Smoothened goes molecular: New pieces in the hedgehog signaling puzzle

Journal of Biological Chemistry

Volumn 290, Issue 6, 2015, Pages 3500-3507

  McCabe, Jacqueline M ^a   Leahy, Daniel J ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MEMBRANES; PROTEINS;

ANIMAL DEVELOPMENT; BIOCHEMICAL CHARACTERIZATION; CANCER THERAPY; HEDGEHOG SIGNALING; HUMAN HEALTH; INDIVIDUAL COMPONENTS; INTEGRAL MEMBRANE PROTEINS;

SIGNAL TRANSDUCTION;

CHOLESTEROL; CYCLOPAMINE; FRIZZLED PROTEIN; OXYSTEROL; PROTEIN PATCHED; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; TALADEGIB; VISMODEGIB; WNT PROTEIN; ANTINEOPLASTIC AGENT; G PROTEIN COUPLED RECEPTOR;

AMELOBLASTOMA; BASAL CELL CARCINOMA; BINDING AFFINITY; CANCER RESISTANCE; CRYSTAL STRUCTURE; DRUG PROTEIN BINDING; DRUG TARGETING; GENE; GENE MUTATION; HUMAN; LIGAND BINDING; MEDULLOBLASTOMA; MENINGIOMA; NONHUMAN; PHENOTYPE; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; PROTEIN TRANSPORT; PTC GENE; REVIEW; SMO GENE; AMINO ACID SEQUENCE; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; GENETICS; METABOLISM; MOLECULAR GENETICS; NEOPLASMS; SIGNAL TRANSDUCTION;

ANIMALIA; ERINACEIDAE;

AMINO ACID SEQUENCE; ANIMALS; ANTINEOPLASTIC AGENTS; HEDGEHOG PROTEINS; HUMANS; MOLECULAR SEQUENCE DATA; NEOPLASMS; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 84922358758     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.R114.617936     Document Type: Review

References (88)

1. Nüsslein-Volhard, C., and Wieschaus, E. (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287, 795-801
2. Ingham, P. W., Nakano, Y., and Seger, C. (2011) Mechanisms and functions of Hedgehog signalling across the metazoa. Nat. Rev. Genet. 12, 393-406
3. Briscoe, J., and Thérond, P. P. (2013) The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 14, 416-429
4. Arwert, E. N., Hoste, E., and Watt, F. M. (2012) Epithelial stem cells, wound healing and cancer. Nat. Rev. Cancer 12, 170-180
5. Heemskerk, J., and DiNardo, S. (1994) Drosophila hedgehog acts as a morphogen in cellular patterning. Cell 76, 449-460
6. Gradilla, A.-C., and Guerrero, I. (2013) Hedgehog on the move: a precise spatial control of Hedgehog dispersion shapes the gradient. Curr. Opin. Genet. Dev. 23, 363-373
7. Ribes, V., and Briscoe, J. (2009) Establishing and interpreting graded Sonic Hedgehog signaling during vertebrate neural tube patterning: the role of negative feedback. Cold Spring Harb. Perspect. Biol. 1, a002014
8. Thérond, P. P. (2012) Release and transportation of Hedgehog molecules. Curr. Opin. Cell Biol. 24, 173-180
9. Ryan, K. E., and Chiang, C. (2012) Hedgehog secretion and signal transduction in vertebrates. J. Biol. Chem. 287, 17905-17913
10. Nakano, Y., Guerrero, I., Hidalgo, A., Taylor, A., Whittle, J. R., and Ingham, P. W. (1989) A protein with several possible membrane-spanning domains encoded by the Drosophila segment polarity gene patched. Nature 341, 508-513
11. Stone, D. M., Hynes, M., Armanini, M., Swanson, T. A., Gu, Q., Johnson, R. L., Scott, M. P., Pennica, D., Goddard, A., Phillips, H., Noll, M., Hooper, J. E., de Sauvage, F., and Rosenthal, A.(1996) The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384, 129-134
12. Alcedo, J., Ayzenzon, M., Von Ohlen, T., Noll, M., and Hooper, J. E. (1996) The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the Hedgehog signal. Cell 86, 221-232
13. van den Heuvel, M., and Ingham, P. W. (1996) smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. Nature 382, 547-551
14. Zheng, X., Mann, R. K., Sever, N., and Beachy, P. A. (2010) Genetic and biochemical definition of the Hedgehog receptor. Genes Dev. 24, 57-71
15. Fuse, N., Maiti, T., Wang, B., Porter, J. A., Hall, T. M. T., Leahy, D. J., and Beachy, P. A. (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, 10992-10999
16. Taipale, J., Cooper, M. K., Maiti, T., and Beachy, P. A. (2002) Patched acts catalytically tosuppress the activity of Smoothened. Nature 418, 892-897
17. Tseng, T. T., Gratwick, K. S., Kollman, J., Park, D., Nies, D. H., Goffeau, A., and Saier, M. H. (1999) The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J. Mol. Microbiol. Biotechnol. 1, 107-125
18. Kuwabara, P. E., and Labouesse, M. (2002) The sterol-sensing domain: multiple families, a unique role? Trends Genet. 18, 193-201
19. Ayers, K. L., and Thérond, P. P.(2010) Evaluating Smoothened as aG-protein-coupled receptor for Hedgehog signalling. Trends Cell Biol. 20, 287-298
20. Beachy, P. A., Hymowitz, S. G., Lazarus, R. A., Leahy, D. J., and Siebold, C. (2010) Interactions between Hedgehog proteins and their binding partners come into view. Genes Dev. 24, 2001-2012
21. Yao, S., Lum, L., and Beachy, P. (2006) The Ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 125, 343-357
22. McLellan, J. S., Yao, S., Zheng, X., Geisbrecht, B. V., Ghirlando, R., Beachy, P. A., and Leahy, D. J. (2006) Structure of a heparin-dependent complex of Hedgehog and Ihog. Proc. Natl. Acad. Sci. U.S.A. 103, 17208-17213
23. McLellan, J. S., Zheng, X., Hauk, G., Ghirlando, R., Beachy, P. A., and Leahy, D. J. (2008) The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. Nature 455, 979-983
24. Bosanac, I., Maun, H. R., Scales, S. J., Wen, X., Lingel, A., Bazan, J. F., de Sauvage, F. J., Hymowitz, S. G., and Lazarus, R. A. (2009) The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling. Nat. Struct. Mol. Biol. 16, 691-697
25. Bishop, B., Aricescu, A. R., Harlos, K., O'Callaghan, C. A., Jones, E. Y., and Siebold, C. (2009) Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. Nat. Struct. Mol. Biol. 16, 698-703
26. Williams, E. H., Pappano, W. N., Saunders, A. M., Kim, M.-S., Leahy, D. J., and Beachy, P. A. (2010) Dally-like core protein and its mammalian homologues mediate stimulatory and inhibitory effects on Hedgehog signal response. Proc. Natl. Acad. Sci. U.S.A. 107, 5869-5874
