Received date: 22 Dec 2015
Accepted date: 05 Jan 2016
Published date: 26 Jan 2016
Copyright
The Hedgehog (Hh) signaling pathway play critical roles in embryonic development and adult tissue homeostasis. A critical step in Hh signal transduction is how Hh receptor Patched (Ptc) inhibits the atypical G protein-coupled receptor Smoothened (Smo) in the absence of Hh and how this inhibition is release by Hh stimulation. It is unlikely that Ptc inhibits Smo by direct interaction. Here we discuss how Hh regulates the phosphorylation and ubiquitination of Smo, leading to cell surface and ciliary accumulation of Smo in Drosophila and vertebrate cells, respectively. In addition, we discuss how PI(4)P phospholipid acts in between Ptc and Smo to regulate Smo phosphorylation and activation in response to Hh stimulation.
Key words： Hh signaling; phospholipid; phosphorylation; Smo; ubiquitination; signal transduction
Kai Jiang , Jianhang Jia . Smoothened regulation in response to Hedgehog stimulation[J]. Frontiers in Biology, 2015 , 10(6) : 475 -486 . DOI: 10.1007/s11515-015-1385-8
| 1 |
Aikin R A, Ayers K L, Thérond P P (2008). The role of kinases in the Hedgehog signalling pathway. EMBO Rep, 9(4): 330–336
|
| 2 |
Alcedo J, Ayzenzon M, Von Ohlen T, Noll M, Hooper J E (1996). The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell, 86(2): 221–232
|
| 3 |
Apionishev S, Katanayeva N M, Marks S A, Kalderon D, Tomlinson A (2005). Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nat Cell Biol, 7(1): 86–92
|
| 4 |
Arensdorf A M, Marada S, Ogden S K (2015). Smoothened Regulation: A Tale of Two Signals. Trends Pharmacol Sci, 37(1): 62–72
|
| 5 |
Atwood S X, Li M, Lee A, Tang J Y, Oro A E (2013). GLI activation by atypical protein kinase C i/l regulates the growth of basal cell carcinomas. Nature, 494(7438): 484–488
|
| 6 |
Atwood S X, Sarin K Y, Whitson R J, Li J R, Kim G, Rezaee M, Ally M S, Kim J, Yao C, Chang A L, Oro A E, Tang J Y (2015). Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell, 27(3): 342–353
|
| 7 |
Balla T (2013). Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol Rev, 93(3): 1019–1137
|
| 8 |
Balmer S, Dussert A, Collu G M, Benitez E, Iomini C, Mlodzik M (2015). Components of intraflagellar transport complex A function independently of the cilium to regulate canonical Wnt signaling in Drosophila. Dev Cell, 34(6): 705–718
|
| 9 |
Bielas S L, Silhavy J L, Brancati F, Kisseleva M V, Al-Gazali L, Sztriha L, Bayoumi R A, Zaki M S, Abdel-Aleem A, Rosti R O, Kayserili H, Swistun D, Scott L C, Bertini E, Boltshauser E, Fazzi E, Travaglini L, Field S J, Gayral S, Jacoby M, Schurmans S, Dallapiccola B, Majerus P W, Valente E M, Gleeson J G (2009). Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet, 41(9): 1032–1036
|
| 10 |
Briscoe J, Thérond P P (2013). The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol, 14(7): 416–429
|
| 11 |
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, Dorsch M (2010). Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med, 2(51): 51ra70
|
| 12 |
Callejo A, Culi J, Guerrero I (2008). Patched, the receptor of Hedgehog, is a lipoprotein receptor. Proc Natl Acad Sci USA, 105(3): 912–917
|
| 13 |
Camp D, Currie K, Labbé A, van Meyel D J, Charron F (2010). Ihog and Boi are essential for Hedgehog signaling in Drosophila. Neural Dev, 5(1): 28
|
| 14 |
Casali A, Struhl G (2004). Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein. Nature, 431(7004): 76–80
|
| 15 |
Casso D J, Liu S, Iwaki D D, Ogden S K, Kornberg T B (2008). A screen for modifiers of hedgehog signaling in Drosophila melanogaster identifies swm and mts. Genetics, 178(3): 1399–1413
|
| 16 |
Chávez M, Ena S, Van Sande J, de Kerchove d’Exaerde A, Schurmans S, Schiffmann S N (2015). Modulation of ciliary phosphoinositide content regulates trafficking and sonic Hedgehog signaling output. Dev Cell, 34(3): 338–350
|
| 17 |
Chen C H, von Kessler D P, Park W, Wang B, Ma Y, Beachy P A (1999). Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Cell, 98(3): 305–316
|
| 18 |
Chen Y, Jiang J (2013). Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res, 23(2): 186–200
|
| 19 |
Chen Y, Li S, Tong C, Zhao Y, Wang B, Liu Y, Jia J, Jiang J (2010). G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila. Genes Dev, 24(18): 2054–2067
|
| 20 |
Chen Y, Sasai N, Ma G, Yue T, Jia J, Briscoe J, Jiang J (2011). Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol, 9(6): e1001083
|
| 21 |
