Abstract
Infection with the human gastric pathogen Helicobacter pylori is associated with a spectrum of diseases including gastritis, peptic ulcers, gastric adenocarcinoma, and gastric mucosa–associated lymphoid tissue lymphoma. The cytotoxin-associated gene A (CagA) protein of H. pylori, which is translocated into host cells via a type IV secretion system, is a major risk factor for disease development. Experiments in gastric tissue culture cells have shown that once translocated, CagA activates the phosphatase SHP-2, which is a component of receptor tyrosine kinase (RTK) pathways whose over-activation is associated with cancer formation. Based on CagA's ability to activate SHP-2, it has been proposed that CagA functions as a prokaryotic mimic of the eukaryotic Grb2-associated binder (Gab) adaptor protein, which normally activates SHP-2. We have developed a transgenic Drosophila model to test this hypothesis by investigating whether CagA can function in a well-characterized Gab-dependent process: the specification of photoreceptors cells in the Drosophila eye. We demonstrate that CagA expression is sufficient to rescue photoreceptor development in the absence of the Drosophila Gab homologue, Daughter of Sevenless (DOS). Furthermore, CagA's ability to promote photoreceptor development requires the SHP-2 phosphatase Corkscrew (CSW). These results provide the first demonstration that CagA functions as a Gab protein within the tissue of an organism and provide insight into CagA's oncogenic potential. Since many translocated bacterial proteins target highly conserved eukaryotic cellular processes, such as the RTK signaling pathway, the transgenic Drosophila model should be of general use for testing the in vivo function of bacterial effector proteins and for identifying the host genes through which they function.
Highlights
The human pathogen, Helicobacter pylori, infects the stomachs of at least half the world’s population and chronic infection is associated with the development of diseases such as gastritis, peptic ulcers and gastric cancer [1]
cytotoxin associated gene A (CagA) has been proposed to function as a mimic of Growth factor receptor-bound protein 2 (Grb2)-associated binder (Gab) proteins that serve as adaptors in this signaling pathway
We demonstrate that CagA can substitute for Gab and restore developmental defects caused by the loss of the Drosophila Gab, including promoting photoreceptor specification in the developing eye
Summary
The human pathogen, Helicobacter pylori, infects the stomachs of at least half the world’s population and chronic infection is associated with the development of diseases such as gastritis, peptic ulcers and gastric cancer [1]. CagA is phosphorylated by Src family kinases on tyrosines contained in repeated five-amino acid motifs (EPIYA) in CagA’s carboxyl terminus. Phosphorylated CagA disrupts receptor tyrosine kinase (RTK) signaling pathways by directly activating Src homology 2 (SH2) domain containing tyrosine phosphatase (SHP-2) (reviewed in [3]). In tissue culture cells CagA has been found to associate with c-Met, Crk(L) and Grb2 [10,11,12]. Based on these interactions, CagA has been hypothesized to mimic Gab proteins and to function as an oncogene by over-activating RTK signaling [13]. The significance of CagA’s interactions with RTK signaling pathway proteins, has only been explored in tissue culture cells
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