A Transgenic Drosophila Model Demonstrates That the Helicobacter pylori CagA Protein Functions as a Eukaryotic Gab Adaptor

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

Isolation of a Drosophila T-box gene closely related to human TBX1

T-box genes, in all metazoans studied from nematode to man, exist in small gene families. They encode transcription factors with a novel, large, and highly conserved DNA binding domain termed the T-domain. In all cases studied, T-box genes have important developmental roles. Two familial diseases, Holt–Oram syndrome and ulnar-mammary syndrome, were recently shown to be caused by mutations in the human T-box genes TBX5 and TBX3, respectively. T-box genes were first identified in Drosophila and mouse. Two of the three known Drosophila T-box genes show a close sequence homology to mammalian genes. Similarities in the phenotypes of fly and mammalian mutants can be taken as evidence of functional conservation. We report here the isolation of a fourth Drosophila T-box gene, optomotor-blind-related gene-1 (org-1), closely related to mouse and human TBX1. We localized TBX1 to chromosomal band 22q11, confirming a recent report, and discuss TBX1 as a candidate gene for DiGeorge and related syndromes