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

Abstract

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.

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Figure 1: Disruption of the tight junction by CagA mutants.
Figure 2: Interaction of CagA with PAR1.
Figure 3: Inhibition of PAR1 kinase by CagA.
Figure 4: Role of PAR1 in the biological activities of CagA.

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Acknowledgements

We thank J. Blenis, A. Toker, A. Harada and G. Drewes for cDNAs, G. K. Ojakian for antibody and K. Kikuchi for help. I.S. was supported by the Iranian Ministry of Science. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and by a research grant from Takeda Science Foundation (M.H.).

Author Contributions I.S., H.H., C.O., M.U., N.M-K., Y.S., H.L., N.O. and T.A. performed biochemical and cell biological experiments and analysed data; T.A., A.S. and S.O. generated reagents and contributed to experimental design; and I.S. and M.H. designed experiments and wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Masanori Hatakeyama.

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Saadat, I., Higashi, H., Obuse, C. et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447, 330–333 (2007). https://doi.org/10.1038/nature05765

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