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

Journal Article · · PLoS Pathogens
 [1];  [2];  [2]
  1. University of Oregon, Eugene, OR (United States); DOE/OSTI
  2. University of Oregon, Eugene, OR (United States)
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 Gabdependent 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.
Research Organization:
University of Oregon, Eugene, OR (United States)
Sponsoring Organization:
American Heart Association; National Institutes of Health; USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI ID:
1627889
Journal Information:
PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 5 Vol. 4; ISSN 1553-7374
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

References (54)

Localized activation of RTK/MAPK pathways during Drosophila development journal March 1998
Signal integration during development: Insights from theDrosophila eye journal January 2003
spalt encodes an evolutionarily conserved zinc finger protein of novel structure which provides homeotic gene function in the head and tail region of the Drosophila embryo. journal January 1994
Use of FLP/FRT System to StudyDrosophilaDevelopment journal April 1998
The role of Shp2 (PTPN11) in cancer journal February 2007
Non-vertebrate hosts in the analysis of host–pathogen interactions journal May 2006
Drosophila: a polyvalent model to decipher host–pathogen interactions journal May 2004
DOS, a Novel Pleckstrin Homology Domain–Containing Protein Required for Signal Transduction between Sevenless and Ras1 in Drosophila journal June 1996
In vivo functional analysis of the Daughter of Sevenless protein in receptor tyrosine kinase signaling journal February 2000
Multiple functions of the EGF receptor in Drosophila eye development journal September 1998
The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling journal June 2003
Grb2 Is a Key Mediator of Helicobacter pylori CagA Protein Activities journal October 2002
Helicobacter pylori CagA—a potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins journal February 2003
Burden of Helicobacter pylori and H. pylori-related diseases in developed countries: recent developments and future implications journal July 2003
Protein-tyrosine phosphatases and cancer journal April 2006
The art and design of genetic screens: Drosophila melanogaster journal March 2002
c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs journal February 2002
Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells journal October 2005
Fighting anthrax with flies journal February 2006
Monoclonal antibodies against the Drosophila nervous system. journal December 1982
Increased expression of Gab2, a scaffolding adaptor of the tyrosine kinase signalling, in gastric carcinomas journal June 2007
Interaction of CagA with Crk plays an important role in Helicobacter pylori–induced loss of gastric epithelial cell adhesion journal November 2005
Recruitment of the protein tyrosine phosphatase CSW by DOS is an essential step during signaling by the Sevenless receptor tyrosine kinase journal December 1999
The role of Gab family scaffolding adapter proteins in the signal transduction of cytokine and growth factor receptors journal December 2003
SHP-2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein journal December 2001
Disruption of the Epithelial Apical-Junctional Complex by Helicobacter pylori CagA journal May 2003
Sevenless: A Cell-Specific Homeotic Mutation of the Drosophila Eye journal January 1986
Helicobacter pylori and Gastric Cancer: What can be Learned by Studying the Response of Gastric Epithelial Cells to the Infection? journal August 2005
The Role of Helicobacter pylori CagA in Gastric Carcinogenesis journal November 2006
Localized activation of RTK/MAPK pathways during Drosophila development journal March 1998
GAL4 system indrosophila: A fly geneticist's swiss army knife journal September 2002
Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase journal November 1991
The gift of Gab journal March 2002
Senseless, a Zn Finger Transcription Factor, Is Necessary and Sufficient for Sensory Organ Development in Drosophila journal August 2000
Cell Signaling by Receptor Tyrosine Kinases journal October 2000
Daughter of Sevenless Is a Substrate of the Phosphotyrosine Phosphatase Corkscrew and Functions during Sevenless Signaling journal June 1996
DOS, a Novel Pleckstrin Homology Domain–Containing Protein Required for Signal Transduction between Sevenless and Ras1 in Drosophila journal June 1996
In vivo functional analysis of the Daughter of Sevenless protein in receptor tyrosine kinase signaling journal February 2000
Multiple functions of the EGF receptor in Drosophila eye development journal September 1998
The ‘Gab’ in signal transduction journal March 2003
The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling journal June 2003
Grb2 Is a Key Mediator of Helicobacter pylori CagA Protein Activities journal October 2002
Helicobacter pylori CagA—a potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins journal February 2003
Burden of Helicobacter pylori and H. pylori-related diseases in developed countries: recent developments and future implications journal July 2003
From The Cover: Anthrax lethal factor and edema factor act on conserved targets in Drosophila journal February 2006
Identification of a human src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew. journal December 1992
Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response journal April 2003
Identification of Genomic Regions That Interact With a Viable Allele of the Drosophila Protein Tyrosine Phosphatase Corkscrew journal October 2000
Conditional gene silencing utilizing the lac repressor reveals a role of SHP-2 in cagA-positive Helicobacter pylori pathogenicity journal May 2004
Helicobacter pylori-host cell interactions mediated by type IV secretion: Helicobacter pylori-host cell interactions journal May 2005
Helicobacter pylori and Gastric Cancer: What can be Learned by Studying the Response of Gastric Epithelial Cells to the Infection? journal August 2005
Analysis of genetic mosaics in developing and adult Drosophila tissues journal April 1993
The SH2-containing tyrosine phosphatase corkscrew is required during signaling by sevenless, Ras1 and Raf journal April 1996
The Role of Helicobacter pylori CagA in Gastric Carcinogenesis journal November 2006

