Targeted expression of the class II phosphoinositide 3-kinase in Drosophila melanogaster reveals lipid kinase-dependent effects on patterning and interactions with receptor signaling pathways.
Phosphoinositide 3-kinases (PI3Ks) can be divided into three distinct classes (I, II, and III) on the basis of their domain structures and the lipid signals that they generate. Functions have been assigned to the class I and class III enzymes but have not been established for the class II PI3Ks. We have obtained the first evidence for a biological function for a class II PI3K by expressing this enzyme during Drosophila melanogaster development and by using deficiencies that remove the endogenous gene. Wild-type and catalytically inactive PI3K_68D transgenes have opposite effects on the number of sensory bristles and on wing venation phenotypes induced by modified epidermal growth factor (EGF) receptor signaling. These results indicate that the endogenous PI3K_68D may act antagonistically to the EGF receptor-stimulated Ras-mitogen-activated protein kinase pathway and downstream of, or parallel to, the Notch receptor. A class II polyproline motif in PI3K_68D can bind the Drk adaptor protein in vitro, primarily via the N-terminal SH3 domain of Drk. Drk may thus be important for the localization of PI3K_68D, allowing it to modify signaling pathways downstream of cell surface receptors. The phenotypes obtained are markedly distinct from those generated by expression of the Drosophila class I PI3K, which affects growth but not pattern formation.
MacDougall
Lindsay K
LK
Biomolecular Sciences, University of Manchester Institute of Science and Technology, PO Box 88, Manchester M60 1QD, UK. lindsay.macdougall@umist.ac.uk
Gagou
Mary Elizabeth
ME
Leevers
Sally J
SJ
Hafen
Ernst
E
Waterfield
Michael D
MD
D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D017344:Genes, Insect; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014921:Wings, Animal / Q000254:growth & development
D029721:Drosophila Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C080530:drk protein, Drosophila; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors