title: Scaling the Drosophila Wing: TOR-Dependent Target Gene Access by the Hippo Pathway Transducer Yorkie.
abstract: Organ growth is controlled by patterning signals that operate locally (e.g., Wingless/Ints [Wnts], Bone Morphogenetic Proteins [BMPs], and Hedgehogs [Hhs]) and scaled by nutrient-dependent signals that act systemically (e.g., Insulin-like peptides [ILPs] transduced by the Target of Rapamycin [TOR] pathway). How cells integrate these distinct inputs to generate organs of the appropriate size and shape is largely unknown. The transcriptional coactivator Yorkie (Yki, a YES-Associated Protein, or YAP) acts downstream of patterning morphogens and other tissue-intrinsic signals to promote organ growth. Yki activity is regulated primarily by the Warts/Hippo (Wts/Hpo) tumour suppressor pathway, which impedes nuclear access of Yki by a cytoplasmic tethering mechanism. Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing. Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes. When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes--a phenomenon we term "nuclear seclusion." Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability.
authors.affiliation: Department of Genetics and Development, Columbia University, New York, New York, United States of America; Division of Biology, Imperial College London, London, United Kingdom.
authors.forename: Joseph
authors.initials: J
authors.lastname: Parker
authors.affiliation: Department of Genetics and Development, Columbia University, New York, New York, United States of America.
authors.forename: Gary
authors.initials: G
authors.lastname: Struhl
mesh_terms: D021581:Active Transport, Cell Nucleus; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D030801:Animals, Genetically Modified; D031204:Caloric Restriction / Q000009:adverse effects; D002467:Cell Nucleus / Q000378:metabolism*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007814:Larva / Q000166:cytology / Q000235:genetics / Q000502:physiology; D008164:Luminescent Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014921:Wings, Animal / Q000201:enzymology / Q000254:growth & development* / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D011993:Recombinant Fusion Proteins; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C471146:bantam microRNA, Drosophila; C416303:target of rapamycin protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases