Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits.
| Title: | Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits. |
|---|---|
| Authors: | Arveseth CD; Department of Oncological Sciences, Department of Biochemistry, Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Happ JT; Department of Oncological Sciences, Department of Biochemistry, Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Hedeen DS; Department of Oncological Sciences, Department of Biochemistry, Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Zhu JF; Department of Oncological Sciences, Department of Biochemistry, Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Capener JL; Department of Oncological Sciences, Department of Biochemistry, Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Klatt Shaw D; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Deshpande I; Department of Pharmaceutical Chemistry, Department of Anaesthesia and Perioperative Care, University of California, San Francisco, California, United States of America.; Liang J; Department of Pharmaceutical Chemistry, Department of Anaesthesia and Perioperative Care, University of California, San Francisco, California, United States of America.; Xu J; Department of Cellular and Molecular Pharmacology, Quantitative Biosciences Institute, University of California, San Francisco, California, United States of America.; J. David Gladstone Institutes, San Francisco, California, United States of America.; Stubben SL; Department of Oncological Sciences, Department of Biochemistry, Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Nelson IB; Department of Oncological Sciences, Department of Biochemistry, Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Walker MF; Department of Oncological Sciences, Department of Biochemistry, Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Kawakami K; Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.; Inoue A; Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.; Krogan NJ; Department of Cellular and Molecular Pharmacology, Quantitative Biosciences Institute, University of California, San Francisco, California, United States of America.; J. David Gladstone Institutes, San Francisco, California, United States of America.; Grunwald DJ; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Hüttenhain R; Department of Cellular and Molecular Pharmacology, Quantitative Biosciences Institute, University of California, San Francisco, California, United States of America.; J. David Gladstone Institutes, San Francisco, California, United States of America.; Manglik A; Department of Pharmaceutical Chemistry, Department of Anaesthesia and Perioperative Care, University of California, San Francisco, California, United States of America.; Myers BR; Department of Oncological Sciences, Department of Biochemistry, Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America. |
| Source: | PLoS biology [PLoS Biol] 2021 Apr 22; Vol. 19 (4), pp. e3001191. Date of Electronic Publication: 2021 Apr 22 (Print Publication: 2021). |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| Language: | English |
| Journal Info: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: eCollection Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: San Francisco, CA : Public Library of Science, [2003]- |
| MeSH Terms: | Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/*antagonists & inhibitors ; Hedgehog Proteins/*metabolism ; Smoothened Receptor/*physiology; Catalytic Domain/genetics ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/chemistry ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/metabolism ; Hedgehog Proteins/genetics ; Protein Interaction Domains and Motifs/genetics ; Signal Transduction/genetics ; Smoothened Receptor/metabolism ; Animals ; Animals, Genetically Modified ; Cells, Cultured ; Embryo, Nonmammalian ; HEK293 Cells ; Humans ; Mice ; Zebrafish |
| Abstract: | The Hedgehog (Hh) pathway is essential for organ development, homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein-coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here, we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase (GRK)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology. |
| Competing Interests: | The authors have declared that no competing interests exist. |
| References: | Development. 1996 Dec;123:153-64. (PMID: 9007237); Sci Signal. 2014 Jul 01;7(332):ra62. (PMID: 24985345); Science. 2004 Dec 24;306(5705):2257-60. (PMID: 15618519); Dev Cell. 2012 Oct 16;23(4):823-35. (PMID: 22981989); Nat Cell Biol. 2000 Jul;2(7):E133-6. (PMID: 10878827); Nature. 1996 Aug 8;382(6591):547-51. (PMID: 8700230); Nature. 2000 Aug 31;406(6799):1005-9. (PMID: 10984056); Genes Dev. 1996 Feb 1;10(3):301-12. (PMID: 8595881); Biochim Biophys Acta. 2013 Jul;1834(7):1271-8. (PMID: 23535202); Nat Med. 2013 Nov;19(11):1505-12. (PMID: 24076664); Dev Dyn. 2008 Aug;237(8):2030-8. (PMID: 18488998); Development. 2011 Nov;138(22):4921-30. (PMID: 22007132); Nat Rev Mol Cell Biol. 2013 Jul;14(7):416-29. (PMID: 23719536); Cell Commun Signal. 2017 Sep 20;15(1):35. (PMID: 28931407); Nat Genet. 2018 Mar;50(3):460-471. (PMID: 29459677); Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17026-31. (PMID: 16282375); Genesis. 2015 Sep;53(9):612-626. (PMID: 26219237); Nat Commun. 2014 Dec 05;5:5680. (PMID: 25477193); Biochemistry. 2001 Jan 9;40(1):225-31. (PMID: 11141074); Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50. (PMID: 12209124); Trends Pharmacol Sci. 2011 Sep;32(9):521-33. (PMID: 21680031); Mol Cell Biol. 2006 Oct;26(20):7550-60. (PMID: 16908539); Cell. 2013 Jan 17;152(1-2):210-23. (PMID: 23332756); J Biol Chem. 1996 Sep 13;271(37):22552-62. (PMID: 8798423); Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13069-13074. (PMID: 27799542); Genes Dev. 1996 Mar 15;10(6):647-58. (PMID: 8598293); Mol Syst Biol. 2011 Oct 11;7:539. (PMID: 21988835); Development. 2011 Jun;138(12):2533-42. (PMID: 21610030); Cell. 2010 Jun 25;141(7):1208-19. (PMID: 20603001); J Mol Biol. 2012 Sep 14;422(2):215-29. (PMID: 22617327); Curr Biol. 2009 Aug 11;19(15):1320-6. (PMID: 19592253); J Cell Biol. 2021 May 3;220(5):. (PMID: 33856408); Development. 2014 Sep;141(18):3445-57. (PMID: 25183867); Development. 2001 Jun;128(12):2385-96. (PMID: 11493557); Cell. 1996 Jul 26;86(2):221-32. (PMID: 8706127); Development. 2018 Jan 8;145(1):. (PMID: 29222391); PLoS One. 2009;4(4):e5182. (PMID: 19365551); Cell Signal. 2017 Sep;37:1-11. (PMID: 28528970); J Cell Biol. 2020 Jul 6;219(7):. (PMID: 32435793); Bioinformatics. 2014 Sep 1;30(17):2524-6. (PMID: 24794931); Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13377-82. (PMID: 19666503); J Cell Biol. 2000 Feb 21;148(4):715-26. (PMID: 10684253); Proc Natl Acad Sci U S A. 2019 Jun 11;116(24):12066-12071. (PMID: 31142652); Sci Rep. 2020 Oct 15;10(1):17395. (PMID: 33060647); Cell. 2000 Feb 18;100(4):423-34. (PMID: 10693759); J Cell Biol. 2016 Mar 28;212(7):861-75. (PMID: 27002170); Curr Biol. 2003 Jul 15;13(14):1169-81. (PMID: 12867027); Structure. 2015 Sep 1;23(9):1563-1572. (PMID: 26278174); Cancer Cell. 2017 Oct 9;32(4):404-410. (PMID: 29017054); Curr Opin Genet Dev. 2000 Jun;10(3):262-9. (PMID: 10826992); Dev Biol. 2008 Sep 1;321(1):188-96. (PMID: 18590719); Mol Pharmacol. 2018 Sep;94(3):1079-1091. (PMID: 29980659); Science. 2008 Jun 27;320(5884):1777-81. (PMID: 18497258); Nature. 2015 Aug 20;524(7565):315-21. (PMID: 26245379); J Exp Med. 2019 Jul 1;216(7):1582-1598. (PMID: 31147448); Nat Biotechnol. 2008 Dec;26(12):1367-72. (PMID: 19029910); Cells. 2020 Jan 03;9(1):. (PMID: 31947770); Annu Rev Cell Dev Biol. 2011;27:513-37. (PMID: 21801010); BMC Cell Biol. 2008 Sep 13;9:49. (PMID: 18789160); ACS Chem Biol. 2016 Feb 19;11(2):400-8. (PMID: 26569370); Trends Cell Biol. 2010 May;20(5):287-98. (PMID: 20207148); Dev Cell. 2006 Feb;10(2):177-86. (PMID: 16459297); Nat Struct Mol Biol. 2018 Mar;25(3):289-296. (PMID: 29434346); Cell. 1995 Feb 24;80(4):563-72. (PMID: 7867064); Cell Rep. 2018 Jan 30;22(5):1169-1184. (PMID: 29386106); Cell. 1995 Feb 24;80(4):553-62. (PMID: 7867063); Sci Signal. 2018 Feb 06;11(516):. (PMID: 29438011); Biochem Biophys Res Commun. 2006 Oct 20;349(2):471-9. (PMID: 16945339); Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11141-E11150. (PMID: 29229834); Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):349-54. (PMID: 15630084); Trends Biochem Sci. 2020 May;45(5):397-410. (PMID: 32311334); PLoS Genet. 2013;9(12):e1003955. (PMID: 24339784); Dev Dyn. 1995 Jul;203(3):253-310. (PMID: 8589427); Nature. 2011 Jan 13;469(7329):175-80. (PMID: 21228869); Dev Dyn. 2000 Nov;219(3):287-303. (PMID: 11066087); Biochemistry. 2015 Jul 21;54(28):4320-9. (PMID: 26120872); Dev Cell. 2013 Aug 26;26(4):346-57. (PMID: 23954590); J Biol Chem. 2000 Aug 25;275(34):26322-7. (PMID: 10835429); Nat Cell Biol. 2014 Jul;16(7):663-72. (PMID: 24952464); PLoS Genet. 2005 Oct;1(4):e53. (PMID: 16254602); Cell Rep. 2017 Apr 18;19(3):617-629. (PMID: 28423323); Dev Biol. 1998 Feb 15;194(2):166-71. (PMID: 9501021); J Cell Sci. 2010 Jan 1;123(Pt 1):62-9. (PMID: 20016067); Dev Cell. 2016 Aug 22;38(4):333-44. (PMID: 27554855); PLoS Genet. 2014 Jul 10;10(7):e1004399. (PMID: 25009998); Cell Chem Biol. 2017 Mar 16;24(3):252-280. (PMID: 28286127); Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450. (PMID: 30395289); Genes Dev. 2010 Apr 1;24(7):670-82. (PMID: 20360384); Annu Rev Biochem. 1999;68:821-61. (PMID: 10872467); EMBO Rep. 2016 May;17(5):739-52. (PMID: 27113758); Nature. 2020 Mar;579(7798):303-308. (PMID: 31945771); Sci Signal. 2018 Feb 06;11(516):. (PMID: 29438014); Trends Pharmacol Sci. 2012 Mar;33(3):154-64. (PMID: 22277298); Proc Natl Acad Sci U S A. 1992 May 15;89(10):4726-30. (PMID: 1584809); Nat Rev Mol Cell Biol. 2012 Oct;13(10):646-58. (PMID: 22992589); Mol Pharmacol. 2013 Mar;83(3):691-7. (PMID: 23292797); Dev Cell. 2005 Feb;8(2):267-78. (PMID: 15691767); Cell Signal. 2018 Jan;41:17-24. (PMID: 28711719); Anal Chem. 2019 Jan 2;91(1):126-141. (PMID: 30457327); Nat Commun. 2014 Oct 07;5:5034. (PMID: 25289679); Nat Rev Genet. 2010 May;11(5):331-44. (PMID: 20395968); Development. 2000 May;127(10):2189-99. (PMID: 10769242); Mol Cell Proteomics. 2018 Jun;17(6):1239-1244. (PMID: 29487113); Cell. 2017 Apr 20;169(3):407-421.e16. (PMID: 28431242); Science. 2007 Jul 20;317(5836):372-6. (PMID: 17641202); Trends Pharmacol Sci. 2007 Aug;28(8):362-5. (PMID: 17629577); Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21666-71. (PMID: 19996169); Nature. 2005 Oct 13;437(7061):1018-21. (PMID: 16136078); Sci Signal. 2009 Jun 23;2(76):ra29. (PMID: 19549984); Cell Rep. 2014 Jan 16;6(1):168-181. (PMID: 24373970); Development. 2006 Jan;133(1):3-14. (PMID: 16339192); J Mol Biol. 2012 Mar 16;417(1-2):95-111. (PMID: 22306739); Bioinformatics. 2010 Apr 1;26(7):966-8. (PMID: 20147306); Mol Pharmacol. 2015 Aug;88(2):347-56. (PMID: 26013542); Wiley Interdiscip Rev Dev Biol. 2020 Nov;9(6):e377. (PMID: 32084300); Eur Phys J E Soft Matter. 2021 Mar 8;44(2):18. (PMID: 33683488); PLoS One. 2018 Jan 11;13(1):e0189209. (PMID: 29324744); Curr Opin Cell Biol. 2014 Apr;27:25-31. (PMID: 24680427); Nature. 2019 Jul;571(7764):284-288. (PMID: 31263273); Nature. 2020 Mar;579(7798):297-302. (PMID: 31945772); Development. 2009 Sep;136(18):3089-98. (PMID: 19700616); Mol Pharmacol. 2020 Feb;97(2):62-71. (PMID: 31591260); Development. 1996 Sep;122(9):2835-46. (PMID: 8787757); Dev Biol. 2010 Mar 15;339(2):407-17. (PMID: 20060823); Development. 2019 May 15;146(10):. (PMID: 31092502); ACS Chem Biol. 2018 Feb 16;13(2):467-474. (PMID: 28892606); Nat Rev Genet. 2011 Jun;12(6):393-406. (PMID: 21502959); Genes Dev. 2001 Dec 1;15(23):3059-87. (PMID: 11731473); Curr Protoc Pharmacol. 2008 Jun;Chapter 1:Unit1.2. (PMID: 22294216); Science. 1991 Jul 26;253(5018):414-20. (PMID: 1862343); Sci Signal. 2015 Jun 02;8(379):ra55. (PMID: 26038600); Dev Cell. 2015 Nov 23;35(4):497-512. (PMID: 26585297); Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12607-12. (PMID: 16885213); BMC Biol. 2010 Apr 19;8:65. (PMID: 20487519); PLoS Biol. 2011 Jun;9(6):e1001083. (PMID: 21695114); Bioinformatics. 2014 Mar 15;30(6):884-6. (PMID: 24162465); Genes Dev. 1999 Feb 15;13(4):388-93. (PMID: 10049354); Cell. 1997 Jun 27;89(7):1043-53. (PMID: 9215627); Cell. 1999 Mar 19;96(6):819-31. (PMID: 10102270); Cell. 2001 Jun 15;105(6):781-92. (PMID: 11440720); Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3196-201. (PMID: 19218434); Science. 2009 Nov 27;326(5957):1220-4. (PMID: 19965465); J Mol Biol. 2011 Aug 26;411(4):823-36. (PMID: 21740913); Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7786-91. (PMID: 27357676); J Biol Chem. 2002 May 31;277(22):19889-96. (PMID: 11886853); Nature. 2013 Mar 28;495(7442):534-8. (PMID: 23515162); Dev Cell. 2018 Jan 8;44(1):113-129.e8. (PMID: 29290584); Mol Biol Cell. 2008 Dec;19(12):5478-89. (PMID: 18815277) |
| Grant Information: | P30 CA042014 United States CA NCI NIH HHS; R35 GM133672 United States GM NIGMS NIH HHS; T32 HD007491 United States HD NICHD NIH HHS |
| Substance Nomenclature: | 0 (Hedgehog Proteins); 0 (SMO protein, human); 0 (Smoothened Receptor); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Catalytic Subunits) |
| Entry Date(s): | Date Created: 20210422 Date Completed: 20210824 Latest Revision: 20240402 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC8096101 |
| DOI: | 10.1371/journal.pbio.3001191 |
| PMID: | 33886552 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.