Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA.
Loss of cell polarity and tissue architecture is a hallmark of carcinomas that arise from epithelial cells. Recent studies on Drosophila tumor suppressors have provided evidence that epithelial polarity and cell proliferation are functionally coupled, suggesting a function for polarity defects in the development of carcinomas. This notion is supported by the findings that mammalian orthologs of these Drosophila tumor suppressors are targeted by a number of viral oncoproteins. Chronic infection with Helicobacter pylori is causally associated with gastric carcinoma. H. pylori virulence factor CagA (cytotoxin-associated gene A), which is delivered into gastric epithelial cells through a bacterial type IV secretion system, has an important function in cell transformation through interacting with and deregulating SHP-2 phosphatase, a bona fide oncoprotein that is associated with human malignancies. Recent studies have further revealed that CagA specifically binds and inhibits PAR1/MARK polarity-regulating kinase, thereby causing junctional and polarity defects in epithelial cells. Thus, the bacterial oncoprotein simultaneously targets the polarity-regulating system and growth-regulatory system. These findings indicate that loss of cell polarity underlies the abnormal proliferation of epithelial cells that directs carcinogenesis.
Hatakeyama
M
M
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. mhata@igm.hokudai.ac.jp
D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism / Q000502:physiology*; D001426:Bacterial Proteins / Q000378:metabolism / Q000502:physiology*; D002277:Carcinoma / Q000209:etiology / Q000378:metabolism; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology* / Q000502:physiology*; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000473:pathology; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D021381:Protein Transport; D015398:Signal Transduction / Q000502:physiology; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000209:etiology / Q000378:metabolism; D037521:Virulence Factors / Q000502:physiology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori