology, Institute for Genetic Medicine and Division of Chemistry, Graduate School of Science, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. mhata@igm.hokudai.ac.jp
Higashi
Hideaki
H
D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000032:analysis* / Q000235:genetics; D001426:Bacterial Proteins / Q000032:analysis* / Q000235:genetics; D002455:Cell Division; D002465:Cell Movement; D016764:Cell Polarity; D002471:Cell Transformation, Neoplastic; D005753:Gastric Mucosa / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000150:complications*; D016480:Helicobacter pylori / Q000166:cytology / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000382:microbiology*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori; D019000:Phosphotyrosine