A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction.
| Title: | A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction. |
|---|---|
| Authors: | 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.; Washington University School of Medicine, St. Louis, MO, USA.; Bruystens J; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.; Bertinetti D; Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, Germany.; Nelson IB; Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, USA.; Olivieri C; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.; Zhang J; Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA.; Hedeen DS; Department of Oncological Sciences, Department of Biochemistry, and Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, UT, 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.; Biological and Biomedical Sciences Program, University of North Carolina, Chapel Hill, NC, USA.; Bröckel JW; Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, Germany.; Vu L; Department of Neurobiology, University of California, San Diego, La Jolla, CA, USA.; King CC; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.; Ruiz-Perez VL; Instituto de Investigaciones Biomédicas 'Alberto Sols,' Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid, Spain.; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.; Ge X; Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA.; Veglia G; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.; Herberg FW; Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, Germany.; Taylor SS; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA. staylor@ucsd.edu.; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA. staylor@ucsd.edu.; Myers BR; 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. |
| Source: | Nature structural & molecular biology [Nat Struct Mol Biol] 2022 Oct; Vol. 29 (10), pp. 990-999. Date of Electronic Publication: 2022 Oct 06. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101186374 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1545-9985 (Electronic) Linking ISSN: 15459985 NLM ISO Abbreviation: Nat Struct Mol Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York : Nature Pub. Group, c2004- |
| MeSH Terms: | Drosophila Proteins*/metabolism ; Antineoplastic Agents*; Cyclic AMP-Dependent Protein Kinases/metabolism ; Hedgehog Proteins/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction/physiology ; Smoothened Receptor/genetics ; Smoothened Receptor/metabolism ; Transcription Factors/metabolism ; Intracellular Signaling Peptides and Proteins |
| 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.; (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.) |
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| Grant Information: | R15 CA235749 United States CA NCI NIH HHS; R03 TR002947 United States TR NCATS NIH HHS; R35 GM133672 United States GM NIGMS NIH HHS; R21 CA274595 United States CA NCI NIH HHS; R01 GM100310 United States GM NIGMS NIH HHS; R01 GM143276 United States GM NIGMS NIH HHS; R35 GM130389 United States GM NIGMS NIH HHS |
| Substance Nomenclature: | 0 (Antineoplastic Agents); 0 (Drosophila Proteins); 0 (Hedgehog Proteins); 0 (Intracellular Signaling Peptides and Proteins); 0 (Receptors, G-Protein-Coupled); 0 (Smoothened Receptor); 0 (Transcription Factors); 0 (protein kinase modulator); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) |
| Entry Date(s): | Date Created: 20221006 Date Completed: 20221018 Latest Revision: 20250104 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9696579 |
| DOI: | 10.1038/s41594-022-00838-z |
| PMID: | 36202993 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't