2. Academic Validation
  3. A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction

A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction

  • Nat Struct Mol Biol. 2022 Oct;29(10):990-999. doi: 10.1038/s41594-022-00838-z.
John T Happ # 1,  Corvin D Arveseth # 1 2,  Jessica Bruystens # 3,  Daniela Bertinetti # 4,  Isaac B Nelson # 1,  Cristina Olivieri # 5,  Jingyi Zhang 6,  Danielle S Hedeen 1,  Ju-Fen Zhu 1,  Jacob L Capener 1 7,  Jan W Bröckel 4,  Lily Vu 8,  C C King 3 9,  Victor L Ruiz-Perez 10 11,  Xuecai Ge 6,  Gianluigi Veglia 5,  Friedrich W Herberg 4,  Susan S Taylor 12 13,  Benjamin R Myers 14
Affiliations

Affiliations

  • 1 Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • 2 Washington University School of Medicine, St. Louis, MO, USA.
  • 3 Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
  • 4 Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, Germany.
  • 5 Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
  • 6 Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA.
  • 7 Biological and Biomedical Sciences Program, University of North Carolina, Chapel Hill, NC, USA.
  • 8 Department of Neurobiology, University of California, San Diego, La Jolla, CA, USA.
  • 9 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • 10 Instituto de Investigaciones Biomédicas 'Alberto Sols,' Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.
  • 11 CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
  • 12 Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA. staylor@ucsd.edu.
  • 13 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA. staylor@ucsd.edu.
  • 14 Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, USA. benjamin.myers@hci.utah.edu.
  • # Contributed equally.
PMID: 36202993 DOI: 10.1038/s41594-022-00838-z
Abstract

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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