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Evolutionarily Conserved Role of G-Protein-Coupled Receptor Kinases in the Hedgehog Signaling Pathway

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G Protein-Coupled Receptor Kinases

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

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Abstract

Hedgehog (Hh) signaling plays a crucial role in the formation and maintenance of tissues in most animals. The key activator of cytoplasmic Hh signaling is an atypical G-protein-coupled receptor (GPCR) family protein called Smoothened (Smo). In response to binding of Hh ligands to their receptor Patched, Smo is conformationally activated by extensive phosphorylation of its cytoplasmic C-terminus and engages downstream pathway components to promote Hh target gene expression. GPCR kinases (GRKs) positively regulate Hh signaling, a function that has been conserved in both invertebrates and vertebrates. Direct phosphorylation of highly conserved clusters of Ser/Thr residues in the proximal Smo C-terminus by GRKs is important in controlling Smo trafficking and activating signaling. GRKs also indirectly affect Hh pathway activity by influencing cellular cAMP levels and thus the activity of protein kinase A, a key regulator of the Cubitus interruptus/GLI family transcription factors that mediate Hh transcriptional responses. This indirect role hints at a broader interconnectivity between GRKs, GPCR signaling, and Hh pathway function, an idea supported by the recent identification of several GPCRs that are capable of modulating Hh target gene expression.

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References

  1. Beachy PA, Karhadkar SS, Berman DM (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432(7015):324–331

    Article  CAS  PubMed  Google Scholar 

  2. Varjosalo M, Taipale J (2008) Hedgehog: functions and mechanisms. Genes Dev 22(18):2454–2472

    Article  CAS  PubMed  Google Scholar 

  3. Jiang J, Hui CC (2008) Hedgehog signaling in development and cancer. Dev Cell 15(6):801–812

    Article  CAS  PubMed  Google Scholar 

  4. McMahon AP, Ingham PW, Tabin CJ (2003) Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 53:1–114

    Article  CAS  PubMed  Google Scholar 

  5. Briscoe J, Therond PP (2013) The mechanisms of hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 14(7):416–429

    Article  PubMed  Google Scholar 

  6. Chen Y, Li S, Tong C, Zhao Y, Wang B, Liu Y, Jia J, Jiang J (2010) G protein-coupled receptor kinase 2 promotes high-level hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila. Genes Dev 24(18):2054–2067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cheng S, Maier D, Neubueser D, Hipfner DR (2010) Regulation of smoothened by Drosophila G-protein-coupled receptor kinases. Dev Biol 337(1):99–109

    Article  CAS  PubMed  Google Scholar 

  8. Molnar C, Holguin H, Mayor FJ, Ruiz-Gomez A, de Celis JF (2007) The G protein-coupled receptor regulatory kinase GPRK2 participates in hedgehog signaling in Drosophila. Proc Natl Acad Sci U S A 104:7963–7968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Philipp M, Fralish GB, Meloni AR, Chen W, MacInnes AW, Barak LS, Caron MG (2008) Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinase. Mol Cel Biol 19(12):5478–5489

    Article  CAS  Google Scholar 

  10. Moore CA, Milano SK, Benovic JL (2007) Regulation of receptor trafficking by GRKs and arrestins. Annu Rev Physiol 69:451–482

    Article  CAS  PubMed  Google Scholar 

  11. Chen Y, Sasai N, Ma G, Yue T, Jia J, Briscoe J, Jiang J (2011) Sonic hedgehog dependent phosphorylation by CK1alpha and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol 9(6):e1001083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Maier D, Cheng S, Faubert D, Hipfner DR (2014) A broadly conserved g-protein-coupled receptor kinase phosphorylation mechanism controls Drosophila smoothened activity. PLoS Genet 10(7):e1004399

    Article  PubMed  PubMed Central  Google Scholar 

  13. Cheng S, Maier D, Hipfner DR (2012) Drosophila G-protein-coupled receptor kinase 2 regulates cAMP-dependent hedgehog signaling. Development 139(1):85–94

    Article  CAS  PubMed  Google Scholar 

  14. Hooper JE, Scott VP (2005) Communicating with hedgehogs. Nat Rev Mol Cell Biol 6(4):306–317

    Article  CAS  PubMed  Google Scholar 

  15. Blair SS (1995) Compartments and appendage development in Drosophila. Bioessays 17(4):299–309

    Article  CAS  PubMed  Google Scholar 

  16. Tabata T, Kornberg TB (1994) Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 76(1):89–102

    Article  CAS  PubMed  Google Scholar 

  17. Eaton S, Kornberg TB (1990) Repression of ci-D in posterior compartments of Drosophila by engrailed. Genes Dev 4(6):1068–1077

    Article  CAS  PubMed  Google Scholar 

  18. Strigini M, Cohen SM (1997) A hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development 124(22):4697–4705

    CAS  PubMed  Google Scholar 

  19. Capdevila J, Guerrero I (1994) Targeted expression of the signaling molecule decapentaplegic induces pattern duplications and growth alterations in Drosophila wings. EMBO J 13(19):4459–4468

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Phillips RG, Roberts IJ, Ingham PW, Whittle JR (1990) The Drosophila segment polarity gene patched is involved in a position-signalling mechanism in imaginal discs. Development 110(1):105–114

    CAS  PubMed  Google Scholar 

  21. Bier E (2005) Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 6(1):9–23

    Article  CAS  PubMed  Google Scholar 

  22. Ribes V, Briscoe J (2009) Establishing and interpreting graded sonic hedgehog signaling during vertebrate neural tube patterning: the role of negative feedback. Cold Spring Harb Perspect Biol 1(2):a002014

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ingham PW, Nakano Y, Seger C (2011) Mechanisms and functions of hedgehog signalling across the metazoa. Nat Rev Genet 12(6):393–406

    Article  CAS  PubMed  Google Scholar 

  24. Chen Y, Jiang J (2013) Decoding the phosphorylation code in hedgehog signal transduction. Cell Res 23(2):186–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Aza-Blanc P, Ramírez-Weber FA, Laget MP, Schwartz C, Kornberg TB (1997) Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89(7):1043–1053

    Article  CAS  PubMed  Google Scholar 

  26. Methot N, Basler K (1999) Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell 96(6):819–831

    Article  CAS  PubMed  Google Scholar 

  27. Wang B, Fallon JF, Beachy PA (2000) Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100(4):423–434

    Article  CAS  PubMed  Google Scholar 

  28. Denef N, Neubüser D, Perez L, Cohen SM (2000) Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 102(4):521–531

    Article  CAS  PubMed  Google Scholar 

  29. Li S, Chen Y, Shi Q, Yue T, Wang B, Jiang J (2012) Hedgehog-regulated ubiquitination controls smoothened trafficking and cell surface expression in Drosophila. PLoS Biol 10(1):e1001239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xia R, Jia H, Fan J, Liu Y, Jia J (2012) USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization. PLoS Biol 10(1):e1001238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nachtergaele S, Mydock LK, Krishnan K, Rammohan J, Schlesinger PH, Covey DF, Rohatgi R (2012) Oxysterols are allosteric activators of the oncoprotein smoothened. Nat Chem Biol 8(2):211–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA (2000) Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature 406(6799):1005–1009

    Article  CAS  PubMed  Google Scholar 

  33. Callejo A, Culi J, Guerrero I (2008) Patched, the receptor of hedgehog, is a lipoprotein receptor. Proc Natl Acad Sci U S A 105(3):912–917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Khaliullina H, Panáková D, Eugster C, Riedel F, Carvalho M, Eaton S (2009) Patched regulates smoothened trafficking using lipoprotein-derived lipids. Development 136(24):4111–4121

    Article  CAS  PubMed  Google Scholar 

  35. Methot N, Basler K (2000) Suppressor of fused opposes hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development 127(18):4001–4010

    CAS  PubMed  Google Scholar 

  36. Monnier V, Dussillol F, Alves G, Lamour-Isnard C, Plessis A (1998) Suppressor of fused links fused and Cubitus interruptus on the hedgehog signalling pathway. Curr Biol 8(10):583–586

    Article  CAS  PubMed  Google Scholar 

  37. Robbins DJ, Nybakken KE, Kobayashi R, Sisson JC, Bishop JM, Thérond PP (1997) Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell 90(2):225–234

    Article  CAS  PubMed  Google Scholar 

  38. Sisson JC, Ho KS, Suyama K, Scott MP (1997) Costal2, a novel kinesin-related protein in the hedgehog signaling pathway. Cell 90(2):235–245

    Article  CAS  PubMed  Google Scholar 

  39. Stegman MA, Vallance JE, Elangovan G, Sosinski J, Cheng Y, Robbins DJ (2000) Identification of a tetrameric hedgehog signaling complex. J Biol Chem 275(29):21809–21812

    Article  CAS  PubMed  Google Scholar 

  40. Wang G, Amanai K, Wang B, Jiang J (2000) Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus. Genes Dev 14(22):2893–2905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Price MA, Kalderon D (1999) Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by protein kinase A. Development 126(19):4331–4339

    CAS  PubMed  Google Scholar 

  42. Price MA, Kalderon D (2002) Proteolysis of the hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell 108(6):823–835

    Article  CAS  PubMed  Google Scholar 

  43. Wang G, Wang B, Jiang J (1999) Protein kinase A antagonizes hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus. Genes Dev 13(21):2828–2837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang W, Zhao Y, Tong C, Wang G, Wang B, Jia J, Jiang J (2005) Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Dev Cell 8(2):267–278

    Article  CAS  PubMed  Google Scholar 

  45. Jia J, Amanai K, Wang G, Tang J, Wang B, Jiang J (2002) Shaggy/GSK3 antagonizes hedgehog signalling by regulating Cubitus interruptus. Nature 416(6880):548–552

    Article  CAS  PubMed  Google Scholar 

  46. Zhao Y, Tong C, Jiang J (2007) Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450(7167):252–258

    Article  CAS  PubMed  Google Scholar 

  47. Apionishev S, Katanayeva NM, Marks SA, Kalderon D, Tomlinson A (2005) Drosophila smoothened phosphorylation sites essential for hedgehog signal transduction. Nat Cell Biol 7(1):86–92

    Article  CAS  PubMed  Google Scholar 

  48. Jia J, Tong C, Wang B, Luo L, Jiang J (2004) Hedgehog signalling activity of smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432(7020):1045–1050

    Article  CAS  PubMed  Google Scholar 

  49. Zhang C, Williams EH, Guo Y, Lum L, Beachy PA (2004) Extensive phosphorylation of smoothened in hedgehog pathway activation. Proc Natl Acad Sci U S A 101(52):17900–17907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jia J, Tong C, Jiang J (2003) Smoothened transduces hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail. Genes Dev 17(21):2709–2720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lum L, Zhang C, Oh S, Mann RK, von Kessler DP, Taipale J, Weis-Garcia F, Gong R, Wang B, Beachy PA (2003) Hedgehog signal transduction via smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol Cell 12(5):1261–1274

    Article  CAS  PubMed  Google Scholar 

  52. Ogden SK, Ascano MJ, Stegman MA, Suber LM, Hooper JE, Robbins DJ (2003) Identification of a functional interaction between the transmembrane protein smoothened and the kinesin-related protein Costal2. Curr Biol 13(22):1998–2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ruel L, Rodriguez R, Gallet A, Lavenant-Staccini L, Thérond PP (2003) Stability and association of smoothened, Costal2 and fused with Cubitus interruptus are regulated by hedgehog. Nat Cell Biol 5(10):907–913

    Article  CAS  PubMed  Google Scholar 

  54. Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15(23):3059–3087

    Article  CAS  PubMed  Google Scholar 

  55. Hui CC, Angers S (2011) Gli proteins in development and disease. Annu Rev Cell Dev Biol 27:513–537

    Article  CAS  PubMed  Google Scholar 

  56. Goetz SC, Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11(5):331–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kuzhandaivel A, Schultz SW, Alkhori L, Alenius M (2014) Cilia-mediated hedgehog signaling in Drosophila. Cell Rep 7(3):672–680

    Article  CAS  PubMed  Google Scholar 

  58. Thérond PP, Knight JD, Kornberg TB, Bishop JM (1996) Phosphorylation of the fused protein kinase in response to signaling from hedgehog. Proc Natl Acad Sci U S A 93(9):4224–4228

    Article  PubMed  PubMed Central  Google Scholar 

  59. Liu Y, Cao X, Jiang J, Jia J (2007) Fused-Costal2 protein complex regulates hedgehog-induced Smo phosphorylation and cell-surface accumulation. Genes Dev 21(15):1949–1963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ruel L, Gallet A, Raisin S, Truchi A, Staccini-Lavenant L, Cervantes A, Thérond PP (2007) Phosphorylation of the atypical kinesin Costal2 by the kinase fused induces the partial disassembly of the Smoothened-Fused-Costal2-Cubitus interruptus complex in hedgehog signalling. Development 134(20):3677–3689

    Article  CAS  PubMed  Google Scholar 

  61. Chen MH, Gao N, Kawakami T, Chuang PT (2005) Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Mol Cell Biol 25(16):7042–7053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Merchant M, Evangelista M, Luoh SM, Frantz GD, Chalasani S, Carano RA, van Hoy M, Ramirez J, Ogasawara AK, McFarland LM, Filvaroff EH, French DM, de Sauvage FJ (2005) Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol 25(16):7054–7068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cheung HO, Zhang X, Ribeiro A, Mo R, Makino S, Puviindran V, Law KK, Briscoe J, Hui CC (2009) The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal 2(76):ra29

    Article  PubMed  Google Scholar 

  64. Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen JW, Phamluong K, Davis M, Scales SJ, Solloway MJ, de Sauvage FJ, Peterson AS (2009) The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol 19(15):1320–1326

    Article  CAS  PubMed  Google Scholar 

  65. Liem KFJ, He M, Ocbina PJ, Anderson KV (2009) Mouse Kif7/Costal2 is a cilia-associated protein that regulates sonic hedgehog signaling. Proc Natl Acad Sci U S A 106(32):13377–13382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cooper AF, Yu KP, Brueckner M, Brailey LL, Johnson L, McGrath JM, Bale AE (2005) Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development 132(19):4407–4417

    Article  CAS  PubMed  Google Scholar 

  67. Svärd J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergström A, Ericson J, Toftgård R, Teglund S (2006) Genetic elimination of suppressor of fused reveals an essential repressor function in the mammalian hedgehog signaling pathway. Dev Cell 10(2):187–197

    Article  PubMed  Google Scholar 

  68. Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, de Sauvage F, Lefkowitz RJ (2004) Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science 306:2257–2260

    Article  CAS  PubMed  Google Scholar 

  69. Meloni AR, Fralish GB, Kelly P, Salahpour A, Chen JK, Wechsler-Reya RJ, Lefkowitz RJ, Caron MG (2006) Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Mol Cell Biol 26(20):7550–7560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cassill JA, Whitney M, Joazeiro CAP, Becker A, Zuker CS (1991) Isolation of Drosophila genes encoding G protein-coupled receptor kinases. Proc Natl Acad Sci U S A 88:11067–11070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fan J, Liu Y, Jia J (2012) Hh-induced smoothened conformational switch is mediated by differential phosphorylation at its C-terminal tail in a dose- and position-dependent manner. Dev Biol 366(2):172–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wilbanks AM, Fralish GB, Kirby ML, Barak LS, Li YX, Caron MG (2004) Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway. Science 306:2264–2267

    Article  CAS  PubMed  Google Scholar 

  73. Molnar C, Ruiz-Gómez A, Martín M, Rojo-Berciano S, Mayor F, de Celis JF (2011) Role of the Drosophila non-visual ss-arrestin kurtz in hedgehog signalling. PLoS Genet 7(3):e1001335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lannutti BJ, Schneider LE (2001) Gprk2 controls cAMP levels in Drosophila development. Dev Biol 233(1):174–185

    Article  CAS  PubMed  Google Scholar 

  75. Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ (2005) Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor. Proc Natl Acad Sci U S A 102:1448–1453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Violin JD, Dewire SM, Barnes WG, Lefkowitz RJ (2006) G protein-coupled receptor kinase and beta-arrestin-mediated desensitization of the angiotensin II type 1A receptor elucidated by diacylglycerol dynamics. J Biol Chem 281(47):36411–36419

    Article  CAS  PubMed  Google Scholar 

  77. Gainetdinov RR, Bohn LM, Walker JK, Laporte SA, Macrae AD, Caron MG, Lefkowitz RJ, Premont RT (1999) Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice. Neuron 24(4):1029–1036

    Article  CAS  PubMed  Google Scholar 

  78. Premont RT, Gainetdinov RR (2007) Physiological roles of G protein-coupled receptor kinases and arrestins. Annu Rev Physiol 69:511–534

    Article  CAS  PubMed  Google Scholar 

  79. Ogden SK, Fei DL, Schilling NS, Ahmed YF, Hwa J, Robbins DJ (2008) G protein Galphai functions immediately downstream of smoothened in hedgehog signalling. Nature 456(7224):967–970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Shen F, Cheng L, Douglas AE, Riobo NA, Manning DR (2013) Smoothened is a fully competent activator of the heterotrimeric G protein G(i). Mol Pharmacol 83(3):691–697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Riobo NA, Saucy B, Dilizio C, Manning DR (2006) Activation of heterotrimeric G proteins by smoothened. Proc Natl Acad Sci U S A 103(33):12607–12612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Brody T, Cravchik A (2000) Drosophila melanogaster G protein-coupled receptors. J Cell Biol 150(2):F83–F88

    Article  CAS  PubMed  Google Scholar 

  83. Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales SJ, Jackson PK (2013) The ciliary G-protein-coupled receptor Gpr161 negatively regulates the sonic hedgehog pathway via cAMP signaling. Cell 152(1–2):210–223

    Article  CAS  PubMed  Google Scholar 

  84. Lelievre V, Seksenyan A, Nobuta H, Yong WH, Chhith S, Niewiadomski P, Cohen JR, Dong H, Flores A, Liau LM, Kornblum HI, Scott MP, Waschek JA (2008) Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice. Dev Biol 313(1):359–370

    Article  CAS  PubMed  Google Scholar 

  85. Nicot A, Lelièvre V, Tam J, Waschek JA, DiCicco-Bloom E (2002) Pituitary adenylate cyclase-activating polypeptide and sonic hedgehog interact to control cerebellar granule precursor cell proliferation. J Neurosci 22(21):9244–9254

    CAS  PubMed  Google Scholar 

  86. Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA, Luster AD (2001) SDF-1 alpha induces chemotaxis and enhances sonic hedgehog-induced proliferation of cerebellar granule cells. Development 128(11):1971–1981

    CAS  PubMed  Google Scholar 

  87. Lum L, Yao S, Mozer B, Rovescalli A, Von Kessler D, Nirenberg M, Beachy PA (2003) Identification of hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299(5615):2039–2045

    Article  CAS  PubMed  Google Scholar 

  88. Low WC, Wang C, Pan Y, Huang XY, Chen JK, Wang B (2008) The decoupling of smoothened from Galphai proteins has little effect on Gli3 protein processing and hedgehog-regulated chick neural tube patterning. Dev Biol 321(1):188–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jiang J, Struhl G (1995) Protein kinase A and hedgehog signaling in Drosophila limb development. Cell 80(4):563–572

    Article  CAS  PubMed  Google Scholar 

  90. Li W, Ohlmeyer JT, Lane ME, Kalderon D (1995) Function of protein kinase A in hedgehog signal transduction and Drosophila imaginal disc development. Cell 80(4):553–562

    Article  CAS  PubMed  Google Scholar 

  91. Salon JA, Lodowski DT, Palczewski K (2011) The significance of G protein-coupled receptor crystallography for drug discovery. Pharmacol Rev 63(4):901–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Epithelial Cell Biology Laboratory, Institut de recherches cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal, QC, Canada, H2W 1R7

    Dominic Maier & David R. Hipfner

  2. Département de médecine, Université de Montréal, Montreal, QC, Canada, H3C 3J7

    David R. Hipfner

  3. Departments of Anatomy and Cell Biology and Biology, McGill University, Montreal, QC, Canada, H3A 1A3

    David R. Hipfner

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  1. Dominic Maier
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  2. David R. Hipfner
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Correspondence to David R. Hipfner .

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Editors and Affiliations

  1. Department of Pharmacology, Vanderbilt University , NASHVILLE, Tennessee, USA

    Vsevolod V. Gurevich

  2. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA

    Eugenia V. Gurevich

  3. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA

    John J.G. Tesmer

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Maier, D., Hipfner, D.R. (2016). Evolutionarily Conserved Role of G-Protein-Coupled Receptor Kinases in the Hedgehog Signaling Pathway. In: Gurevich, V., Gurevich, E., Tesmer, J. (eds) G Protein-Coupled Receptor Kinases. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3798-1_14

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