Helicobacter pylori is a pathogenic Gram-negative bacterium that colonizes over 50% of the world’s human population. Colonization with H. pylori is linked to numerous gastric disorders including gastritis, peptic ulcer disease and gastric adenocarcinoma (Blaser

802 INTRODUCTION Helicobacter pylori is a pathogenic Gram-negative bacterium that colonizes over 50% of the world’s human population. Colonization with H. pylori is linked to numerous gastric disorders including gastritis, peptic ulcer disease and gastric adenocarcinoma (Blaser and Atherton, 2004). Although gastric cancer occurs in fewer than 1% of people colonized by H. pylori (Amieva and El-Omar, 2008), it is still the second-most common cause of cancer mortality worldwide (Peek and Blaser, 2002), and more than 50% of gastric adenocarcinomas can be attributed to infection with H. pylori (Asghar and Parsonnet, 2001). Most people infected with H. pylori, however, do not develop gastric cancer and the molecular mechanisms underlying this disparity have yet to be fully elucidated. Although there are many factors that appear to contribute to the carcinogenicity of H. pylori, strains that translocate the CagA protein into host cells are significantly more likely to cause gastric cancer than strains lacking this ability. CagA is one of 28 gene products encoded by the cag pathogenicity island (cag PAI), a 40kb stretch of DNA shown to be present in most strains isolated from patients with severe gastric pathology (Censini et al., 1996). During infection with H. pylori, CagA is translocated into host cells via a type IV secretion system (TFSS), where it interacts with a multitude of host cell proteins. These interactions have been shown to affect signal transduction pathways, the cytoskeleton and cell junctions (Bourzac and Guillemin, 2005). After translocation into host cells by the H. pylori TFSS, CagA can be phosphorylated by Src family kinases on tyrosine residues within conserved Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs (Selbach et al., 2002; Stein et al., 2002). After phosphorylation, CagA has been shown to induce morphological changes in cultured epithelial cells through interaction with a variety of host-cell proteins such as SHP2, Met, Csk, Grb2 and ZO-1 (Amieva et al., 2003; Churin et al., 2003; Higashi et al., 2002; Tsutsumi et al., 2003; Mimuro et al., 2002). In addition to its phosphorylation-dependent effects, CagA has also been shown to interact in a phosphorylation-independent manner with pathways associated with proliferation and inflammation (Suzuki et al., 2009). Although it is not yet clear which of these myriad interactions are required for the development of gastric cancer in persons colonized by H. pylori, the ability of CagA to interact with components of the canonical Wnt signaling pathway provides a potential link between the observed oncogenic effects of CagA and a host signaling pathway frequently deregulated in gastrointestinal cancers (Franco et al., 2005). In addition to its role in early embryogenesis, the canonical Wnt signaling pathway plays a crucial role in regulating the proliferation and homeostasis of gastrointestinal epithelia. In normal stomach and intestinal epithelia, Wnt signaling has been shown to be important for proliferation, stem cell maintenance, and tissue renewal (Barker et al., 2010; Sato et al., 2011; Pinto et al., 2003; Ootani et al., 2009; Sato et al., 2004). On the other hand, activation of Wnt signaling has been shown to result in cancers of the stomach Disease Models & Mechanisms 6, 802-810 (2013) doi:10.1242/dmm.011163