Overview of Hedgehog Signaling Pathway

  • Chi-chung HuiEmail author
  • Jin Jiang


Initially discovered in Drosophila and later found in all vertebrate model organisms, the Hedgehog (Hh) family of secreted proteins plays critical roles in both embryonic development and adult tissue homeostasis [41, 84]. Numerous human genetic disorders and cancer have been associated with aberrant Hh signaling activity [41, 63, 84].


Primary Cilium Ciliary Localization Ciliary Entry 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



C. C. H. is supported by the Canadian Cancer Society Research Institute, and J. J. is supported by grants from NIH, CPRIT, and Welch Foundation (I-1603). We thank Julie Yu for help in illustrations.


  1. 1.
    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 21:1244–1257PubMedGoogle Scholar
  2. 2.
    Amanai K, Jiang J (2001) Distinct roles of Central missing and Dispatched in sending the Hedgehog signal. Development 128:5119–5127PubMedGoogle Scholar
  3. 3.
    Aanstad P, Santos N, Corbit KC, Scherz PJ, le Trinh A, Salvenmoser W, Huisken J, Reiter JF, Stainier DY (2009) The extracellular domain of Smoothened regulates ciliary localization and is required for high-level Hh signaling. Curr Biol 19:1034–1039PubMedGoogle Scholar
  4. 4.
    Apionishev S, Katanayeva NM, Marks SA, Kalderon D, Tomlinson A (2005) Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nat Cell Biol 7:86–92PubMedGoogle Scholar
  5. 5.
    Barzi M, Berenguer J, Menendez A, Alvarez-Rodriguez R, Pons S (2010) Sonic hedgehog mediated proliferation requires the localization of PKA to the cilium base. J Cell Sci 123:62–69PubMedGoogle Scholar
  6. 6.
    Bijlsma MF, Spek CA, Zivkovic D, van de Water S, Rezaee F, Peppelenbosch MP (2006) Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol 4:e232PubMedGoogle Scholar
  7. 7.
    Burke R, Nellen D, Bellotto M, Hafen E, Senti KA, Dickson BJ, Basler K (1999) Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 99:803–815PubMedGoogle Scholar
  8. 8.
    Capurro MI, Xu P, Shi W, Li F, Jia A, Filmus J (2008) Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. Dev Cell 14:700–711PubMedGoogle Scholar
  9. 9.
    Chamoun Z, Mann RK, Nellen D, von Kessler DP, Bellotto M, Beachy PA, Basler K (2001) Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293:2080–2084PubMedGoogle Scholar
  10. 10.
    Chen JK, Taipale J, Cooper MK, Beachy PA (2002) Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 16:2743–2748PubMedGoogle Scholar
  11. 11.
    Chen JK, Taipale J, Young KE, Maiti T, Beachy PA (2002) Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA 99:14071–14076PubMedGoogle Scholar
  12. 12.
    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 25:7042–7053PubMedGoogle Scholar
  13. 13.
    Chen MH, Wilson CW, Li JY, Law KK, Lu CS, Gacayan R, Zhang X, Hui C-c, Chuang PT (2009) Cilium-independent regulation of Gli proteins by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev 23:1910–1928PubMedGoogle Scholar
  14. 14.
    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 306:2257–2260PubMedGoogle Scholar
  15. 15.
    Cheng SY, Bishop JM (2002) Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci USA 99:5442–5447PubMedGoogle Scholar
  16. 16.
    Cheung HO-L, Zhang X, Ribeiro A, Mo R, Makino S, Puviindran V, Law KKL, Briscoe J, Hui C-C (2009) The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal 2:1–7Google Scholar
  17. 17.
    Chuang PT, Kawcak T, McMahon AP (2003) Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung. Genes Dev 17:342–347PubMedGoogle Scholar
  18. 18.
    Chuang PT, McMahon AP (1999) Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397:617–621PubMedGoogle Scholar
  19. 19.
    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 132:4407–4417PubMedGoogle Scholar
  20. 20.
    Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF (2005) Vertebrate Smoothened functions at the primary cilium. Nature 437:1018–1021PubMedGoogle Scholar
  21. 21.
    Corcoran RB, Scott MP (2006) Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci USA 103:8408–8413PubMedGoogle Scholar
  22. 22.
    Denef N, Neubuser D, Perez L, Cohen SM (2000) Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 102:521–531PubMedGoogle Scholar
  23. 23.
    Di Marcotullio L, Ferretti E, Greco A, De Smaele E, Po A, Sico MA, Alimandi M, Giannini G, Maroder M, Screpanti I et al (2006) Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Nat Cell Biol 8:1415–1423PubMedGoogle Scholar
  24. 24.
    Ding Q, Fukami S, Meng X, Nishizaki Y, Zhang X, Sasaki H, Dlugosz A, Nakafuku M, Hui C-C (1999) Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Curr Biol 9:1119–1122PubMedGoogle Scholar
  25. 25.
    Dwyer JR, Sever N, Carlson M, Nelson SF, Beachy PA, Parhami F (2007) Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells. J Biol Chem 282:8959–8968PubMedGoogle Scholar
  26. 26.
    Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen J-W, 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 19:1320–1326PubMedGoogle Scholar
  27. 27.
    Evangelista M, Lim TY, Lee J, Parker L, Ashique A, Peterson AS, Ye W, Davis DP, de Sauvage FJ (2008) Kinome siRNA screen identifies regulators of ciliogenesis and Hedgehog signal transduction. Sci Signal 1:ra7PubMedGoogle Scholar
  28. 28.
    Farzan SF, Ascano M Jr, Ogden SK, Sanial M, Brigui A, Plessis A, Robbins DJ (2008) Costal2 functions as a kinesin-like protein in the hedgehog signal transduction pathway. Curr Biol 18:1215–1220PubMedGoogle Scholar
  29. 29.
    Etheridge LA, Crawford TQ, Zhang S, Roelink H (2010) Evidence for a role of vertebrate Disp1 in long-range signaling. Development 137:133–140PubMedGoogle Scholar
  30. 30.
    Goetz SC, Anderson KV (2010) The primary cilium: a signaling centre during vertebrate development. Nat Rev Genet 11:331–344PubMedGoogle Scholar
  31. 31.
    Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E, Taipale J (2006) Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell 124:47–59PubMedGoogle Scholar
  32. 32.
    Han Y-G, Kim HJ, Dlugosz AA, Ellison DW, Gilbertson RJ, Alvarez-Buylla A (2009) Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med 15:1062–1065PubMedGoogle Scholar
  33. 33.
    Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1:e53PubMedGoogle Scholar
  34. 34.
    Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R (2010) The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes Dev 24:670–682PubMedGoogle Scholar
  35. 35.
    Huntzicker EG, Estay IS, Zhen H, Lokteva LA, Jackson PK, Oro AE (2006) Dual degradation signals control Gli protein stability and tumor formation. Genes Dev 20:276–281PubMedGoogle Scholar
  36. 36.
    Jeong J, McMahon AP (2005) Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1. Development 132:143–154PubMedGoogle Scholar
  37. 37.
    Jia J, Kolterud A, Zeng H, Hoover A, Teglund S, Toftgård R, Liu A (2009) Suppressor of fused inhibits mammalian Hedgehog signaling in the absence of cilia. Dev Biol 330:452–460PubMedGoogle Scholar
  38. 38.
    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 17:2709–2720PubMedGoogle Scholar
  39. 39.
    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 432:1045–1050PubMedGoogle Scholar
  40. 40.
    Jia J, Zhang L, Zhang Q, Tong C, Wang B, Hou F, Amanai K, Jiang J (2005) Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/beta-TRCP-mediated proteolytic processing. Dev Cell 9:819–830PubMedGoogle Scholar
  41. 41.
    Jiang J, Hui C-C (2008) Hedgehog signaling in development and cancer. Dev Cell 15:801–812PubMedGoogle Scholar
  42. 42.
    Jiang J, Struhl G (1998) Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391:493–496PubMedGoogle Scholar
  43. 43.
    Johnson RL, Milenkovic L, Scott MP (2000) In vivo functions of the patched protein: requirement of the C terminus for target gene inactivation but not Hedgehog sequestration. Mol Cell 6:467–478PubMedGoogle Scholar
  44. 44.
    Khaliullina H, Panakova D, Eugster C, Riedel F, Carvalho M, Eaton S (2009) Patched regulates Smoothened trafficking using lipoprotein-derived lipids. Development 136:4111–4121PubMedGoogle Scholar
  45. 45.
    Kent D, Bush EW, Hooper JE (2006) Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus. Development 133:2001–2010PubMedGoogle Scholar
  46. 46.
    Kim J, Kato M, Beachy PA (2009) Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus. Proc Natl Acad Sci USA 106:21666–21671PubMedGoogle Scholar
  47. 47.
    Kise Y, Morinaka A, Teglund S, Miki H (2009) Sufu recruits GSK3β for efficient processing of Gli3. Biochem Biophys Res Commun 387:569–574PubMedGoogle Scholar
  48. 48.
    Kovacs JJ, Whalen EJ, Liu R, Xiao K, Kim J, Chen M, Wang J, Chen W, Lefkowitz RJ (2008) Beta-arrestin-mediated localization of smoothened to the primary cilium. Science 320:1777–1781PubMedGoogle Scholar
  49. 49.
    Li Y, Zhang H, Litingtung Y, Chiang C (2006) Cholesterol modification restricts the spread of Shh gradient in the limb bud. Proc Natl Acad Sci USA 103:6548–6553PubMedGoogle Scholar
  50. 50.
    Lin X (2004) Functions of heparan sulfate proteoglycans in cell signaling during development. Development 131:6009–6021PubMedGoogle Scholar
  51. 51.
    Liem KF Jr, He M, Ocbina PJR, Anderson KV (2009) Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc Natl Acad Sci USA 106:13377–13382PubMedGoogle Scholar
  52. 52.
    Lipinski RJ, Bijlsma MF, Gipp JJ, Podhaizer DJ, Bushman W (2008) Establishment and characterization of immortalized Gli-null mouse embryonic fibroblast cell lines. BMC Cell Biol 9:49.Google Scholar
  53. 53.
    Low W-C, Wang C, Pan Y, Huang X-Y, Chen JK, Wang B (2008) The decoupling of Smoothened from Gαi has little effect on Gli3 protein processing and Hedgehog-regulated chick neural tube patterning. Dev Biol 321:188–196PubMedGoogle Scholar
  54. 54.
    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 12:1261–1274PubMedGoogle Scholar
  55. 55.
    Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, Beachy PA (2002) Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111:63–75PubMedGoogle Scholar
  56. 56.
    Maloverjan A, Piirsoo M, Michelson P, Kogerman P, Osterlund T (2010) Identification of a novel serine/threonine kinase ULK3 as a positive regulator of Hedgehog pathway. Exp Cell Res 316:627–637.Google Scholar
  57. 57.
    Mao J, Maye P, Kogerman P, Tejedor FJ, Toftgard R, Xie W, Wu G, Wu D (2002) Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J Biol Chem 277:35156–35161.Google Scholar
  58. 58.
    Martinelli DC, Fan C-M (2007) Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev 21:1231–1243PubMedGoogle Scholar
  59. 59.
    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 26:7550–7560PubMedGoogle Scholar
  60. 60.
    Merchant M, Evangelista M, Luoh SM, Frantz GD, Chalasani S, Carano RA, van Hoy M, Ramirez J, Ogasawara AK, McFarland LM et al (2005) Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol 25:7054–7068PubMedGoogle Scholar
  61. 61.
    Methot N, Basler K (1999) Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell 96:819–831PubMedGoogle Scholar
  62. 62.
    Milenkovic L, Scott MP, Rohatgi R (2009) Lateral transport of smoothened from the plasma membrane to the membrane of the cilium. J Cell Biol 187:365–374PubMedGoogle Scholar
  63. 63.
    Nieuwenhuis E, Hui C-C (2005) Hedgehog signaling and congenital malformations. Clin Genet 67:193–208PubMedGoogle Scholar
  64. 64.
    Ocbina PJ, Anderson KV (2008) Intraflagellar transport, cilia, and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev Dyn 237:2030–2038PubMedGoogle Scholar
  65. 65.
