Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling

Nature Chemical Biology

Volumn 9, Issue 9, 2013, Pages 557-564

  Nedelcu, Daniel ^a   Liu, Jing ^a   Xu, Yangqing ^a   Jao, Cindy ^a   Salic, Adrian ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AZASTEROL; CHOLESTEROL DERIVATIVE; CYSTEINE; ITRACONAZOLE; LIPID BINDING PROTEIN; OXYSTEROL; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; UNCLASSIFIED DRUG; VISMODEGIB;

ANIMAL CELL; ARTICLE; BINDING SITE; CELL CULTURE; CHOLESTEROL SYNTHESIS; DIASTEREOISOMER; IMMUNOFLUORESCENCE; MOUSE; NONHUMAN; POLYACRYLAMIDE GEL ELECTROPHORESIS; PRIORITY JOURNAL; REAL TIME POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION;

AMINO ACID SEQUENCE; ANIMALS; BINDING SITES; DROSOPHILA MELANOGASTER; EVOLUTION, MOLECULAR; HEDGEHOG PROTEINS; MICE; MOLECULAR SEQUENCE DATA; PROTEIN STRUCTURE, TERTIARY; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; STEROLS; STRUCTURE-ACTIVITY RELATIONSHIP; XENOPUS LAEVIS;

ERINACEIDAE; VERTEBRATA;

EID: 84883185477     PISSN: 15524450     EISSN: 15524469     Source Type: Journal    
DOI: 10.1038/nchembio.1290     Document Type: Article

References (31)

1. Lum, L. & Beachy, P.A. The Hedgehog response network: sensors, switches, and routers. Science 304, 1755-1759 (2004).
2. Ingham, P.W. & McMahon, A.P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059-3087 (2001).
3. Taipale, J., Cooper, M.K., Maiti, T. & Beachy, P.A. Patched acts catalytically to suppress the activity of Smoothened. Nature 418, 892-897 (2002).
4. Chen, J.K., Taipale, J., Cooper, M.K. & Beachy, P.A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16, 2743-2748 (2002).
5. Frank-Kamenetsky, M. et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1, 10 (2002).
6. Robarge, K.D. et al. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg. Med. Chem. Lett. 19, 5576-5581 (2009).
7. Chen, J.K., Taipale, J., Young, K.E., Maiti, T. & Beachy, P.A. Small molecule modulation of Smoothened activity. Proc. Natl. Acad. Sci. USA 99, 14071-14076 (2002).
8. Sinha, S. & Chen, J.K. Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat. Chem. Biol. 2, 29-30 (2006).
9. Dwyer, J.R. et al. Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells. J. Biol. Chem. 282, 8959-8968 (2007).
10. Corcoran, R.B. & Scott, M.P. Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc. Natl. Acad. Sci. USA 103, 8408-8413 (2006).
11. Kim, W.K., Meliton, V., Amantea, C.M., Hahn, T.J. & Parhami, F. 20(S)-hydroxycholesterol inhibits PPARγ expression and adipogenic differentiation of bone marrow stromal cells through a hedgehog-dependent mechanism. J. Bone Miner. Res. 22, 1711-1719 (2007).
12. Nachtergaele, S. et al. Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat. Chem. Biol. 8, 211-220 (2012).
13. Rohatgi, R., Milenkovic, L. & Scott, M.P. Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372-376 (2007).
14. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005-1009 (2000).
15. Svärd, J. et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev. Cell 10, 187-197 (2006); erratum 10, 409.
16. Cooper, M.K. et al. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat. Genet. 33, 508-513 (2003).
17. Corbit, K.C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018-1021 (2005).
18. Wang, Y., Zhou, Z., Walsh, C.T. & McMahon, A.P. Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc. Natl. Acad. Sci. USA 106, 2623-2628 (2009).
19. Rohatgi, R., Milenkovic, L., Corcoran, R.B. & Scott, M.P. Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc. Natl. Acad. Sci. USA 106, 3196-3201 (2009).
20. Kim, J. et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17, 388-399 (2010).
21. Bazan, J.F. & de Sauvage, F.J. Structural ties between cholesterol transport and morphogen signaling. Cell 138, 1055-1056 (2009).
22. Wang, Y. et al. Glucocorticoid compounds modify smoothened localization and hedgehog pathway activity. Chem. Biol. 19, 972-982 (2012).
23. Janda, C.Y., Waghray, D., Levin, A.M., Thomas, C. & Garcia, K.C. Structural basis of Wnt recognition by Frizzled. Science 337, 59-64 (2012).
24. Dorn, K.V., Hughes, C.E. & Rohatgi, R.A. Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev. Cell 23, 823-835 (2012).
25. Infante, R.E. et al. Purified NPC1 protein: II. Localization of sterol binding to a 240-amino acid soluble luminal loop. J. Biol. Chem. 283, 1064-1075 (2008).
26. Motamed, M. et al. Identification of luminal Loop 1 of Scap protein as the sterol sensor that maintains cholesterol homeostasis. J. Biol. Chem. 286, 18002-18012 (2011).
27. Nakano, Y. et al. Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech. Dev. 121, 507-518 (2004).
28. Aanstad, P. et al. The extracellular domain of Smoothened regulates ciliary localization and is required for high-level Hh signaling. Curr. Biol. 19, 1034-1039 (2009).
29. Tukachinsky, H., Lopez, L. & Salic, A. A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J. Cell Biol. 191, 415-428 (2010).
30. Tukachinsky, H., Kuzmickas, R.P., Jao, C.Y., Liu, J. & Salic, A. Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand. Cell Rep. 2, 308-320 (2012).
31. Klein, U., Gimpl, G. & Fahrenholz, F. Alteration of the myometrial plasma membrane cholesterol content with β-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry 34, 13784-13793 (1995).