Cited By (29)

Helicobacter pylori CagA Phosphorylation-Independent Function in Epithelial Proliferation and Inflammation journal January 2009
Helicobacter pylori CagA and Gastric Cancer: A Paradigm for Hit-and-Run Carcinogenesis journal March 2014
Gab Docking Proteins in Cardiovascular Disease, Cancer, and Inflammation journal January 2013
Effector prediction in host-pathogen interaction based on a Markov model of a ubiquitous EPIYA motif journal January 2010
Targeting focal adhesions:Helicobacter pylori-host communication in cell migration journal August 2008
Function, regulation and pathological roles of the Gab/DOS docking proteins journal September 2009
Use of larvae of the wax moth Galleria mellonella as an in vivo model to study the virulence of Helicobacter pylori journal August 2014
Deconstructing host-pathogen interactions inDrosophila journal January 2012
Helicobacter pylori CagA Disrupts Epithelial Patterning by Activating Myosin Light Chain journal March 2011
Helicobacter pylori Usurps Cell Polarity to Turn the Cell Surface into a Replicative Niche journal May 2009
Transgenic Expression of the Helicobacter pylori Virulence Factor CagA Promotes Apoptosis or Tumorigenesis through JNK Activation in Drosophila journal October 2012
Identification of genetic modifiers of CagA-induced epithelial disruption in Drosophila journal January 2012
Drosophila at the intersection of infection, inflammation, and cancer journal January 2013
A Tale of Two Toxins: Helicobacter Pylori CagA and VacA Modulate Host Pathways that Impact Disease journal January 2010
Helicobacter pyloriinduces cancer cell motility independent of the c-Met receptor journal January 2009
Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics journal February 2013
Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways journal September 2017
Mutual reinforcement of inflammation and carcinogenesis by the Helicobacter pylori CagA oncoprotein journal May 2015
Order and disorder in large multi-site docking proteins of the Gab family—implications for signalling complex formation and inhibitor design strategies journal January 2012
Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host journal May 2011
Bacterial EPIYA effectors - Where do they come from? What are they? Where are they going?: Bacterial EPIYA effector family journal November 2012
Expression of CEACAM1 or CEACAM5 in AZ-521 cells restores the type IV secretion deficiency for translocation of CagA by Helicobacter pylori journal November 2018
SseF, a type III effector protein from the mammalian pathogen Salmonella enterica , requires resistance‐gene‐mediated signalling to activate cell death in the model plant Nicotiana benthamiana journal April 2012
The Versatility of Helicobacter pylori CagA Effector Protein Functions: The Master Key Hypothesis: The Versatility of H. pylori CagA journal June 2010
The Versatility of Helicobacter pylori CagA Effector Protein Functions: the Master Key Hypothesis journal September 2010
Subversion of host kinases: a key network in cellular signaling hijacked by Helicobacter pylori CagA: Host kinases hijacked by CagA journal May 2017
c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains journal April 2012
Tailor-Made Detection of Individual Phosphorylated and Non-Phosphorylated EPIYA-Motifs of Helicobacter pylori Oncoprotein CagA journal August 2019
Helicobacter pylori -induced inflammation and epigenetic changes during gastric carcinogenesis journal January 2015

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