Skip to main content
SpringerLink
Log in
Book cover

The Smoothened Receptor in Cancer and Regenerative Medicine pp 13–42Cite as

Canonical and Non-Canonical Hedgehog Signaling Pathways: Role of G Proteins

  • Chapter
  • First Online:

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 16))

Abstract

The Hedgehog (Hh) signaling pathway has received a great deal of attention in the past decade due to its involvement in cancer, angiogenesis, and fibrosis. Several inhibitors of the pathway were developed which target the 7-transmembrane protein Smoothened (Smo), core component of the canonical pathway that controls Gli-dependent transcriptional activity. However, recent studies revealed that the Hh pathway has other transcription-independent functions, collectively known as “non-canonical signaling.” This review describes the role and function of each Hh pathway component in canonical and non-canonical signaling, with emphasis on the role of Smo as a GPCR that selectively activates heterotrimeric Gi proteins.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

12TM:

12 transmembrane

20(S)OHC:

20(S)-Hydroxycholesterol

25OHC:

25-hydroxycholesterol

5HT:

5-hydroxytriptamine

7TM:

7 transmembrane

AMP:

Adenosine monophosphate

cAMP:

3′-5′-cyclic adenosine monophosphate

CCK:

Cholecystokinin

ChIP:

Chromatin immunoprecipitation

CoA:

Coenzyme A

cyclopamine:

(2′R,3S,3′R,3′aS,6′S,6aS,6bS,7′aR,11aS,11bR)-1,2,3,3′a,4,4′,5′,6,6′,6a,6b,7,7′,7′a,8,11,11a,11b-Octadecahydro-3′,6′,10,11b-tetramethylspiro[9H-benzo[a]fluorene-9,2′(3′H)-furo[3,2-b]pyridin]-3-ol

GDC-0449:

(2-chloro-N-[4-chloro-3-pyridin-2-yl-phenyl]-4-methane-sulfonyl benzamide)

GSA-10:

4-[[(1-Hexyl-1,2-dihydro-2-oxo-3-quinolinyl)carbonyl]amino]benzoic acid propyl ester

GTP:

Guanosine-5′-triphosphate

GTPγ[S]:

Guanosine 5′-O-[γ-thio]triphosphate

H89:

N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide

LDE-225:

N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4′-(trifluoromethoxy)biphenyl-3-carboxamide

M25:

N-[[1-(2-Methoxyphenyl)-1H-indazol-5-yl]methyl]-2-propylpentanamide

NES:

Nuclear export signal

PI4P:

Phosphatidylinositol 4-phosphate

SAG:

N-Methyl-N′-(3-pyridinylbenzyl)-N′-(3-chlorobenzo[b]thiophene-2-carbonyl)-1,4-diaminocyclohexane

SANT-1:

(4-Benzyl-piperazin-1-yl)-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethylene)-amine

siRNA:

Small interference RNA

XL-139:

N-(2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2-yl)amino)benzamide

References

  1. Robbins DJ, Fei DL, Riobo NA (2012) The Hedgehog signal transduction network. Sci Signal 5(246):re6

    Google Scholar 

  2. Brennan D, Chen X, Cheng L, Mahoney M, Riobo NA (2012) Noncanonical Hedgehog signaling. Vitam Horm 88:55–72

    CAS  Google Scholar 

  3. Nozawa YI, Lin C, Chuang PT (2013) Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction. Curr Opin Genet Dev 23(4):429–437

    CAS  Google Scholar 

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

    Google Scholar 

  5. Hall TM, Porter JA, Beachy PA, Leahy DJ (1995) A potential catalytic site revealed by the 1.7-A crystal structure of the amino-terminal signalling domain of Sonic hedgehog. Nature 378(6553):212–216

    CAS  Google Scholar 

  6. Fuse N, Maiti T, Wang B et al (1999) Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for Patched. Proc Natl Acad Sci U S A 96(20):10992–10999

    CAS  Google Scholar 

  7. Hall TM, Porter JA, Young KE et al (1997) Crystal structure of a Hedgehog autoprocessing domain: homology between Hedgehog and self-splicing proteins. Cell 91(1):85–97

    CAS  Google Scholar 

  8. Lee JJ, Ekker SC, von Kessler DP et al (1994) Autoproteolysis in hedgehog protein biogenesis. Science 266(5190):1528–1537

    CAS  Google Scholar 

  9. Porter JA, von Kessler DP, Ekker SC et al (1995) The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature 374(6520):363–366

    CAS  Google Scholar 

  10. Porter JA, Ekker SC, Park WJ et al (1996) Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell 86(1):21–34

    CAS  Google Scholar 

  11. Porter JA, Young KE, Beachy PA (1996) Cholesterol modification of hedgehog signaling proteins in animal development. Science 274(5285):255–259

    CAS  Google Scholar 

  12. Tokhunts R, Singh S, Chu T et al (2010) The full-length unprocessed hedgehog protein is an active signaling molecule. J Biol Chem 285(4):2562–2568

    CAS  Google Scholar 

  13. Pepinsky RB, Zeng C, Wen D et al (1998) Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem 273(22):14037–14045

    CAS  Google Scholar 

  14. Mann RK, Beachy PA (2004) Novel lipid modifications of secreted protein signals. Annu Rev Biochem 73:891–923

    CAS  Google Scholar 

  15. Farazi TA, Waksman G, Gordon JI (2001) The biology and enzymology of protein N-myristoylation. J Biol Chem 276:39501–39504

    CAS  Google Scholar 

  16. Buglino JA, Resh MD (2012) Palmitoylation of Hedgehog proteins. Vitam Horm 88:229–252

    CAS  Google Scholar 

  17. Buglino JA, Resh MD (2008) Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. J Biol Chem 283:22076–22088

    CAS  Google Scholar 

  18. Chen MH, Li YJ, Kawakami T et al (2004) Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev 18:641–659

    CAS  Google Scholar 

  19. Martinez-Chinchilla P, Riobo NA (2008) Purification and bioassay of hedgehog ligands for the study of cell death and survival. Methods Enzymol 446:189–204

    CAS  Google Scholar 

  20. Caspary T, Garcia-Garcia MJ, Huangfu D et al (2002) Mouse Dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr Biol 12:1628–1632

    CAS  Google Scholar 

  21. Kawakami T, Kawcak T, Li YJ et al (2002) Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development 129:5753–5765

    CAS  Google Scholar 

  22. Ma Y, Erkner A, Gong R et al (2002) Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111:63–75

    CAS  Google Scholar 

  23. Creanga A, Glenn TD, Mann RK et al (2012) Scube/You activity mediates release of dually lipid-modified Hedgehog signal in soluble form. Genes Dev 26(12):1312–1325

    CAS  Google Scholar 

  24. Zeng X, Goetz JA, Suber LM et al (2001) A freely diffusible form of Sonic hedgehog mediates long-range signalling. Nature 411:716–720

    CAS  Google Scholar 

  25. Gallet A, Ruel L, Staccini-Lavenant L, Therond PP (2006) Cholesterol modification is necessary for controlled planar long-range activity of Hedgehog in Drosophila epithelia. Development 133:407–418

    CAS  Google Scholar 

  26. Martínez MC, Larbret F, Zobairi F et al (2006) Transfer of differentiation signal by membrane microvesicles harboring hedgehog morphogens. Blood 108(9):3012–3020

    Google Scholar 

  27. Soleti R, Benameur T, Porro C et al (2009) Microparticles harboring Sonic Hedgehog promote angiogenesis through the upregulation of adhesion proteins and proangiogenic factors. Carcinogenesis 30(4):580–588

    CAS  Google Scholar 

  28. Benameur T, Soleti R, Porro C et al (2010) Microparticles carrying Sonic hedgehog favor neovascularization through the activation of nitric oxide pathway in mice. PLoS One 5(9):e12688

    Google Scholar 

  29. Witek RP, Yang L, Liu R et al (2009) Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells. Gastroenterology 136(1):320–330

    CAS  Google Scholar 

  30. Roy S, Hsiung F, Kornberg TB (2011) Specificity of Drosophila cytonemes for distinct signaling pathways. Science 332(6027):354–358

    CAS  Google Scholar 

  31. Bischoff M, Gradilla AC, Seijo I et al (2013) Cytonemes are required for the establishment of a normal Hedgehog morphogen gradient in Drosophila epithelia. Nat Cell Biol 15(11):1269–1281

    CAS  Google Scholar 

  32. Sanders TA, Llagostera E, Barna M (2013) Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Nature 497(7451):628–632

    CAS  Google Scholar 

  33. Tseng TT, Gratwick KS, Kollman J et al (1999) The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J Mol Microbiol Biotechnol 1(1):107–125

    CAS  Google Scholar 

  34. Strutt H, Thomas C, Nakano Y et al (2001) Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation. Curr Biol 11:608–613

    CAS  Google Scholar 

  35. Johnson RL, Zhou L, Bailey EC (2002) Distinct consequences of sterol sensor mutations in Drosophila and mouse patched homologs. Dev Biol 242:224–235

    CAS  Google Scholar 

  36. Hime GR, Lada H, Fietz MJ et al (2004) Functional analysis in Drosophila indicates that the NBCCS/PTCH1 mutation G509V results in activation of smoothened through a dominant-negative mechanism. Dev Dyn 229(4):780–790

    CAS  Google Scholar 

  37. Lu X, Liu S, Kornberg TB (2006) The C-terminal tail of the Hedgehog receptor Patched regulates both localization and turnover. Genes Dev 20:2539–2551

    CAS  Google Scholar 

  38. Thibert C, Teillet MA, Lapointe F et al (2003) Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog. Science 301(5634):843–846

    CAS  Google Scholar 

  39. Mille F, Thibert C, Fombonne J et al (2009) The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. Nat Cell Biol 11(6):739–746

    CAS  Google Scholar 

  40. Lindstrom E, Shimokawa T, Toftgard R, Zaphiropoulos PG (2006) PTCH mutations: distribution and analyses. Hum Mutat 27:215–219

    CAS  Google Scholar 

  41. Taipale J, Cooper MK, Maiti T, Beachy PA (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature 418:892–897

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  43. Yavari A, Nagaraj R, Owusu-Ansah E et al (2010) Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev Cell 19(1):54–65

    CAS  Google Scholar 

  44. Bijlsma MF, Spek CA, Zivkovic D et al (2006) Repression of smoothened by patched-dependent pro-vitamin D3 secretion. PLoS Biol 4(8):e232

    Google Scholar 

  45. Uhmann A, Niemann H, Lammering B et al (2011) Antitumoral effects of calcitriol in basal cell carcinomas involve inhibition of hedgehog signaling and induction of vitamin D receptor signaling and differentiation. Mol Cancer Ther 10(11):2179–2188

    CAS  Google Scholar 

  46. Tang JY, Xiao TZ, Oda Y et al (2011) Vitamin D3 inhibits hedgehog signaling and proliferation in murine Basal cell carcinomas. Cancer Prev Res (Phila) 4(5):744–751

    CAS  Google Scholar 

  47. Dormoy V, Béraud C, Lindner V et al (2012) Vitamin D3 triggers antitumor activity through targeting hedgehog signaling in human renal cell carcinoma. Carcinogenesis 33(11):2084–2093

    CAS  Google Scholar 

  48. DeBerardinis AM, Banerjee U, Miller M et al (2012) Probing the structural requirements for vitamin D3 inhibition of the hedgehog signaling pathway. Bioorg Med Chem Lett 22(14):4859–4863

    CAS  Google Scholar 

  49. Bidet M, Joubert O, Lacombe B et al (2011) The hedgehog receptor patched is involved in cholesterol transport. PLoS One 6(9):e23834

    CAS  Google Scholar 

  50. Corbit KC, Aanstad P, Singla V et al (2005) Vertebrate Smoothened functions at the primary cilium. Nature 437(7061):1018–1021

    CAS  Google Scholar 

  51. Rohatgi R, Milenkovic L, Scott MP (2007) Patched1 regulates hedgehog signaling at the primary cilium. Science 317(5836):372–376

    CAS  Google Scholar 

  52. Bailey EC, Milenkovic L, Scott MP et al (2002) Several PATCHED1 missense mutations display activity in patched1-deficient fibroblasts. J Biol Chem 277(37):33632–33640

    CAS  Google Scholar 

  53. Huang S, Zhang Z, Zhang C et al (2013) Activation of Smurf E3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover. PLoS Biol 11(11):e1001721

    Google Scholar 

  54. Tenzen T, Allen BL, Cole F et al (2006) The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell 10(5):647–656

    CAS  Google Scholar 

  55. Allen BL, Song JY, Izzi L et al (2011) Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev Cell 20(6):775–787

    CAS  Google Scholar 

  56. Kang JS, Gao M, Feinleib JL et al (1997) CDO: an oncogene-, serum-, and anchorage-regulated member of the Ig/fibronectin type III repeat family. J Cell Biol 138(1):203–213

    CAS  Google Scholar 

  57. McLellan JS, Zheng X, Hauk G et al (2008) The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. Nature 455(7215):979–983

    CAS  Google Scholar 

  58. McLellan JS, Yao S, Zheng X et al (2006) Structure of a heparin-dependent complex of Hedgehog and Ihog. Proc Natl Acad Sci U S A 103(46):17208–17213

    CAS  Google Scholar 

  59. Mullor JL, Ruiz i Altaba A (2002) Growth, hedgehog and the price of GAS. Bioessays 24(1):22–26

    CAS  Google Scholar 

  60. Allen BL, Tenzen T, McMahon AP (2007) The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev 21:1244–1257

    CAS  Google Scholar 

  61. Pineda-Alvarez DE, Roessler E, Hu P et al (2012) Missense substitutions in the GAS1 protein present in holoprosencephaly patients reduce the affinity for its ligand, SHH. Hum Genet 131(2):301–310

    CAS  Google Scholar 

  62. Bae GU, Domené S, Roessler E et al (2011) Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. Am J Hum Genet 89(2):231–240

    CAS  Google Scholar 

  63. Zhang W, Hong M, Bae GU et al (2011) Boc modifies the holoprosencephaly spectrum of Cdo mutant mice. Dis Model Mech 4(3):368–380

    CAS  Google Scholar 

  64. Kristiansen K (2004) Molecular mechanisms of ligand binding, signaling, and regulation within the superfamily of G-protein-coupled receptors: molecular modeling and mutagenesis approaches to receptor structure and function. Pharmacol Ther 103(1):21–80

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  66. Wang C, Wu H, Katritch V et al (2013) Structure of the human smoothened receptor bound to an antitumour agent. Nature 497(7449):338–343

    CAS  Google Scholar 

  67. Nachtergaele S, Whalen DM, Mydock LK et al (2013) Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. Elife 2:e01340

    Google Scholar 

  68. Myers BR, Sever N, Chong YC et al (2013) Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response. Dev Cell 26(4):346–357

    CAS  Google Scholar 

  69. Nedelcu D, Liu J, Xu Y et al (2013) Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling. Nat Chem Biol 9(9):557–564

    CAS  Google Scholar 

  70. Corcoran RB, Scott MP (2006) Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci U S A 103(22):8408–8413

    CAS  Google Scholar 

  71. Dwyer JR, Sever N, Carlson M et al (2007) Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells. J Biol Chem 282(12):8959–8968

    CAS  Google Scholar 

  72. Nachtergaele S, Mydock LK, Krishnan K et al (2012) Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat Chem Biol 8(2):211–220

    CAS  Google Scholar 

  73. Chen Y, Li S, Tong C et al (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

    CAS  Google Scholar 

  74. Chen W, Ren XR, Nelson CD et al (2004) Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science 306(5705):2257–2260

    CAS  Google Scholar 

  75. Wilbanks AM, Fralish GB, Kirby ML et al (2004) Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway. Science 306(5705):2264–2267

    CAS  Google Scholar 

  76. Kovacs JJ, Whalen EJ, Liu R et al (2008) Beta-arrestin-mediated localization of smoothened to the primary cilium. Science 320(5884):1777–1781

    CAS  Google Scholar 

  77. Shi Q, Li S, Jia J, Jiang J (2011) The Hedgehog-induced Smoothened conformational switch assembles a signaling complex that activates Fused by promoting its dimerization and phosphorylation. Development 138(19):4219–4231

    CAS  Google Scholar 

  78. Lum L, Zhang C, Oh S et al (2003) Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol Cell 12(5):1261–1274

    CAS  Google Scholar 

  79. Chen Y, Sasai N, Ma G et al (2011) Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol 9(6):e1001083

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  81. Li S, Chen Y, Shi Q et al (2012) Hedgehog-regulated ubiquitination controls smoothened trafficking and cell surface expression in Drosophila. PLoS Biol 10(1):e1001239

    CAS  Google Scholar 

  82. 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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  84. Polizio AH, Chinchilla P, Chen X et al (2011) Heterotrimeric Gi proteins link Hedgehog signaling to activation of Rho small GTPases to promote fibroblast migration. J Biol Chem 286(22):19589–19596

    CAS  Google Scholar 

  85. Ogden SK, Fei DL, Schilling NS et al (2008) G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature 456(7224):967–970

    CAS  Google Scholar 

  86. Hammerschmidt M, McMahon AP (1998) The effect of pertussis toxin on zebrafish development: a possible role for inhibitory G-proteins in hedgehog signaling. Dev Biol 194(2):166–171

    CAS  Google Scholar 

  87. Low WC, Wang C, Pan Y et al (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

    CAS  Google Scholar 

  88. Barzi M, Kostrz D, Menendez A, Pons S (2011) Sonic Hedgehog-induced proliferation requires specific Gα inhibitory proteins. J Biol Chem 286(10):8067–8074

    CAS  Google Scholar 

  89. Preat T (1992) Characterization of Suppressor of fused, a complete suppressor of the fused segment polarity gene of Drosophila melanogaster. Genetics 132:725–736

    CAS  Google Scholar 

  90. Cooper AF, Yu KP, Brueckner M et al (2005) Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development 132:4407–4417

    CAS  Google Scholar 

  91. Sv¨ard J, Heby-Henricson K, Persson-Lek M et al (2006) Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell 10:187–197

    Google Scholar 

  92. Kogerman P, Grimm T, Kogerman L et al (1999) Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol 1(5):312–319

    CAS  Google Scholar 

  93. Ding Q, Si F, Meng X et al (1999) Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Curr Biol 9(19):1119–1122

    CAS  Google Scholar 

  94. Zhang Y, Fu L, Qi X et al (2013) Structural insight into the mutual recognition and regulation between Suppressor of Fused and Gli/Ci. Nat Commun 4:2608

    Google Scholar 

  95. Cherry AL, Finta C, Karlström M et al (2013) Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation. Acta Crystallogr D Biol Crystallogr 69(12):2563–2579

    CAS  Google Scholar 

  96. M´ethot N, Basler K (2000) Suppressor of Fused opposes Hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development 127:4001–4110

    Google Scholar 

  97. Wang QT, Holmgren RA (2000) Nuclear import of Cubitus interruptus is regulated by Hedgehog via mechanism distinct from Ci stabilization and Ci activation. Development 127:3131–3139

    CAS  Google Scholar 

  98. Wang G, Amanai K, Jiang J et al (2000) Interactions with Costal2 and Suppressor of fused regulate nuclear translocation and activity of Cubitus interruptus. Genes Dev 14:2893–2905

    CAS  Google Scholar 

  99. Barnfield PC, Zhang X, Thanabalasingham V et al (2005) Negative regulation of Gli1 and Gli2 activator function by Suppressor of fused through multiple mechanisms. Differentiation 73:397–405

    CAS  Google Scholar 

  100. Murone M, Luoh SM, Stone D et al (2000) Gli regulation by the opposing activities of Fused and Suppressor of Fused. Nat Cell Biol 2:310–312

    CAS  Google Scholar 

  101. Merchant M, Vajdos FF, Ultsch M et al (2004) Suppressor of fused regulates Gli activity through a dual binding mechanism. Mol Cell Biol 24(19):8627–8641

    CAS  Google Scholar 

  102. Evangelista M, Lim TY, Lee J et al (2008) Kinome siRNA screen identifies regulators of ciliogenesis and Hedgehog signal transduction. Sci Signal 1:ra7

    Google Scholar 

  103. Chen MH, Wilson CW, Li YJ et al (2009) Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev 23(16):1910–1928

    CAS  Google Scholar 

  104. Wang C, Pan Y, Wang B (2010) Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development 137:2001–2009

    CAS  Google Scholar 

  105. Wen X, Lai CK, Evangelista M et al (2010) Kinetics of Hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation. Mol Cell Biol 30:1910–1922

    CAS  Google Scholar 

  106. Humke EW, Dorn KV, Milenkovic L et al (2010) The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes Dev 24(7):670–682

    CAS  Google Scholar 

  107. Tukachinsky H, Lopez LV, Salic A (2010) A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J Cell Biol 191(2):415–428

    CAS  Google Scholar 

  108. Cheung HO, Zhang X, Ribeiro A et al (2009) The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal 2(76):ra29

    Google Scholar 

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

    CAS  Google Scholar 

  110. Kinzler KW, Vogelstein B (1990) The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Biol 10(2):634–642

    CAS  Google Scholar 

  111. Hatayama M, Aruga J (2012) Gli protein nuclear localization signal. Vitam Horm 88:73–89

    CAS  Google Scholar 

  112. 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

    CAS  Google Scholar 

  113. Riobó NA, Lu K, Ai X et al (2006) Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci U S A 103(12):4505–4510

    Google Scholar 

  114. Niewiadomski P, Kong JH, Ahrends R et al (2014) Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling. Cell Rep 6(1):168–181

    CAS  Google Scholar 

  115. Pan Y, Wang C, Wang B (2009) Phosphorylation of Gli2 by protein kinase A is required for Gli2 processing and degradation and the Sonic Hedgehog-regulated mouse development. Dev Biol 326(1):177–189

    CAS  Google Scholar 

  116. Schrader EK, Harstad KG, Holmgren RA, Matouschek A (2011) A three-part signal governs differential processing of Gli1 and Gli3 proteins by the proteasome. J Biol Chem 286(45):39051–39058

    CAS  Google Scholar 

  117. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T (1994) The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78(5):773–785

    CAS  Google Scholar 

  118. Pan Y, Wang B (2007) A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. J Biol Chem 282(15):10846–10852

    CAS  Google Scholar 

  119. Bhatia N, Thiyagarajan S, Elcheva I et al (2006) Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. J Biol Chem 281(28):19320–19326

    CAS  Google Scholar 

  120. Schwend T, Jin Z, Jiang K et al (2013) Stabilization of speckle-type POZ protein (Spop) by Daz interacting protein 1 (Dzip1) is essential for Gli turnover and the proper output of Hedgehog signaling. J Biol Chem 288(45):32809–32820

    CAS  Google Scholar 

  121. Di Marcotullio L, Greco A, Mazzà D et al (2011) Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal. Oncogene 30(1):65–76

    Google Scholar 

  122. Mazzà D, Infante P, Colicchia V et al (2013) PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress. Cell Death Differ 20(12):1688–1697

    Google Scholar 

  123. Malatesta M, Steinhauer C, Mohammad F et al (2013) Histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and cancer cell proliferation. Cancer Res 73(20):6323–6333

    CAS  Google Scholar 

  124. Canettieri G, Di Marcotullio L, Greco A et al (2010) Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nat Cell Biol 12(2):132–142

    CAS  Google Scholar 

  125. Coni S, Antonucci L, D’Amico D et al (2013) Gli2 acetylation at lysine 757 regulates hedgehog-dependent transcriptional output by preventing its promoter occupancy. PLoS One 8(6):e65718

    CAS  Google Scholar 

  126. Dai P, Akimaru H, Tanaka Y et al (1999) Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem 274(12):8143–8152

    CAS  Google Scholar 

  127. Zhou H, Kim S, Ishii S, Boyer TG (2006) Mediator modulates Gli3-dependent Sonic hedgehog signaling. Mol Cell Biol 26(23):8667–8682

    CAS  Google Scholar 

  128. Dai P, Shinagawa T, Nomura T et al (2002) Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3. Genes Dev 16(22):2843–2848

    CAS  Google Scholar 

  129. Cheng SY, Bishop JM (2002) Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci U S A 99(8):5442–5447

    CAS  Google Scholar 

  130. Dennler S, André J, Alexaki I et al (2007) Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res 67(14):6981–6986

    CAS  Google Scholar 

  131. Dennler S, André J, Verrecchia F, Mauviel A (2009) Cloning of the human GLI2 Promoter: transcriptional activation by transforming growth factor-beta via SMAD3/beta-catenin cooperation. J Biol Chem 284(46):31523–31531

    CAS  Google Scholar 

  132. Laufer E, Nelson CE, Johnson RL et al (1994) Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud. Cell 79(6):993–1003

    CAS  Google Scholar 

  133. Kessaris N, Jamen F, Rubin LL, Richardson WD (2004) Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors. Development 131(6):1289–1298

    CAS  Google Scholar 

  134. Ye W, Shimamura K, Rubenstein JL et al (1998) FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93(5):755–766

    CAS  Google Scholar 

  135. Riobo NA, Haines GM, Emerson CP Jr (2006) Protein kinase C-delta and mitogen-activated protein/extracellular signal-regulated kinase-1 control GLI activation in hedgehog signaling. Cancer Res 66(2):839–845

    CAS  Google Scholar 

  136. Whisenant TC, Ho DT, Benz RW et al (2010) Computational prediction and experimental verification of new MAP kinase docking sites and substrates including Gli transcription factors. PLoS Comput Biol 26:6(8)

    Google Scholar 

  137. Douglas AE, Heim JA, Shen F et al (2011) The alpha subunit of the G protein G13 regulates activity of one or more Gli transcription factors independently of smoothened. J Biol Chem 286(35):30714–30722

    CAS  Google Scholar 

  138. Bredesen DE, Mehlen P, Rabizadeh S (2004) Apoptosis and dependence receptors: a molecular basis for cellular addiction. Physiol Rev 84(2):411–430

    CAS  Google Scholar 

  139. Chinchilla P, Xiao L, Kazanietz MG, Riobo NA (2010) Hedgehog proteins activate pro-angiogenic responses in endothelial cells through non-canonical signaling pathways. Cell Cycle 9(3):570–579

    CAS  Google Scholar 

  140. Polizio AH, Chinchilla P, Chen X et al (2011) Sonic Hedgehog activates the GTPases Rac1 and RhoA in a Gli-independent manner through coupling of smoothened to Gi proteins. Sci Signal 4(200):pt7

    Google Scholar 

  141. Bijlsma MF, Borensztajn KS, Roelink H et al (2007) Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites. Cell Signal 19(12):2596–2604

    CAS  Google Scholar 

  142. Yam PT, Langlois SD, Morin S, Charron F (2009) Sonic hedgehog guides axons through a noncanonical, Src-family-kinase-dependent signaling pathway. Neuron 62(3):349–362

    CAS  Google Scholar 

  143. Yam PT, Kent CB, Morin S et al (2012) 14-3-3 proteins regulate a cell-intrinsic switch from sonic hedgehog-mediated commissural axon attraction to repulsion after midline crossing. Neuron 76(4):735–749

    CAS  Google Scholar 

  144. Bijlsma MF, Damhofer H, Roelink H (2012) Hedgehog-stimulated chemotaxis is mediated by smoothened located outside the primary cilium. Sci Signal 5(238):ra60

    Google Scholar 

  145. Kanda S, Mochizuki Y, Suematsu T et al (2003) Sonic hedgehog induces capillary morphogenesis by endothelial cells through phosphoinositide 3-kinase. J Biol Chem 278(10):8244–8249

    CAS  Google Scholar 

  146. Shinozaki S, Ohnishi H, Hama K et al (2008) Indian hedgehog promotes the migration of rat activated pancreatic stellate cells by increasing membrane type-1 matrix metalloproteinase on the plasma membrane. J Cell Physiol 216(1):38–46

    CAS  Google Scholar 

  147. Razumilava N, Gradilone SA, Smoot RL et al (2014) Non-canonical Hedgehog signaling contributes to chemotaxis in cholangiocarcinoma. J Hepatol 60(3):599–605

    CAS  Google Scholar 

  148. Trousse F, Martí E, Gruss P et al (2001) Control of retinal ganglion cell axon growth: a new role for Sonic hedgehog. Development 128(20):3927–3936

    CAS  Google Scholar 

  149. Belgacem YH, Borodinsky LN (2011) Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord. Proc Natl Acad Sci U S A 108(11):4482–4487

    CAS  Google Scholar 

  150. Teperino R, Amann S, Bayer M et al (2012) Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 151(2):414–426

    CAS  Google Scholar 

  151. Proctor AE, Thompson LA, O’Bryant CL (2014) Vismodegib: an inhibitor of the Hedgehog signaling pathway in the treatment of basal cell carcinoma. Ann Pharmacother 48(1):99–106

    CAS  Google Scholar 

  152. Qu C, Liu Y, Kunkalla K, Singh RR et al (2013) Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-κB activation in diffuse large B-cell lymphoma. Blood 121(23):4718–4728

    CAS  Google Scholar 

  153. Kasai K, Takahashi M, Osumi N et al (2004) The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling. Genes Cells 9(1):49–58

    CAS  Google Scholar 

  154. Gorojankina T, Hoch L, Faure H et al (2013) Discovery, molecular and pharmacological characterization of GSA-10, a novel small-molecule positive modulator of Smoothened. Mol Pharmacol 83(5):1020–1029

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology and Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    Natalia A. Riobo

Authors
  1. Natalia A. Riobo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Natalia A. Riobo .

Editor information

Editors and Affiliations

  1. Institute of Neurosciences Paris-Saclay (Neuro-PSI), National Centre for Scientific Research, Gif-Yvette, France

    Martial Ruat

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Riobo, N.A. (2014). Canonical and Non-Canonical Hedgehog Signaling Pathways: Role of G Proteins. In: Ruat, M. (eds) The Smoothened Receptor in Cancer and Regenerative Medicine. Topics in Medicinal Chemistry, vol 16. Springer, Cham. https://doi.org/10.1007/7355_2014_63

Download citation

Publish with us

Policies and ethics

Search

Navigation