27. Kim, M.-S., Saunders, A.M., Hamaoka, B. Y., Beachy, P. A., and Leahy, D.J. (2011) Structure of the protein core of the glypican Dally-like and localization of a region important for hedgehog signaling. Proc. Natl. Acad. Sci. U.S.A. 108, 13112-13117
28. Izzi, L., Lévesque, M., Morin, S., Laniel, D., Wilkes, B. C., Mille, F., Krauss, R. S., McMahon, A. P., Allen, B. L., and Charron, F. (2011) Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev. Cell 20, 788-801
29. Allen, B. L., Song, J. Y., Izzi, L., Althaus, I. W., Kang, J.-S., Charron, F., Krauss, R. S., and McMahon, A. P. (2011) Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev. Cell 20, 775-787
30. Zhang, C., Williams, E. H., Guo, Y., Lum, L., and Beachy, P. A. (2004) Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc. Natl. Acad. Sci. U.S.A. 101, 17900-17907
31. Jia, J., Tong, C., Wang, B., Luo, L., and Jiang, J. (2004) Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432, 1045-1050
32. Zhao, Y., Tong, C., and Jiang, J. (2007) Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450, 252-258
33. Hui, C.-C., and Angers, S. (2011) Gli proteins in development and disease. Annu. Rev. Cell Dev. Biol. 27, 513-537
34. Rohatgi, R., Milenkovic, L., and Scott, M. P. (2007) Patched1 regulates Hedgehog signaling at the primary cilium. Science 317, 372-376
35. Huangfu, D., Liu, A., Rakeman, A. S., Murcia, N. S., Niswander, L., and Anderson, K. V. (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83-87
36. Rohatgi, R., Milenkovic, L., Corcoran, R. B., and Scott, M. P.(2009) Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc. Natl. Acad. Sci. U.S.A. 106, 3196-3201
37. Denef, N., Neubüser, D., Perez, L., and Cohen, S. M. (2000) Hedgehog induces opposite changes in turnover and subcellular localization of Patched and Smoothened. Cell 102, 521-531
38. Cooper, M. K., Porter, J. A., Young, K. E., and Beachy, P. A. (1998) Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280, 1603-1607
39. Taipale, J., Chen, J. K., Cooper, M. K., Wang, B., Mann, R. K., Milenkovic, L., Scott, M. P., and Beachy, P. A. (2000) Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005-1009
40. Chen, J. K., Taipale, J., Young, K. E., Maiti, T., and Beachy, P. A. (2002) Small molecule modulation of Smoothened activity. Proc. Natl. Acad. Sci. U.S.A. 99, 14071-14076
41. Bijlsma, M. F., Spek, C. A., Zivkovic, D., van de Water, S., Rezaee, F., and Peppelenbosch, M. P. (2006) Repression of Smoothened by Patched-dependent (Pro-)vitamin D3 Secretion. PLoS Biol. 4, e232
42. Wang, C., Wu, H., Katritch, V., Han, G. W., Huang, X.-P., Liu, W., Siu, F. Y., Roth, B. L., Cherezov, V., and Stevens, R. C. (2013) Structure of the human smoothened receptor bound to an antitumour agent. Nature 497, 338-343
43. Wang, C., Wu, H., Evron, T., Vardy, E., Han, G. W., Huang, X.-P., Hufeisen, S. J., Mangano, T. J., Urban, D. J., Katritch, V., Cherezov, V., Caron, M. G., Roth, B. L., and Stevens, R. C. (2014) Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat. Commun. 5, 4355
44. Weierstall, U., James, D., Wang, C., White, T. A., Wang, D., Liu, W., Spence, J. C. H., Doak, R. B., Nelson, G., Fromme, P., Fromme, R., Grotjohann, I., Kupitz, C., Zatsepin, N. A., Liu, H., Basu, S., Wacker, D., Han, G. W., Katritch, V., Boutet, S., Messerschmidt, M., Williams, G. J., Koglin, J. E., Seibert, M. M., Klinker, M., Gati, C., Shoeman, R. L., Barty, A., Chapman, H. N., Kirian, R. A., Beyerlein, K. R., Stevens, R. C., Li, D., Shah, S. T. A., Howe, N., Caffrey, M., and Cherezov, V. (2014) Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography. Nat. Commun. 5, 3309
45. Venkatakrishnan, A. J., Deupi, X., Lebon, G., Tate, C. G., Schertler, G. F., and Babu, M. M. (2013) Molecular signatures of G-protein-coupled receptors. Nature 494, 185-194
46. Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J.M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr, and de Sauvage, F. J. (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90-92
47. Riobo, N. A., Saucy, B., DiLizio, C., and Manning, D. R. (2006) Activation of heterotrimeric G proteins by Smoothened. Proc. Natl. Acad. Sci. U.S.A. 103, 12607-12612
