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Exp Cell Res. 2007 Oct 1;313(16):3459-71. Epub 2007 Jul 24.

CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity.

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Junior Research Group, Paul-Ehrlich Institute, Paul-Ehrlich Str 51-59, D-63225, Langen, Germany.


Infection with Helicobacter pylori (H. pylori) leads to depolarization and migration of polarized epithelial cells, both strongly enhanced by injection of the pathogenic factor CagA (cytotoxin-associated gene A) into the host cytoplasm. Depolarization and migration of epithelial cells imply the disruption of cell adhesion junctions (AJs) comprising a protein complex of E-cadherin, beta-catenin, p120(ctn), and alpha-catenin. Here, we analyzed the disintegration of E-cadherin-mediated AJs and demonstrated that loss of E-cadherin-dependent cell-cell contacts is entirely independent of CagA. Upon infection with H. pylori, either wild-type (wt) or a cagA mutant (DeltacagA), interaction between E-cadherin and alpha-catenin dissociated rapidly, while binding of E-cadherin to beta-catenin and p120(ctn) was hardly affected. Simultaneously, loss of cell adhesion involved E-cadherin cleavage induced by a bacterial factor secreted by H. pylori. Finally, beta-catenin-mediated transcription, a hallmark of many carcinomas, was not activated in H. pylori-infected epithelial cells at this stage of infection. Altogether, our data indicate that H. pylori-induced pathogenesis is a multi-step process initiated by CagA-independent mechanisms. These include proteolytical cleavage of E-cadherin and dissociation of the E-cadherin/beta-catenin/p120(ctn) complex from the actin cytoskeleton by disrupting binding to alpha-catenin.

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