title: Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations.
abstract: Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, causes Noonan syndrome (NS), an autosomal dominant disorder with pleomorphic developmental abnormalities. Certain germline and somatic PTPN11 mutations cause leukemias. Mutations have gain-of-function (GOF) effects with the commonest NS allele, N308D, being weaker than the leukemia-causing mutations. To study the effects of disease-associated PTPN11 alleles, we generated transgenic fruitflies with GAL4-inducible expression of wild-type or mutant csw, the Drosophila orthologue of PTPN11. All three transgenic mutant CSWs rescued a hypomorphic csw allele's eye phenotype, documenting activity. Ubiquitous expression of two strong csw mutant alleles were lethal, but did not perturb development from some CSW-dependent receptor tyrosine kinase pathways. Ubiquitous expression of the weaker N308D allele caused ectopic wing veins, identical to the EGFR GOF phenotype. Epistatic analyses established that csw(N308D)'s ectopic wing vein phenotype required intact EGF ligand and receptor, and that this transgene interacted genetically with Notch, DPP and JAK/STAT signaling. Expression of the mutant csw transgenes increased RAS-MAP kinase activation, which was necessary but not sufficient for transducing their phenotypes. The findings from these fly models provided hypotheses testable in mammalian models, in which these signaling cassettes are largely conserved. In addition, these fly models can be used for sensitized screens to identify novel interacting genes as well as for high-throughput screening of therapeutic compounds for NS and PTPN11-related cancers.
authors.affiliation: Departments of Pediatrics and Human Genetics, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1498, New York, NY 10029, USA.
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Oishi
authors.forename: Konstantin
authors.initials: K
authors.lastname: Gaengel
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Krishnamoorthy
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kamiya
authors.forename: In-Kyong
authors.initials: IK
authors.lastname: Kim
authors.forename: Huiwen
authors.initials: H
authors.lastname: Ying
authors.forename: Ursula
authors.initials: U
authors.lastname: Weber
authors.forename: Lizabeth A
authors.initials: LA
authors.lastname: Perkins
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Marek
authors.initials: M
authors.lastname: Mlodzik
authors.forename: Leslie
authors.initials: L
authors.lastname: Pick
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics* / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases