The Rho Guanine Nucleotide Exchange Factor DRhoGEF2 Is a Genetic Modifier of the PI3K Pathway in Drosophila

• Published in: PloS one Vol. 11; no. 3; p. e0152259
• Main Authors: Chang, Ying-Ju, Zhou, Lily, Binari, Richard, Manoukian, Armen, Mak, Tak, McNeill, Helen, Stambolic, Vuk
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.03.2016; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Animals; Binary system; Biology and Life Sciences; Biophysics; Cancer; Cell adhesion & migration; Cell cycle; Cell Cycle Proteins; Cell division; Cell growth; Crosstalk; Developmental stages; Drosophila; Drosophila - genetics; Drosophila - growth & development; Drosophila melanogaster; Drosophila Proteins - biosynthesis; Drosophila Proteins - genetics; Embryos; Engineering and Technology; Eye; Eye - growth & development; Eye - metabolism; Gene expression; Gene Expression Regulation, Developmental; Genetic aspects; Genetic screening; Genetics; Guanine; Guanine nucleotide exchange factor; Health care networks; Homeostasis; Humans; Insects; Insulin; Insulin - genetics; Insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Insulin-like growth factors; Kinases; Larvae; Ligands; Mammals; Medical research; Medicine and Health Sciences; Mutation; Nucleotides; Phosphatase; Phosphatidylinositol 3-Kinases - genetics; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - genetics; PTEN protein; Regulation; Research and Analysis Methods; rho GTP-Binding Proteins - biosynthesis; rho GTP-Binding Proteins - genetics; Signal Transduction; Signaling; Toronto Ontario Canada; Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0152259

The insulin/IGF-1 signaling pathway mediates various physiological processes associated with human health. Components of this pathway are highly conserved throughout eukaryotic evolution. In Drosophila, the PTEN ortholog and its mammalian counterpart downregulate insulin/IGF signaling by antagonizing the PI3-kinase function. From a dominant loss-of-function genetic screen, we discovered that mutations of a Dbl-family member, the guanine nucleotide exchange factor DRhoGEF2 (DRhoGEF22(l)04291), suppressed the PTEN-overexpression eye phenotype. dAkt/dPKB phosphorylation, a measure of PI3K signaling pathway activation, increased in the eye discs from the heterozygous DRhoGEF2 wandering third instar larvae. Overexpression of DRhoGEF2, and it's functional mammalian ortholog PDZ-RhoGEF (ArhGEF11), at various stages of eye development, resulted in both dPKB/Akt-dependent and -independent phenotypes, reflecting the complexity in the crosstalk between PI3K and Rho signaling in Drosophila.