48. Philipp, M., and Caron, M. G. (2009) Hedgehog signaling: is Smo a G protein-coupled receptor? Curr. Biol. 19, R125-R127
49. i proteins link Hedgehog signaling to activation of Rho small GTPases to promote fibroblast migration. J. Biol. Chem. 286, 19589-19596
50. i proteins. Sci. Signal. 4, pt7
51. i. Mol. Pharmacol. 83, 691-697
52. i proteins mediate activation of the canonical hedgehog pathway in the myocardium. Am. J. Physiol. Heart Circ. Physiol. 307, H66-H72
53. Hanson, M. A., Roth, C. B., Jo, E., Griffith, M. T., Scott, F. L., Reinhart, G., Desale, H., Clemons, B., Cahalan, S. M., Schuerer, S.C., Sanna, M. G., Han, G. W., Kuhn, P., Rosen, H., and Stevens, R. C. (2012) Crystal structure of a lipid G protein-coupled receptor. Science 335, 851-855
54. Carroll, C. E., Marada, S., Stewart, D. P., Ouyang, J. X., and Ogden, S. K. (2012) The extracellular loops of Smoothened play a regulatory role in control of Hedgehog pathway activation. Development 139, 612-621
55. 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., Bazan, J. F., Kan, Z., Seshagiri, S., Hann, C. L., Gould, S. E., Low, J. A., Rudin, C. M., and de Sauvage, F. J. (2009) Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326, 572-574
56. Robarge, K. D., Brunton, S. A., Castanedo, G. M., Cui, Y., Dina, M. S., Goldsmith, R., Gould, S. E., Guichert, O., Gunzner, J. L., Halladay, J., Jia, W., Khojasteh, C., Koehler, M. F. T., Kotkow, K., La, H., Lalonde, R. L., Lau, K., Lee, L., Marshall, D., Marsters, J. C., Jr., Murray, L. J., Qian, C., Rubin, L. L., Salphati, L., Stanley, M. S., Stibbard, J. H. A., Sutherlin, D. P., Ubhayaker, S., Wang, S., Wong, S., and Xie, M. (2009) GDC-0449 - a potent inhibitor of the hedgehog pathway. Bioorg. Med. Chem. Lett. 19, 5576-5581
57. Bender, M. H., Hipskind, P. A., Capen, A. R., Cockman, M., Credille, K. M., Gao, H., Bastian, J. A., Clay, J. M., Lobb, K. L., Sall, D. J., Thompson, M. L., Wilson, T., Wishart, G. N, and Patel, B. K. R. (2011) Abstract 2819: Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated hedgehog signaling. Cancer Res. 71, 2819
58. 1-adrenergic receptor. Nature 469, 241-244
59. 2-adrenergic receptor activation. Cell 152, 532-542
60. 2-adrenoceptor stabilized by an engineered nanobody. Nature 502, 575-579
61. Myers, B. R., Sever, N, Chong, Y. C., Kim, J., Belani, J. D., Rychnovsky, S., Bazan, J. F., and Beachy, P. A. (2013) Hedgehog pathway modulation by multiple lipid binding sites on the Smoothened effector of signal response. Dev. Cell 26, 346-357
62. Nedelcu, D., Liu, J., Xu, Y., Jao, C., and Salic, A. (2013) Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling. Nat. Chem. Biol. 9, 557-564
63. Nachtergaele, S., Whalen, D. M., Mydock, L. K., Zhao, Z., Malinauskas, T., Krishnan, K., Ingham, P. W., Covey, D. F., Siebold, C, and Rohatgi, R. (2013) Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. Elife 2, e01340
64. Corcoran, R. B., and Scott, M. P. (2006) Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc. Natl. Acad. Sci. U.S.A. 103, 8408-8413
65. Dwyer, J. R., Sever, N, Carlson, M., Nelson, S. F., Beachy, P. A., and Parhami, F. (2007) Oxysterols are novel activators of the Hedgehog signaling pathway in pluripotent mesenchymal cells. J. Biol. Chem. 282, 8959-8968
66. Nachtergaele, S., Mydock, L. K., Krishnan, K., Rammohan, J., Schlesinger, P. H, Covey, D. F., and Rohatgi, R. (2012) Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat Chem. Biol. 8, 211-220
67. Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C, and Garcia, K. C. (2012) Structural basis of Wnt recognition by Frizzled. Science 337, 59-64
68. Bazan, J. F., and de Sauvage, F. J. (2009) Structural ties between cholesterol transport and morphogen signaling. Cell 138, 1055-1056
69. Rana, R., Carroll, C. E., Lee, H.-J., Bao, J., Marada, S., Grace, C. R. R., Guibao, C. D., Ogden, S. K., and Zheng, J. J. (2013) Structural insights into the role of Smoothened cysteine-rich domain in Hedgehog signaling. Nat Commun. 4, 2965
70. Wang, Y., Davidow, L., Arvanites, A. C, Blanchard, J., Lam, K., Xu, K., Oza, V., Yoo, J. W., Ng, J. M. Y., Curran, T., Rubin, L. L., and McMahon, A. P. (2012) Glucocorticoid compounds modify Smoothened localization and Hedgehog pathway activity. Chem. Biol. 19, 972-982
71. Cooper, M. K., Wassif, C. A., Krakowiak, P. A., Taipale, J., Gong, R., Kelley, R. I., Porter, F. D., and Beachy, P. A. (2003) A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet. 33, 508-513
