Hedgehog signaling: From basic research to clinical applications

Journal of the Formosan Medical Association

Volumn 114, Issue 7, 2015, Pages 569-576

  Yao, Erica ^a   Chuang, Pao Tien ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Cancer; Cilium; Development; Hedgehog; Mechanism; Signaling

Indexed keywords

SONIC HEDGEHOG PROTEIN;

BASIC RESEARCH; BIOGENESIS; CARCINOGENESIS; CONGENITAL MALFORMATION; CYTOLOGY; EUKARYOTIC FLAGELLUM; FEEDBACK SYSTEM; GENE EXPRESSION; GENETICS; HEDGEHOG SIGNALING; HOMEOSTASIS; HUMAN; IN VITRO STUDY; IN VIVO STUDY; NEOPLASM; NONHUMAN; POSITIVE FEEDBACK; REVIEW; SIGNAL TRANSDUCTION; TISSUE REGENERATION; TISSUE REPAIR; ANIMAL; GENE EXPRESSION REGULATION; METABOLISM; MOUSE; REGENERATION;

ANIMALS; CILIA; GENE EXPRESSION REGULATION; HEDGEHOG PROTEINS; HOMEOSTASIS; HUMANS; MICE; NEOPLASMS; REGENERATION; SIGNAL TRANSDUCTION;

EID: 84937253762     PISSN: 09296646     EISSN: 18760821     Source Type: Journal    
DOI: 10.1016/j.jfma.2015.01.005     Document Type: Review

References (92)

1. Chen Y., Jiang J. Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res 2013, 23:186-200.
2. Ingham P.W., Nakano Y., Seger C. Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet 2011, 12:393-406.
3. Briscoe J., Thérond P.P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 2013, 14:416-429.
4. Petrova R., Joyner A.L. Roles for Hedgehog signaling in adult organ homeostasis and repair. Development 2014, 141:3445-3457.
5. Scales S.J., de Sauvage F.J. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 2009, 30:303-312.
6. Barakat M.T., Humke E.W., Scott M.P. Learning from Jekyll to control Hyde: hedgehog signaling in development and cancer. Trends Mol Med 2010, 16:337-348.
7. Bijlsma M.F., Roelink H. Non-cell-autonomous signaling by Shh in tumors: challenges and opportunities for therapeutic targets. Expert Opin Ther Targets 2010, 14:693-702.
8. Porter J.A., Young K.E., Beachy P.A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 1996, 274:255-259.
9. Pepinsky R.B., Zeng C., Wen D., Rayhorn P., Baker D.P., Williams K.P., et al. Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem 1998, 273:14037-14045.
10. Buglino J.A., Resh M.D. Palmitoylation of Hedgehog proteins. Vitam Horm 2012, 88:229-252.
11. Li Y., Zhang H., Litingtung Y., Chiang C. Cholesterol modification restricts the spread of Shh gradient in the limb bud. Proc Natl Acad Sci U S A 2006, 103:6548-6553.
12. Zeng X., Goetz J.A., Suber L.M., Scott W.J., Schreiner C.M., Robbins D.J. A freely diffusible form of sonic hedgehog mediates long-range signalling. Nature 2001, 411:716-720.
13. Panáková D., Sprong H., Marois E., Thiele C., Eaton S. Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature 2005, 435:58-65.
14. Ramírez-Weber F.A., Kornberg T.B. Cytonemes: cellular processes that project to the principal signaling center in Drosophila imaginal discs. Cell 1999, 97:599-607.
15. Wang Y., McMahon A.P., Allen B.L. Shifting paradigms in Hedgehog signaling. Curr Opin Cell Biol 2007, 19:159-165.
16. Ryan K.E., Chiang C. Hedgehog secretion and signal transduction in vertebrates. J Biol Chem 2012, 287:17905-17913.
17. Farzan S.F., Singh S., Schilling N.S., Robbins D.J. The adventures of sonic hedgehog in development and repair. III. Hedgehog processing and biological activity. Am J Physiol Gastrointest Liver Physiol 2008, 294:G844-G849.
18. Beachy P.A., Hymowitz S.G., Lazarus R.A., Leahy D.J., Siebold C. Interactions between Hedgehog proteins and their binding partners come into view. Genes Dev 2010, 24:2001-2012.
19. Filmus J., Capurro M. The role of glypicans in Hedgehog signaling. Matrix Biol 2014, 35:248-252.
20. Izzi L., Lévesque M., Morin S., Laniel D., Wilkes B.C., Mille F., et al. Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev Cell 2011, 20:788-801.
21. Allen B.L., Song J.Y., Izzi L., Althaus I.W., Kang J.S., Charron F., et al. Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev Cell 2011, 20:775-787.
22. Myers B.R., Sever N., Chong Y.C., Kim J., Belani J.D., Rychnovsky S., et al. Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response. Dev Cell 2013, 26:346-357.
23. Nachtergaele S., Whalen D.M., Mydock L.K., Zhao Z., Malinauskas T., Krishnan K., et al. Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. Elife 2013, 2:e01340.
24. Nedelcu D., Liu J., Xu Y., Jao C., Salic A. Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling. Nat Chem Biol 2013, 9:557-564.
25. Taipale J., Cooper M.K., Maiti T., Beachy P.A. Patched acts catalytically to suppress the activity of Smoothened. Nature 2002, 418:892-897.
26. Corcoran R.B., Scott M.P. Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci U S A 2006, 103:8408-8413.
27. Hui C.C., Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol 2011, 27:513-537.
28. Aberger F., Ruiz I., Atalba A. Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy. Semin Cell Dev Biol 2014, 33:93-104.
29. Bai C.B., Stephen D., Joyner A.L. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev Cell 2004, 6:103-115.
30. Pan Y., Bai C.B., Joyner A.L., Wang B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol 2006, 26:3365-3377.
31. Li J., Wang C., Pan Y., Bai Z., Wang B. Increased proteolytic processing of full-length Gli2 transcription factor reduces the hedgehog pathway activity invivo. Dev Dyn 2011, 240:766-774.
