title: Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling.
abstract: Gli proteins are transcriptional effectors of the Hedgehog (Hh) pathway in both normal development and cancer. We describe a program of multisite phosphorylation that regulates the conversion of Gli proteins into transcriptional activators. In the absence of Hh ligands, Gli activity is restrained by the direct phosphorylation of six conserved serine residues by protein kinase A (PKA), a master negative regulator of the Hh pathway. Activation of signaling leads to a global remodeling of the Gli phosphorylation landscape: the PKA target sites become dephosphorylated, while a second cluster of sites undergoes phosphorylation. The pattern of Gli phosphorylation can regulate Gli transcriptional activity in a graded fashion, suggesting a phosphorylation-based mechanism for how a gradient of Hh signaling in a morphogenetic field can be converted into a gradient of transcriptional activity.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.|Department of Cell Biology, Nencki Institute of Experimental Biology, 02-093 Warszawa, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Niewiadomski
authors.affiliation: Department of Neurobiology, Eli and Edythe Broad Stem Cell Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Kong
authors.affiliation: Department of Biochemistry, and Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.|Laboratory of Quantitative Systems Analysis, Leibniz-Institute for Analytical Sciences - ISAS - e.V., 44227 Dortmund, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Ahrends
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Humke
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sohini
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Biochemistry, and Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mary N
authors.initials: MN
authors.lastname: Teruel
authors.affiliation: Department of Neurobiology, Eli and Edythe Broad Stem Cell Research Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Bennett G
authors.initials: BG
authors.lastname: Novitch
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Rajat
authors.initials: R
authors.lastname: Rohatgi
mesh_terms: D000818:Animals; D002642:Chick Embryo; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases