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A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction.
Happ, John T; Arveseth, Corvin D; Bruystens, Jessica; Bertinetti, Daniela; Nelson, Isaac B; Olivieri, Cristina; Zhang, Jingyi; Hedeen, Danielle S; Zhu, Ju-Fen; Capener, Jacob L; Bröckel, Jan W; Vu, Lily; King, C C; Ruiz-Perez, Victor L; Ge, Xuecai; Veglia, Gianluigi; Herberg, Friedrich W; Taylor, Susan S; Myers, Benjamin R.
Afiliación
  • Happ JT; Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Arveseth CD; Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Bruystens J; Washington University School of Medicine, St. Louis, MO, USA.
  • Bertinetti D; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
  • Nelson IB; Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, Germany.
  • Olivieri C; Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Zhang J; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
  • Hedeen DS; Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA.
  • Zhu JF; Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Capener JL; Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Bröckel JW; Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Vu L; Biological and Biomedical Sciences Program, University of North Carolina, Chapel Hill, NC, USA.
  • King CC; Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, Germany.
  • Ruiz-Perez VL; Department of Neurobiology, University of California, San Diego, La Jolla, CA, USA.
  • Ge X; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
  • Veglia G; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • Herberg FW; Instituto de Investigaciones Biomédicas 'Alberto Sols,' Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.
  • Taylor SS; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
  • Myers BR; Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA.
Nat Struct Mol Biol ; 29(10): 990-999, 2022 10.
Article en En | MEDLINE | ID: mdl-36202993
The Hedgehog (Hh) cascade is central to development, tissue homeostasis and cancer. A pivotal step in Hh signal transduction is the activation of glioma-associated (GLI) transcription factors by the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO). How SMO activates GLI remains unclear. Here we show that SMO uses a decoy substrate sequence to physically block the active site of the cAMP-dependent protein kinase (PKA) catalytic subunit (PKA-C) and extinguish its enzymatic activity. As a result, GLI is released from phosphorylation-induced inhibition. Using a combination of in vitro, cellular and organismal models, we demonstrate that interfering with SMO-PKA pseudosubstrate interactions prevents Hh signal transduction. The mechanism uncovered echoes one used by the Wnt cascade, revealing an unexpected similarity in how these two essential developmental and cancer pathways signal intracellularly. More broadly, our findings define a mode of GPCR-PKA communication that may be harnessed by a range of membrane receptors and kinases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Drosophila / Antineoplásicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Drosophila / Antineoplásicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Struct Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos