Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response

Developmental Cell

Volumn 26, Issue 4, 2013, Pages 346-357

  Myers, BenjaminR ^a   Sever, Navdar ^a   Chong, YongChun ^a   Kim, James ^a,e   Belani, JitendraD ^b   Rychnovsky, Scott ^b   Bazan, J Fernando ^c,d   Beachy, PhilipA ^a  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c 4th and Aspen Life Sciences ^*  (United States)

^d UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

^e UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BINDING PROTEIN; CYCLOPAMINE; FRIZZLED PROTEIN; LIPID; MEVINOLIN; OXYSTEROL; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; STEROL; WNT PROTEIN;

ANIMAL CELL; ARTICLE; BINDING SITE; CELL FUNCTION; CELLULAR DISTRIBUTION; CONTROLLED STUDY; CYSTEINE RICH DOMAIN; DRUG MECHANISM; EXTRACELLULAR MATRIX; FEEDBACK SYSTEM; HUMAN; HUMAN CELL; IN VITRO STUDY; MEDIATOR; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LIPID INTERACTION; PROTEIN METABOLISM; SIGNAL TRANSDUCTION;

AMINO ACIDS; ANIMALS; BINDING SITES; CONSERVED SEQUENCE; FRIZZLED RECEPTORS; HEDGEHOG PROTEINS; HEK293 CELLS; HUMANS; LIGANDS; MICE; MODELS, MOLECULAR; NIH 3T3 CELLS; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY; RECEPTORS, CELL SURFACE; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; STEROLS; STRUCTURE-ACTIVITY RELATIONSHIP; WNT PROTEINS;

ERINACEIDAE;

EID: 84883051342     PISSN: 15345807     EISSN: 18781551     Source Type: Journal    
DOI: 10.1016/j.devcel.2013.07.015     Document Type: Article

References (62)

1. Aanstad P., Santos N., Corbit K.C., Scherz P.J., Trinh A., Salvenmoser W., Huisken J., Reiter J.F., Stainier D.Y.R. The extracellular domain of Smoothened regulates ciliary localization and is required for high-level Hh signaling. Curr. Biol. 2009, 19:1034-1039.
2. Ayers K.L., Thérond P.P. Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling. Trends Cell Biol. 2010, 20:287-298.
3. Bazan J.F., de Sauvage F.J. Structural ties between cholesterol transport and morphogen signaling. Cell 2009, 138:1055-1056.
4. Beachy P.A., Karhadkar S.S., Berman D.M. Tissue repair and stem cell renewal in carcinogenesis. Nature 2004, 432:324-331.
5. 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.
6. Belani J.D., Rychnovsky S.D. A concise synthesis of ent-Cholesterol. J.Org. Chem. 2008, 73:2768-2773.
7. Benned-Jensen T., Norn C., Laurent S., Madsen C.M., Larsen H.M., Arfelt K.N., Wolf R.M., Frimurer T., Sailer A.W., Rosenkilde M.M. Molecular characterization of oxysterol binding to the Epstein-Barr virus-induced gene 2 (GPR183). J.Biol. Chem. 2012, 287:35470-35483.
8. Bhanot P., Brink M., Samos C.H., Hsieh J.C., Wang Y., Macke J.P., Andrew D., Nathans J., Nusse R. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 1996, 382:225-230.
9. Briscoe J., Chen Y., Jessell T.M., Struhl G. A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube. Mol. Cell 2001, 7:1279-1291.
10. Buonamici S., Williams J., Morrissey M., Wang A., Guo R., Vattay A., Hsiao K., Yuan J., Green J., Ospina B., et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med. 2010, 2. 51ra70.
11. Burger K., Gimpl G., Fahrenholz F. Regulation of receptor function by cholesterol. Cell. Mol. Life Sci. 2000, 57:1577-1592.
12. Cadigan K.M., Fish M.P., Rulifson E.J., Nusse R. Wingless repression of Drosophila frizzled 2 expression shapes the Wingless morphogen gradient in the wing. Cell 1998, 93:767-777.
13. Carroll C.E., Marada S., Stewart D.P., Ouyang J.X., Ogden S.K. The extracellular loops of Smoothened play a regulatory role in control of Hedgehog pathway activation. Development 2012, 139:612-621.
14. Chen Y., Struhl G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 1996, 87:553-563.
15. Chen Y., Struhl G. Invivo evidence that Patched and Smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex. Development 1998, 125:4943-4948.
16. Chen J.K., Taipale J., Cooper M.K., Beachy P.A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002, 16:2743-2748.
17. Chen J.K., Taipale J., Young K.E., Maiti T., Beachy P.A. Small molecule modulation of Smoothened activity. Proc. Natl. Acad. Sci. USA 2002, 99:14071-14076.
18. Clevers H., Nusse R. Wnt/β-catenin signaling and disease. Cell 2012, 149:1192-1205.
19. Cooper M.K., Wassif C.A., Krakowiak P.A., Taipale J., Gong R., Kelley R.I., Porter F.D., Beachy P.A. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat. Genet. 2003, 33:508-513.
20. Corcoran R.B., Scott M.P. Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc. Natl. Acad. Sci. USA 2006, 103:8408-8413.
21. Coughlin S.R. Thrombin signalling and protease-activated receptors. Nature 2000, 407:258-264.
22. Denef N., Neubüser D., Perez L., Cohen S.M. Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 2000, 102:521-531.
23. Dijkgraaf G.J.P., Alicke B., Weinmann L., Januario T., West K., Modrusan Z., Burdick D., Goldsmith R., Robarge K., Sutherlin D., et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011, 71:435-444.
24. Dorn K.V., Hughes C.E., Rohatgi R. A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev. Cell 2012, 23:823-835.
25. Dukkipati A., Park H.H., Waghray D., Fischer S., Garcia K.C. BacMam system for high-level expression of recombinant soluble and membrane glycoproteins for structural studies. Protein Expr. Purif. 2008, 62:160-170.
26. Dwyer J.R., Sever N., Carlson M., Nelson S.F., Beachy P.A., Parhami F. Oxysterols are novel activators of the hedgehog signaling pathway inpluripotent mesenchymal cells. J.Biol. Chem. 2007, 282:8959-8968.
27. Eaton S. Multiple roles for lipids in the Hedgehog signalling pathway. Nat. Rev. Mol. Cell Biol. 2008, 9:437-445.
28. Hausmann G., von Mering C., Basler K. The hedgehog signaling pathway: where did it come from?. PLoS Biol. 2009, 7:e1000146.
29. Heo G.-Y., Bederman I., Mast N., Liao W.-L., Turko I.V., Pikuleva I.A. Conversion of 7-ketocholesterol to oxysterol metabolites by recombinant CYP27A1 and retinal pigment epithelial cells. J.Lipid Res. 2011, 52:1117-1127.
30. Huangfu D., Anderson K.V. Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 2006, 133:3-14.
31. Ingham P.W., Nakano Y., Seger C. Mechanisms and functions of Hedgehog signalling across the metazoa. Nat. Rev. Genet. 2011, 12:393-406.
32. Janda C.Y., Waghray D., Levin A.M., Thomas C., Garcia K.C. Structural basis of Wnt recognition by Frizzled. Science 2012, 337:59-64.
33. 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. USA 2009, 106:21666-21671.
34. Kim J., Tang J.Y., Gong R., Kim J., Lee J.J., Clemons K.V., Chong C.R., Chang K.S., Fereshteh M., Gardner D., et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 2010, 17:388-399.
35. Kim J., Aftab B.T., Tang J.Y., Kim D., Lee A.H., Rezaee M., Kim J., Chen B., King E.M., Borodovsky A., et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell 2013, 23:23-34.
36. Lagerström M.C., Schiöth H.B. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat. Rev. Drug Discov. 2008, 7:339-357.
37. Lum L., Beachy P.A. The Hedgehog response network: sensors, switches, and routers. Science 2004, 304:1755-1759.
38. Maity T., Fuse N., Beachy P.A. Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. Proc. Natl. Acad. Sci. USA 2005, 102:17026-17031.
39. Mann R.K., Beachy P.A. Novel lipid modifications of secreted protein signals. Annu. Rev. Biochem. 2004, 73:891-923.
40. Milenkovic L., Scott M.P., Rohatgi R. Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium. J.Cell Biol. 2009, 187:365-374.
41. Muenke M., Beachy P.A. Genetics of ventral forebrain development and holoprosencephaly. Curr. Opin. Genet. Dev. 2000, 10:262-269.
42. Nachtergaele S., Mydock L.K., Krishnan K., Rammohan J., Schlesinger P.H., Covey D.F., Rohatgi R. Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat. Chem. Biol. 2012, 8:211-220.
43. Nakano Y., Nystedt S., Shivdasani A.A., Strutt H., Thomas C., Ingham P.W. Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech. Dev. 2004, 121:507-518.
44. 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, in press. Published online July 7, 2013. 10.1038/nchembio.1290.
45. Povelones M., Nusse R. The role of the cysteine-rich domain of Frizzled in Wingless-Armadillo signaling. EMBO J. 2005, 24:3493-3503.
46. Roberg-Larsen H., Strand M.F., Grimsmo A., Olsen P.A., Dembinski J.L., Rise F., Lundanes E., Greibrokk T., Krauss S., Wilson S.R. High sensitivity measurements of active oxysterols with automated filtration/filter backflush-solid phase extraction-liquid chromatography-mass spectrometry. J.Chromatogr. A 2012, 1255:291-297.
47. Rohatgi R., Scott M.P. Patching the gaps in Hedgehog signalling. Nat. Cell Biol. 2007, 9:1005-1009.
48. Rohatgi R., Milenkovic L., Scott M.P. Patched1 regulates hedgehog signaling at the primary cilium. Science 2007, 317:372-376.
49. Rudin C.M., Hann C.L., Laterra J., Yauch R.L., Callahan C.A., Fu L., Holcomb T., Stinson J., Gould S.E., Coleman B., et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N.Engl. J. Med. 2009, 361:1173-1178.
50. Taipale J., Chen J.K., Cooper M.K., Wang B., Mann R.K., Milenkovic L., Scott M.P., Beachy P.A. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 2000, 406:1005-1009.
51. Taipale J., Cooper M.K., Maiti T., Beachy P.A. Patched acts catalytically to suppress the activity of Smoothened. Nature 2002, 418:892-897.
52. Tang J.Y., Mackay-Wiggan J.M., Aszterbaum M., Yauch R.L., Lindgren J., Chang K., Coppola C., Chanana A.M., Marji J., Bickers D.R., Epstein E.H. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N.Engl. J. Med. 2012, 366:2180-2188.
53. Teglund S., Toftgård R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim. Biophys. Acta 2010, 1805:181-208.
54. Teperino R., Amann S., Bayer M., McGee S.L., Loipetzberger A., Connor T., Jaeger C., Kammerer B., Winter L., Wiche G., et al. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 2012, 151:414-426.
55. Varjosalo M., Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008, 22:2454-2472.
56. Varjosalo M., Li S.-P., Taipale J. Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev. Cell 2006, 10:177-186.
57. Venkatakrishnan A.J., Deupi X., Lebon G., Tate C.G., Schertler G.F., Babu M.M. Molecular signatures of G-protein-coupled receptors. Nature 2013, 494:185-194.
58. Von Hoff D.D., LoRusso P.M., Rudin C.M., Reddy J.C., Yauch R.L., Tibes R., Weiss G.J., Borad M.J., Hann C.L., Brahmer J.R., et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N.Engl. J. Med. 2009, 361:1164-1172.
59. Wang C., Wu H., Katritch V., Han G.W., Huang X.-P., Liu W., Siu F.Y., Roth B.L., Cherezov V., Stevens R.C. Structure of the human smoothened receptor bound to an antitumour agent. Nature 2013, 497:338-343.
60. Yauch R.L., Dijkgraaf G.J.P., Alicke B., Januario T., Ahn C.P., Holcomb T., Pujara K., Stinson J., Callahan C.A., Tang T., et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 2009, 326:572-574.
61. Zhang L., Shih A.Y., Yang X.V., Kuei C., Wu J., Deng X., Mani N.S., Mirzadegan T., Sun S., Lovenberg T.W., Liu C. Identification of structural motifs critical for epstein-barr virus-induced molecule 2 function and homology modeling of the ligand docking site. Mol. Pharmacol. 2012, 82:1094-1103.
62. Zhao Y., Tong C., Jiang J. Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 2007, 450:252-258.