    Ogden SK, Ascano M Jr, 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 13:1998–2003PubMedGoogle Scholar
  66. 66.
    Ogden SK, Fei DL, Schilling NS, Ahmed YF, Hwa J, Robbins DJ (2008) G protein Gαi functions immediately downstream of Smoothened in Hedgehog signaling. Nature 456:967–970PubMedGoogle Scholar
  67. 67.
    Okada A, Charron F, Morin S, Shin DS, Wong K, Fabre PJ, Tessier-Lavigne M, McConnell SK (2006) Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444:369–373PubMedGoogle Scholar
  68. 68.
    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 282:10846–10852PubMedGoogle Scholar
  69. 69.
    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 Biol Cell 19:5478–5489PubMedGoogle Scholar
  70. 70.
    Porter JA, Young KE, Beachy PA (1996) Cholesterol modification of Hedgehog signaling proteins in animal development. Science 274:255–258PubMedGoogle Scholar
  71. 71.
    Riobo NA, Saucy B, DiLizio C, Manning DR (2006) Activation of heterotrimeric G proteins by Smoothened. Proc Natl Acad Sci USA 103:12607–12612PubMedGoogle Scholar
  72. 72.
    Rohatgi R, Milenkovic L, Scott MP (2007) Patched1 regulates hedgehog signaling at the primary cilium. Science 317:372–376PubMedGoogle Scholar
  73. 73.
    Rohatgi R, Milenkovic L, Corcoran RB, Scott MP (2009) Hedgehog signal transduction by Smoothened: pharmacologic evidence of a 2-step activation process. Proc Natl Acad Sci USA 106:3196–3201PubMedGoogle Scholar
  74. 74.
    Ruel L, Gallet A, Raisin S, Truchi A, Staccini-Lavenant L, Cervantes A, Therond 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 134:3677–3689PubMedGoogle Scholar
  75. 75.
    Ruel L, Rodriguez R, Gallet A, Lavenant-Staccini L, Therond PP (2003) Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nat Cell Biol 5:907–913PubMedGoogle Scholar
  76. 76.
    Smelkinson MG, Kalderon D (2006) Processing of the Drosophila hedgehog signaling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component slimb. Curr Biol 16:110–116PubMedGoogle Scholar
  77. 77.
    Smelkinson MG, Zhou Q, Kalderon D (2007) Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedgehog pathway activity by Ci phosphorylation. Dev Cell 13:481–495PubMedGoogle Scholar
  78. 78.
    Svard J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergstrom A, Ericson J, Toftgard R, Teglund S (2006) Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell 10:187–197PubMedGoogle Scholar
  79. 79.
    Taipale J, Cooper MK, Maiti T, Beachy PA (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature 418:892–897PubMedGoogle Scholar
  80. 80.
    Tempe D, Casas M, Karaz S, Blanchet-Tournier MF, Concordet JP (2006) Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Mol Cell Biol 26:4316–4326PubMedGoogle Scholar
  81. 81.
    Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, McMahon AP (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 10:647–656PubMedGoogle Scholar
  82. 82.
    Varjosalo M, Bjorklund M, Cheng F, Syvanen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He WW et al (2008) Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell 133:537–548PubMedGoogle Scholar
  83. 83.
    Varjosalo M, Li SP, Taipale J (2006) Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev Cell 10:177–186PubMedGoogle Scholar
  84. 84.
    Varjosalo M, Taipale J (2008) Hedgehog: functions and mechanisms. Genes Dev 22:2454–2472PubMedGoogle Scholar
  85. 85.
    Vokes SA, Ji H, McCuine S, Tenzen T, Giles S, Zhong S, Longabaugh WJ, Davidson EH, Wong WH, McMahon AP (2007) Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development 134:1977–1989PubMedGoogle Scholar
  86. 86.
    Vyas N, Goswami D, Manonmani A, Sharma P, Ranganath HA, VijayRaghavan K, Shashidhara LS, Sowdhamini R, Mayor S (2008) Nanoscale organization of hedgehog is essential for long-range signaling. Cell 133:1214–1227PubMedGoogle Scholar
  87. 87.
    Wang B, Li Y (2006) Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci USA 103:33–38PubMedGoogle Scholar
  88. 88.
    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 137:2001–2009PubMedGoogle Scholar
  89. 89.
    Wang Y, Zhou Z, Walsh CT, McMahon AP (2009) Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc Natl Acad Sci USA 106:2623–2628PubMedGoogle Scholar
  90. 90.
    Wen X, Lai CK, Evangelista M, Hongo J-A, de Sauvage FJ, Scales SJ (2010) Kinetics of Hedgehog-induced full-length Gli3 accumulation in primary cilia and subsequent degradation. Mol Cell Biol 30:1910–1922PubMedGoogle Scholar
  91. 91.
    Wigley WC, Fabunmi RP, Lee MG, Marino CR, Muallem S, DeMartino GN, Thomas PJ (1999) Dynamic association of proteasomal machinery with the centrosome. J Cell Biol 145:481–490PubMedGoogle Scholar
  92. 92.
    Williams EH, Pappano WN, Saunders AM, Kim M-S, Leahy DJ, Beachy PA (2010) Dally-like core protein and its mammalian homologues mediate stimulatory and inhibitory effects on Hedgehog signal response. Proc Natl Acad Sci USA 107:5869–5874PubMedGoogle Scholar
  93. 93.
    Wong SY, Seol AD, So P-L, Ermilov AN, Bichakjian CK, Epstein EH, Dlugosz AA, Reiter JF (2009) Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat Med 15:1055–1061PubMedGoogle Scholar
  94. 94.
    Yam PT, Langlois SD, Morin S, Charron F (2009) Sonic hedgehog guides axons through a noncanonical, Src-family-kinase-dependent signaling pathway. Neuron 62:349–362PubMedGoogle Scholar
  95. 95.
    Yan D, Lin X (2009) Shaping morphogen gradients by proteoglycans. Cold Spring Harb Perspect Biol 1:a002493PubMedGoogle Scholar
  96. 96.
    Yan D, Wu Y, Yang Y, Belenkaya TY, Tang X, Lin X (2010) The cell-surface proteins Dally-like and Ihog differentially regulate Hedgehog signaling strength and range during development. Development 137:2033–2044PubMedGoogle Scholar
  97. 97.
    Yao S, Lum L, Beachy P (2006) The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 125:343–357PubMedGoogle Scholar
  98. 98.
    Yavari A, Nagaraj R, Owusu-Ansah E, Folick A, Ngo K, Hillman T, Call G, Rohatgi R, Scott MP, Banerjee U (2010) Role of lipid metabolism in Smoothened derepression in Hedgehog signaling. Dev Cell 19:54–65PubMedGoogle Scholar
  99. 99.
    Zhang C, Williams EH, Guo Y, Lum L, Beachy PA (2004) Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc Natl Acad Sci USA 101:17900–17907PubMedGoogle Scholar
  100. 100.
    Zhang Q, Zhang L, Wang B, Ou CY, Chien CT, Jiang J (2006) A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor. Dev Cell 10:719–729PubMedGoogle Scholar
  101. 101.
    Zhang Q, Shi S, Chen Y, Yue T, Li S, Wang B, Jiang J (2009) Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase. Proc Natl Acad Sci USA 106:21191–21196PubMedGoogle Scholar
  102. 102.
    Zhang W, Kang JS, Cole F, Yi MJ, Krauss RS (2006) Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell 10:657–665PubMedGoogle Scholar
  103. 103.
    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 8:267–278PubMedGoogle Scholar
  104. 104.
    Zhao Y, Tong C, Jiang J (2007) Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450:252–258PubMedGoogle Scholar
  105. 105.
    Zheng X, Mann RK, Sever N, Beachy PA (2010) Genetic and biochemical definition of the Hedgehog receptor. Genes Dev 24:57–71PubMedGoogle Scholar
  106. 106.
    Zhu AJ, Zheng L, Suyama K, Scott MP (2003) Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. Genes Dev 17:1240–1252PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Program in Developmental and Stem Cell BiologyThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Department of Molecular GeneticsUniversity of TorontoTorontoCanada

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