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 adenocarcinoma. CagA is delivered into gastric epithelial cells and, on tyrosine phosphorylation, specifically binds and activates the SHP2 oncoprotein, thereby inducing the formation of an elongated cell shape known as the 'hummingbird' phenotype. In polarized epithelial cells, CagA also disrupts the tight junction and causes loss of apical-basolateral polarity. We show here that H. pylori CagA specifically interacts with PAR1/MARK kinase, which has an essential role in epithelial cell polarity. Association of CagA inhibits PAR1 kinase activity and prevents atypical protein kinase C (aPKC)-mediated PAR1 phosphorylation, which dissociates PAR1 from the membrane, 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. 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.

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…Inhibition of PAR1 by CagA causes junctional and polarity defects, which are followed by disorganization of the epithelial monolayer (Figure 2c). Interestingly, induction of the hummingbird phenotype by CagAderegulated SHP-2 requires simultaneous inhibition of the PAR1 kinase activity by CagA (Saadat et al, 2007). The observation indicates that the phosphorylation-dependent CagA activity is also dependent on the phosphorylation-independent CagA activity.…”

“…Hence, CagA induces cellular changes that resemble the epithelial-tomesenchymal transition. This CagA activity is mediated by specific interaction of CagA with PAR1 (Saadat et al, 2007: Zeaiter et al, 2008 (Figure 1), one of the six PAR proteins isolated in C. elegans. PAR1 is a serine/ threonine kinase that has a central function in the establishment and maintenance of the basolateral membrane domain in epithelial cells (Hurov et al, 2004;Suzuki et al, 2004) (Figure 2a).…”

“…CagA interacts with the kinase catalytic domain of PAR1, from PAR1a to PAR1d, and thereby inhibits PAR1 kinase activity (Saadat et al, 2007) (Figure 1). Conversely, PAR1 binds to the C-terminal 16-aminoacid sequence of CagA known as the CagA-multimerization sequence (Ren et al, 2006) (Figure 1).…”

“…If transformed cells cannot form apical junctional complexes with 'normal' neighboring cells, they are excluded from the polarized epithelial monolayer and acquire the ability to initiate abnormal proliferation in the absence of growth inhibitory cues, which may otherwise be generated through epithelial cell-cell interaction. In this regard, the CagA-PAR1-SHP-2 complex has a dual function; disruption of the epithelial polarity and aberrant activation of the Ras-MAPK pathway, indicating that the protein complex coordinates cell polarity defects and oncogenic signaling to promote epithelial cell transformation (Saadat et al, 2007). Such functional cooperativity has already been indicated by the observation that tumors induced by an oncogenic Ras in Drosophila do not have metastatic potential, whereas those induced by oncogenic Ras under the condition of loss of heterozygosity for lgl, dlg and scrib show more malignant phenotypes and frequently metastasize (Brumby and Richardson, 2003;Pagliarini and Xu, 2003).…”

Helicobacter pylori CagA promotes Snail-mediated epithelial–mesenchymal transition by reducing GSK-3 activity

“…The EPIYA phosphorylation status of CagA also affects the signal switch between the SHP2/ ERK and JAK/STAT3 pathways via gp130 in gastric epithelial cells 8 . While the causality of CagA on gastric cancer has been clearly demonstrated in vivo 9 and several membranous targets of CagA, such as gp130 and PAR1, have been identified 8,10 , the molecular mechanism by which intracellular target of CagA results in cellular transformation and carcinogenesis has not been fully elucidated.…”