title: Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused.
abstract: Smoothened (SMO) is a G-protein-coupled receptor-related protein required for the transduction of Hedgehog (HH). The HH gradient leads to graded phosphorylation of SMO, mainly by the PKA and CKI kinases. How thresholds in HH morphogen regulate SMO to promote switch-like transcriptional responses is a central unsolved issue. Using the wing imaginal disc model inDrosophila, we identified new SMO phosphosites that enhance the effects of the PKA/CKI kinases on SMO accumulation, its localization at the plasma membrane and its activity. Surprisingly, phosphorylation at these sites is induced by the kinase Fused (FU), a known downstream effector of SMO. In turn, activation of SMO induces FU to act on its downstream targets. Overall, our data provide evidence for a SMO/FU positive regulatory loop nested within a multikinase phosphorylation cascade. We propose that this complex interplay amplifies signaling above a threshold that allows high HH signaling.
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Sanial
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bécam
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France.
authors.forename: Line
authors.initials: L
authors.lastname: Hofmann
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Behague
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Argüelles
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gourhand
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France.
authors.forename: Lucia
authors.initials: L
authors.lastname: Bruzzone
authors.affiliation: Department of Molecular Bioscience, Northwestern University, Evanston, IL 60208-3500, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Holmgren
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris F-75205, France anne.plessis@ijm.fr.
authors.forename: Anne
authors.identifier: 0000-0001-9193-7031
authors.initials: A
authors.lastname: Plessis
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor / Q000235:genetics / Q000378:metabolism*; D014921:Wings, Animal / Q000196:embryology / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D000072086:Smoothened Receptor; C100664:smo protein, Drosophila; D047389:Casein Kinase I; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Drosophila; Fused kinase; Hedgehog; Phosphorylation; SNAP-tag labeling; Signal transduction; Smoothened