32. Wang B., Fallon J.F., Beachy P.A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 2000, 100:423-434.
33. Ding Q., Motoyama J., Gasca S., Mo R., Sasaki H., Rossant J., et al. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development 1998, 125:2533-2543.
34. Matise M.P., Epstein D.J., Park H.L., Platt K.A., Joyner A.L. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Development 1998, 125:2759-2770.
35. Bowers M., Eng L., Lao Z., Turnbull R.K., Bao X., Riedel E., et al. Limb anterior-posterior polarity integrates activator and repressor functions of GLI2 as well as GLI3. Dev Biol 2012, 370:110-124.
36. Cao T., Wang C., Yang M., Wu C., Wang B. Mouse limbs expressing only the Gli3 repressor resemble those of sonic hedgehog mutants. Dev Biol 2013, 379:221-228.
37. Liu J., Heydeck W., Zeng H., Liu A. Dual function of suppressor of fused in Hh pathway activation and mouse spinal cord patterning. Dev Biol 2012, 362:141-153.
38. Rabinowitz A.H., Vokes S.A. Integration of the transcriptional networks regulating limb morphogenesis. Dev Biol 2012, 368:165-180.
39. Falkenstein K.N., Vokes S.A. Transcriptional regulation of graded Hedgehog signaling. Semin Cell Dev Biol 2014, 33:73-80.
40. Vokes S.A., Ji H., McCuine S., Tenzen T., Giles S., Zhong S., et al. Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development 2007, 134:1977-1989.
41. Vokes S.A., Ji H., Wong W.H., McMahon A.P. A genome-scale analysis of the cis-regulatory circuitry underlying Sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev 2008, 22:2651-2663.
42. Balaskas N., Ribeiro A., Panovska J., Dessaud E., Sasai N., Page K.M., et al. Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube. Cell 2012, 148:273-284.
43. Cooper A.F., Yu K.P., Brueckner M., Brailey L.L., Johnson L., McGrath J.M., et al. Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development 2005, 132:4407-4417.
44. Svärd J., Heby-Henricson K., Persson-Lek M., Rozell B., Lauth M., et al. Genetic elimination of suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell 2006, 10:187-197.
45. Ding Q., Fukami Si, Meng X., Nishizaki Y., Zhang X., Sasaki H., et al. Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Curr Biol 1999, 9:1119-1122.
46. Kogerman P., Grimm T., Kogerman L., Krause D., Undén A.B., Sandstedt B., et al. Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol 1999, 1:312-319.
47. Murone M., Luoh S.M., Stone D., Li W., Gurney A., Armanini M., et al. Gli regulation by the opposing activities of fused and suppressor of fused. Nat Cell Biol 2000, 2:310-312.
48. Barnfield P.C., Zhang X., Thanabalasingham V., Yoshida M., Hui C.C. Negative regulation of Gli1 and Gli2 activator function by Suppressor of fused through multiple mechanisms. Differentiation 2005, 73:397-405.
49. Chen M.H., Wilson C.W., Li Y.J., Law K.K., Lu C.S., Gacayan R., et al. Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev 2009, 23:1910-1928.
50. Jia J., Kolterud A., Zeng H., Hoover A., Teglund S., Toftgård R., et al. Suppressor of Fused inhibits mammalian Hedgehog signaling in the absence of cilia. Dev Biol 2009, 330:452-460.
51. Wang C., Pan Y., Wang B. Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development 2010, 137:2001-2009.
52. Tukachinsky H., Lopez L.V., Salic A. A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J Cell Biol 2010, 191:415-428.
53. Humke E.W., Dorn K.V., Milenkovic L., Scott M.P., Rohatgi R. The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes Dev 2010, 24:670-682.
54. Goodrich L.V., Johnson R.L., Milenkovic L., McMahon J.A., Scott M.P. Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev 1996, 10:301-312.
55. Chuang P.T., McMahon A.P. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999, 397:617-621.
56. Tenzen T., Allen B.L., Cole F., Kang J.S., Krauss R.S., McMahon A.P. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell 2006, 10:647-656.
57. Harfe B.D., Scherz P.J., Nissim S., Tian H., McMahon A.P., Tabin C.J. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 2004, 118:517-528.
58. Wilson C.W., Chuang P.T. Mechanism and evolution of cytosolic Hedgehog signal transduction. Development 2010, 137:2079-2094.
59. Hausmann G., von Mering C., Basler K. The hedgehog signaling pathway: where did it come from?. PLoS Biol 2009, 7:e1000146.
60. Nozawa Y.I., Lin C., Chuang P.T. Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction. Curr Opin Genet Dev 2013, 23:429-437.
