title: Identification of a novel actin-dependent signal transducing module allows for the targeted degradation of GLI1.
abstract: The Down syndrome-associated DYRK1A kinase has been reported as a stimulator of the developmentally important Hedgehog (Hh) pathway, but cells from Down syndrome patients paradoxically display reduced Hh signalling activity. Here we find that DYRK1A stimulates GLI transcription factor activity through phosphorylation of general nuclear localization clusters. In contrast, in vivo and in vitro experiments reveal that DYRK1A kinase can also function as an inhibitor of endogenous Hh signalling by negatively regulating ABLIM proteins, the actin cytoskeleton and the transcriptional co-activator MKL1 (MAL). As a final effector of the DYRK1A-ABLIM-actin-MKL1 sequence, we identify the MKL1 interactor Jumonji domain demethylase 1A (JMJD1A) as a novel Hh pathway component stabilizing the GLI1 protein in a demethylase-independent manner. Furthermore, a Jumonji-specific small-molecule antagonist represents a novel and powerful inhibitor of Hh signal transduction by inducing GLI1 protein degradation in vitro and in vivo.
authors: Department of Medicine, Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Hans-Meerwein-Street 3, 35043 Marburg, Germany.
authors: Philipp
authors: P
authors: Schneider
authors: Department of Pharmacology, UT Southwestern Medical Center, 6000 Harry Hines boulevard, Dallas, Texas 75390-8593, USA.
authors: Juan Miguel
authors: JM
authors: Bayo-Fina
authors: Department of Medicine, Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Hans-Meerwein-Street 3, 35043 Marburg, Germany.
authors: Rajeev
authors: R
authors: Singh
authors: Department of Medicine, Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Hans-Meerwein-Street 3, 35043 Marburg, Germany.
authors: Pavan
authors: P
authors: Kumar Dhanyamraju
authors: Department of Medicine, Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Hans-Meerwein-Street 3, 35043 Marburg, Germany.
authors: Philipp
authors: P
authors: Holz
authors: Department of Surgery, Philipps University, Baldingerstraße 1, 35033 Marburg, Germany.
authors: Aninja
authors: A
authors: Baier
authors: Department of Surgery, Philipps University, Baldingerstraße 1, 35033 Marburg, Germany.
authors: Volker
authors: V
authors: Fendrich
authors: Department of Pathology, Philipps University, Baldingerstraße 1, 35033 Marburg, Germany.
authors: Annette
authors: A
authors: Ramaswamy
authors: Department of Biology, Philipps University, Karl-von-Frisch-Straße 8, 35043 Marburg, Germany.
authors: Stefan
authors: S
authors: Baumeister
authors: Department of Pharmacology, UT Southwestern Medical Center, 6000 Harry Hines boulevard, Dallas, Texas 75390-8593, USA.
authors: Elisabeth D
authors: ED
authors: Martinez
authors: Department of Medicine, Philipps University, Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology, Hans-Meerwein-Street 3, 35043 Marburg, Germany.
authors: Matthias
authors: M
authors: Lauth
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins; D000818:Animals; D045744:Cell Line, Tumor; D004314:Down Syndrome / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1; D000097603:Dyrk Kinases
chemical_list: D000199:Actins; D053823:Hedgehog Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; D051741:Kruppel-Like Transcription Factors; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000097603:Dyrk Kinases; C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; C431575:MRTFA protein, human; C511173:Mrtfa protein, mouse; C530247:KDM3A protein, human; C511045:Kdm3a protein, mouse