72. Kim, J., Aftab, B. T., Tang, J. Y., Kim, D., Lee, A. H, Rezaee, M., Kim, J., Chen, B., King, E. M., Borodovsky, A., Riggins, G. J., Epstein, E. H, Jr., Beachy, P. A., and Rudin, C. M. (2013) Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell 23, 23-34
73. 2-adrenergic receptor. Structure 16, 897-905
74. Ballesteros, J. A., and Weinstein, H. (1995) Integrated methods for the construction of three dimensional models and computational probing of structure-function relations in G-protein coupled receptors. Methods Neurosci. 25, 366-428
75. Goodrich, L. V., Milenković, L., Higgins, K. M., and Scott, M. P. (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109-1113
76. Sweeney, R. T., McClary, A. C., Myers, B. R., Biscocho, J., Neahring, L., Kwei, K. A., Qu, K., Gong, X., Ng, T., Jones, C. D., Varma, S., Odegaard, J.I., Sugiyama, T., Koyota, S., Rubin, B. P., Troxell, M. L., Pelham, R. J., Zehnder, J. L., Beachy, P. A., Pollack, J. R., and West, R. B. (2014) Identification of recurrent SMO and BRAF mutations in ameloblastomas. Nat. Genet. 46, 722-725
77. Brastianos, P. K., Horowitz, P. M., Santagata, S., Jones, R. T., McKenna, A., Getz, G., Ligon, K. L., Palescandolo, E., Van Hummelen, P., Ducar, M. D., Raza, A., Sunkavalli, A., Macconaill, L. E., Stemmer-Rachamimov, A. O., Louis, D. N., Hahn, W. C., Dunn, I. F., and Beroukhim, R. (2013) Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat. Genet. 45, 285-289
78. Clark, V. E., Erson-Omay, E. Z., Serin, A., Yin, J., Cotney, J., Ozduman, K, Avar, T., Li, J., Murray, P. B, Henegariu, O, Yilmaz, S, Günel, J. M., Carrión-Grant, G., Yilmaz, B., Grady, C, Tanrikulu, B., Bakircioglu, M, Kaymakçalan, H, Caglayan, A. O., Sencar, L., Ceyhun, E., Atik, A. F., Bayri, Y., Bai, H, Kolb, L. E., Hebert, R. M., Omay, S. B., Mishra-Gorur, K., Choi, M., Overton, J. D, Holland, E. C, Mane, S., State, M. W, Bilgüvar, K., Baehring, J. M., Gutin, P. H., Piepmeier, J. M, Vortmeyer, A, Brennan, C. W., Pamir, M. N., Kiliç, T, Lifton, R. P., Noonan, J. P., Yasuno, K., and Günel, M. (2013) Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339, 1077-1080
79. 2-adrenergic receptor. Biochemistry 34, 15407-15414
80. Rosenbaum, D. M., Rasmussen, S. G. F., and Kobilka, B. K. (2009) The structure and function of G-protein-coupled receptors. Nature 459, 356-363
81. Deupi, X., Edwards, P., Singhal, A., Nickle, B., Oprian, D., Schertler, G., and Standfuss, J. (2012) Stabilized G protein binding site in the structure of constitutively active metarhodopsin-II. Proc. Natl. Acad. Sci. U.S.A. 109, 119-124
82. Kruse, A. C, Ring, A. M., Manglik, A., Hu, J., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C, Sexton, P. M., Christopoulos, A., Felder, C. C, Gmeiner, P., Steyaert, J., Weis, W. I., Garcia, K. C, Wess, J., and Kobilka, B. K. (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504, 101-106
83. Deupi, X., and Standfuss, J. (2011) Structural insights into agonist-induced activation of G-protein-coupled receptors. Curr. Opin. Struct. Biol. 21, 541-551
84. Chang, A. L. S., and Oro, A. E. (2012) Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma. Arch. Dermatol. 148, 1324-1325
85. Buonamici, S., Williams, J., Morrissey, M., Wang, A., Guo, R., Vattay, A., Hsiao, K., Yuan, J., Green, J., Ospina, B., Yu, Q., Ostrom, L., Fordjour, P., Anderson, D. L., Monahan, J. E., Kelleher, J. F., Peukert, S., Pan, S., Wu, X., Maira, S.-M., García-Echeverría, C, Briggs, K. J., Watkins, D. N., Yao, Y.-M., Lengauer, C, Warmuth, M., Sellers, W. R., and Dorsch, M. (2010) Interfering with resistance to Smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med. 2, 51ra70
86. Brinkhuizen, T., Reinders, M. G., van Geel, M., Hendriksen, A. J. L., Paulussen, A. D. C, Winnepenninckx, V. J., Keymeulen, K. B., Soetekouw, P. M. M. B., van Steensel, M. A. M., and Mosterd, K. (2014) Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma. J. Am. Acad. Dermatol. 71, 1005-1008
87. Chen, W. (2004) Activity-Dependent Internalization of Smoothened mediated by β-arrestin 2 and GRK2. Science 306, 2257-2260
88. Chen, Y., Sasai, N., Ma, G., Yue, T., Jia, J., Briscoe, J., and Jiang, J. (2011) Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of Smoothened. PLoS Biol. 9, e1001083