title: Salt-inducible kinases regulate growth through the Hippo signalling pathway in Drosophila.
abstract: The specification of tissue size during development involves the coordinated action of many signalling pathways responding to organ-intrinsic signals, such as morphogen gradients, and systemic cues, such as nutrient status. The conserved Hippo (Hpo) pathway, which promotes both cell-cycle exit and apoptosis, is a major determinant of size control. The pathway core is a kinase cassette, comprising the kinases Hpo and Warts (Wts) and the scaffold proteins Salvador (Sav) and Mats, which inactivates the pro-growth transcriptional co-activator Yorkie (Yki). We performed a split-TEV-based genome-wide RNAi screen for modulators of Hpo signalling. We characterize the Drosophila salt-inducible kinases (Sik2 and Sik3) as negative regulators of Hpo signalling. Activated Sik kinases increase Yki target expression and promote tissue overgrowth through phosphorylation of Sav at Ser 413. As Sik kinases have been implicated in nutrient sensing, this suggests a link between the Hpo pathway and systemic growth control.
authors.affiliation: Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wehr
authors.forename: Maxine V
authors.initials: MV
authors.lastname: Holder
authors.forename: Ieva
authors.initials: I
authors.lastname: Gailite
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Saunders
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Maile
authors.forename: Elena
authors.initials: E
authors.lastname: Ciirdaeva
authors.forename: Rachael
authors.initials: R
authors.lastname: Instrell
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.forename: Moritz J
authors.initials: MJ
authors.lastname: Rossner
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tapon
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000254:growth & development / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D009929:Organ Size; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014921:Wings, Animal / Q000201:enzymology / Q000254:growth & development; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C465504:sav protein, Drosophila; C559671:salt-inducible kinase 3, Drosophila; C578378:Sik2 protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases