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Letter

Nature 447, 330-333 (17 May 2007) | doi:10.1038/nature05765; Received 14 February 2007; Accepted 21 March 2007

Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity

Iraj Saadat1, Hideaki Higashi1, Chikashi Obuse2, Mayumi Umeda1, Naoko Murata-Kamiya1, Yasuhiro Saito1, Huaisheng Lu1, Naomi Ohnishi1, Takeshi Azuma3, Atsushi Suzuki4, Shigeo Ohno4 & Masanori Hatakeyama1

  1. Division of Molecular Oncology, Institute for Genetic Medicine and Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0815, Japan
  2. Division of Molecular Life Science, Hokkaido University, Graduate School of Life Science, Sapporo 001-0021, Japan
  3. Internal Center for Medical Research and Treatment, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
  4. Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Yokohama 236-0004, Japan

Correspondence to: Masanori Hatakeyama1 Correspondence and requests for materials should be addressed to M.H. (Email: mhata@igm.hokudai.ac.jp).

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Helicobacter pylori cagA-positive strains are associated with gastritis, ulcerations and gastric adenocarcinoma1. CagA is delivered into gastric epithelial cells2 and, on tyrosine phosphorylation, specifically binds and activates the SHP2 oncoprotein3, 4, 5, 6, 7, thereby inducing the formation of an elongated cell shape known as the 'hummingbird' phenotype2, 3. In polarized epithelial cells, CagA also disrupts the tight junction and causes loss of apical–basolateral polarity8, 9. We show here that H. pylori CagA specifically interacts with PAR1/MARK kinase, which has an essential role in epithelial cell polarity10, 11. Association of CagA inhibits PAR1 kinase activity and prevents atypical protein kinase C (aPKC)-mediated PAR1 phosphorylation, which dissociates PAR1 from the membrane12, 13, collectively causing junctional and polarity defects. Because of the multimeric nature of PAR1 (ref. 14), PAR1 also promotes CagA multimerization, which stabilizes the CagA–SHP2 interaction15. Furthermore, induction of the hummingbird phenotype by CagA-activated SHP2 requires simultaneous inhibition of PAR1 kinase activity by CagA. Thus, the CagA–PAR1 interaction not only elicits the junctional and polarity defects but also promotes the morphogenetic activity of CagA. Our findings revealed that PAR1 is a key target of H. pylori CagA in the disorganization of gastric epithelial architecture underlying mucosal damage, inflammation and carcinogenesis.