61. Kim S., Dynlacht B.D. Assembling a primary cilium. Curr Opin Cell Biol 2013, 25:506-511.
62. Goetz S.C., Anderson K.V. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 2010, 11:331-344.
63. Drummond I.A. Cilia functions in development. Curr Opin Cell Biol 2012, 24:24-30.
64. Eggenschwiler J.T., Anderson K.V. Cilia and developmental signaling. Annu Rev Cell Dev Biol 2007, 23:345-373.
65. Bay S.N., Caspary T. What are those cilia doing in the neural tube?. Cilia 2012, 1:19.
66. Berbari N.F., O'Connor A.K., Haycraft C.J., Yoder B.K. The primary cilium as a complex signaling center. Curr Biol 2009, 19:R526-R535.
67. DeRouen M.C., Oro A.E. The primary cilium: a small yet mighty organelle. J Invest Dermatol 2009, 129:264-265.
68. Oh E.C., Katsanis N. Cilia in vertebrate development and disease. Development 2012, 139:443-448.
69. Wong S.Y., Reiter J.F. The primary cilium at the crossroads of mammalian hedgehog signaling. Curr Top Dev Biol 2008, 85:225-260.
70. Mukhopadhyay S., Rohatgi R. G-protein-coupled receptors, Hedgehog signaling and primary cilia. Semin Cell Dev Biol 2014, 33:63-72.
71. Nachury M.V. How do cilia organize signalling cascades?. Philos Trans R Soc Lond B Biol Sci 2014, 369:20130465.
72. Haycraft C.J., Banizs B., Aydin-Son Y., Zhang Q., Michaud E.J., Yoder B.K. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 2005, 1:e53.
73. Corbit K.C., Aanstad P., Singla V., Norman A.R., Stainier D.Y., Reiter J.F. Vertebrate Smoothened functions at the primary cilium. Nature 2005, 437:1018-1021.
74. Rohatgi R., Milenkovic L., Scott M.P. Patched1 regulates hedgehog signaling at the primary cilium. Science 2007, 317:372-376.
75. Liem K.F., He M., Ocbina P.J., Anderson K.V. Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc Natl Acad Sci U S A 2009, 106:13377-13382.
76. Endoh-Yamagami S., Evangelista M., Wilson D., Wen X., Theunissen J.W., Phamluong K., et al. The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol 2009, 19:1320-1326.
77. Kim J., Kato M., Beachy P.A. Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus. Proc Natl Acad Sci U S A 2009, 106:21666-21671.
78. He M., Subramanian R., Bangs F., Omelchenko T., Liem K.F., Kapoor T.M., et al. The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. Nat Cell Biol 2014, 16:663-672.
79. Kuzhandaivel A., Schultz S.W., Alkhori L., Alenius M. Cilia-mediated hedgehog signaling in Drosophila. Cell Rep 2014, 7:672-680.
80. Kornberg T.B. The contrasting roles of primary cilia and cytonemes in Hh signaling. Dev Biol 2014, 394:1-5.
81. Bijlsma M.F., Damhofer H., Roelink H. Hedgehog-stimulated chemotaxis is mediated by smoothened located outside the primary cilium. Sci Signal 2012, 5:ra60.
82. Callier P., Calvel P., Matevossian A., Makrythanasis P., Bernard P., Kurosaka H., et al. Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling. PLoS Genet 2014, 10:e1004340.
83. Ahn S., Joyner A.L. Invivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 2005, 437:894-897.
84. Berman D.M., Karhadkar S.S., Maitra A., Montes De Oca R., Gerstenblith M.R., Briggs K., et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003, 425:846-851.
85. Thayer S.P., di Magliano M.P., Heiser P.W., Nielsen C.M., Roberts D.J., Lauwers G.Y., et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003, 425:851-856.
86. Von Hoff D.D., LoRusso P.M., Rudin C.M., Reddy J.C., Yauch R.L., Tibes R., et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New Engl J Med 2009, 361:1164-1172.
87. Rudin C.M., Hann C.L., Laterra J., Yauch R.L., Callahan C.A., Fu L., et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. New Engl J Med 2009, 361:1173-1178.
88. Yauch R.L., Dijkgraaf G.J., Alicke B., Januario T., Ahn C.P., Holcomb T., et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009, 326:572-574.
89. Kimura H., Ng J.M., Curran T. Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 2008, 13:249-260.
90. Lauth M., Bergström A., Shimokawa T., Toftgård R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci U S A 2007, 104:8455-8460.
91. Lee J.J., Perera R.M., Wang H., Wu D.C., Liu X.S., Han S., et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci U S A 2014, 111:E3091-E3100.
92. Shin K., Lim A., Zhao C., Sahoo D., Pan Y., Spiekerkoetter E., et al. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 2014, 26:521-533.