title: Structural and functional diversity in the PAR1b/MARK2-binding region of Helicobacter pylori CagA.
abstract: Helicobacter pylori (H. pylori) cagA-positive strains are associated with gastritis, peptic ulcerations, and gastric adenocarcinoma. Upon delivery into gastric epithelial cells, the cagA-encoded CagA protein specifically binds and aberrantly activates SHP-2 oncoprotein in a manner that is dependent on CagA tyrosine phosphorylation. CagA-deregulated SHP-2 then elicits aberrant Erk activation while causing an elongated cell shape known as the hummingbird phenotype. In polarized epithelial cells, CagA also binds to PAR1b/MARK2 and inhibits the PAR1b kinase activity, thereby disrupting tight junctions and epithelial cell polarity independent of CagA tyrosine phosphorylation. We show here that the CagA-multimerization (CM) sequence that mediates interaction of CagA with PAR1b is not only essential for the CagA-triggered junctional defects but also plays an important role in induction of the hummingbird phenotype by potentiating CagA-SHP-2 complex formation. We also show that the CM sequence of CagA isolated from East Asian H. pylori (referred to as the E-CM sequence) binds PAR1b more strongly than that of CagA isolated from Western H. pylori (referred to as the W-CM sequence). Within Western CagA species, the ability to bind PAR1b is proportional to the number of W-CM sequences. Furthermore, the level of PAR1b-binding activity of CagA correlates with the magnitude of junctional defects and the degree of hummingbird phenotype induction. Our findings reveal that structural diversity in the CM sequence is an important determinant for the degree of virulence of CagA, a bacterial oncoprotein that is associated with gastric carcinogenesis.
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Graduate School of Science, Hokkaido University, Sapporo, Japan.
authors.forename: Huai-Sheng
authors.initials: HS
authors.lastname: Lu
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Mayumi
authors.initials: M
authors.lastname: Umeda
authors.forename: Naoko
authors.initials: N
authors.lastname: Murata-Kamiya
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Zhang
authors.forename: Hideaki
authors.initials: H
authors.lastname: Higashi
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D040501:Calgranulin A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016764:Cell Polarity; D002522:Chlorocebus aethiops; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005822:Genetic Vectors; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D013270:Stomach / Q000166:cytology; D019108:Tight Junctions / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection; D014774:Virulence / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D040501:Calgranulin A; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11