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

H. pylori beats PAR Helicobacter pylori infects more than half of the world's population, and though usually well tolerated, it can cause gastric mucosal damage, peptic ulcers, gastritis and adenocarcinoma. CagA is the main virulence factor of H. pylori , delivered directly by the bacterium into epithelial cells where it interferes with cell signalling. CagA is now shown to bind to the polarity protein, Par-1, inhibiting its phosphorylation and disrupting epithelial cell polarity. This study provides the first molecular link between a human pathogen and the PAR cell polarity machinery, and points to a possible general role for PAR1 inhibition in gastrointestinal carcinogenesis. CagA is the main virulence factor of Helicobacter pylori and is delivered directly by the bacterium into epithelial cells where it interferes with cell signalling. Here Hatekeyama and colleagues show that CagA binds to the polarity protein, PAR1, inhibiting its phosphorylation and disrupting epithelial cell polarity: this study provides the first molecular link between a human pathogen and the PAR cell polarity machinery. Helicobacter pylori cagA- positive strains are associated with gastritis, ulcerations and gastric adenocarcinoma 1 . CagA is delivered into gastric epithelial cells 2 and, on tyrosine phosphorylation, specifically binds and activates the SHP2 oncoprotein 3 , 4 , 5 , 6 , 7 , thereby inducing the formation of an elongated cell shape known as the ‘hummingbird’ phenotype 2 , 3 . In polarized epithelial cells, CagA also disrupts the tight junction and causes loss of apical–basolateral polarity 8 , 9 . We show here that H. pylori CagA specifically interacts with PAR1/MARK kinase, which has an essential role in epithelial cell polarity 10 , 11 . Association of CagA inhibits PAR1 kinase activity and prevents atypical protein kinase C (aPKC)-mediated PAR1 phosphorylation, which dissociates PAR1 from the membrane 12 , 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 interaction 15 . 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 disorganizati