Corbit K C, Aanstad P, Singla V, Norman A R, Stainier D Y, Reiter J F (2005). Vertebrate Smoothened functions at the primary cilium. Nature, 437(7061): 1018–1021
|
| 22 |
DeCaen P G, Delling M, Vien T N, Clapham D E (2013). Direct recording and molecular identification of the calcium channel of primary cilia. Nature, 504(7479): 315–318
|
| 23 |
Delling M, DeCaen P G, Doerner J F, Febvay S, Clapham D E (2013). Primary cilia are specialized calcium signalling organelles. Nature, 504(7479): 311–314
|
| 24 |
Denef N, Neubüser D, Perez L, Cohen S M (2000). Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell, 102(4): 521–531
|
| 25 |
Di Paolo G, De Camilli P (2006). Phosphoinositides in cell regulation and membrane dynamics. Nature, 443(7112): 651–657
|
| 26 |
Dorn K V, Hughes C E, Rohatgi R (2012). A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev Cell, 23(4): 823–835
|
| 27 |
Du J, Zhang J, Su Y, Liu M, Ospina J K, Yang S, Zhu A J (2011). In vivo RNAi screen reveals neddylation genes as novel regulators of Hedgehog signaling. PLoS ONE, 6(9): e24168
|
| 28 |
Dussillol-Godar F, Brissard-Zahraoui J, Limbourg-Bouchon B, Boucher D, Fouix S, Lamour-Isnard C, Plessis A, Busson D (2006). Modulation of the Suppressor of fused protein regulates the Hedgehog signaling pathway in Drosophila embryo and imaginal discs. Dev Biol, 291(1): 53–66
|
| 29 |
Eaton S (2008). Multiple roles for lipids in the Hedgehog signalling pathway. Nat Rev Mol Cell Biol, 9(6): 437–445
|
| 30 |
Fan J, Jiang K, Liu Y, Jia J (2013). Hrs promotes ubiquitination and mediates endosomal trafficking of smoothened in Drosophila hedgehog signaling. PLoS ONE, 8(11): e79021
|
| 31 |
Fan J, Liu Y, Jia J (2012). Hh-induced Smoothened conformational switch is mediated by differential phosphorylation at its C-terminal tail in a dose- and position-dependent manner. Dev Biol, 366(2): 172–184
|
| 32 |
Fan S, Hurd T W, Liu C J, Straight S W, Weimbs T, Hurd E A, Domino S E, Margolis B (2004). Polarity proteins control ciliogenesis via kinesin motor interactions. Curr Biol, 14(16): 1451–1461
|
| 33 |
Fukumoto T, Watanabe-Fukunaga R, Fujisawa K, Nagata S, Fukunaga R (2001). The fused protein kinase regulates Hedgehog-stimulated transcriptional activation in Drosophila Schneider 2 cells. J Biol Chem, 276(42): 38441–38448
|
| 34 |
Garcia-Gonzalo F R, Phua S C, Roberson E C, Garcia G 3rd, Abedin M, Schurmans S, Inoue T, Reiter J F (2015). Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling. Dev Cell, 34(4): 400–409
|
| 35 |
Goetz S C, Anderson K V (2010). The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet, 11(5): 331–344
|
| 36 |
He Q, Wang G, Dasgupta S, Dinkins M, Zhu G, Bieberich E (2012). Characterization of an apical ceramide-enriched compartment regulating ciliogenesis. Mol Biol Cell, 23(16): 3156–3166
|
| 37 |
Heo J S, Lee M Y, Han H J (2007). Sonic hedgehog stimulates mouse embryonic stem cell proliferation by cooperation of Ca2+/protein kinase C and epidermal growth factor receptor as well as Gli1 activation. Stem Cells, 25(12): 3069–3080
|
| 38 |
Hildebrandt F, Benzing T, Katsanis N (2011). Ciliopathies. N Engl J Med, 364(16): 1533–1543
|
| 39 |
Ho K S, Suyama K, Fish M, Scott M P (2005). Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused. Development, 132(6): 1401–1412
|
| 40 |
Hooper J E, Scott M P (2005). Communicating with Hedgehogs. Nat Rev Mol Cell Biol, 6(4): 306–317
|
| 41 |
Hsia E Y, Gui Y, Zheng X (2015). Regulation of Hedgehog signaling by ubiquitination. Front Biol (Beijing), 10(3): 203–220
|
| 42 |
Huangfu D, Anderson K V (2005). Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA, 102(32): 11325–11330
|
| 43 |
Huangfu D, Liu A, Rakeman A S, Murcia N S, Niswander L, Anderson K V (2003). Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature, 426(6962): 83–87
|
| 44 |
Humbert M C, Weihbrecht K, Searby C C, Li Y, Pope R M, Sheffield V C, Seo S (2012). ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proc Natl Acad Sci USA, 109(48): 19691–19696
|
| 45 |
Ingham P W, McMahon A P (2001). Hedgehog signaling in animal development: paradigms and principles. Genes Dev, 15(23): 3059–3087
|
| 46 |
Jacoby M, Cox J J, Gayral S, Hampshire D J, Ayub M, Blockmans M, Pernot E, Kisseleva M V, Compère P, Schiffmann S N, Gergely F, Riley J H, Pérez-Morga D, Woods C G, Schurmans S (2009). INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet, 41(9): 1027–1031
|
| 47 |
Jia H, Liu Y, Xia R, Tong C, Yue T, Jiang J, Jia J (2010). Casein kinase 2 promotes Hedgehog signaling by regulating both smoothened and Cubitus interruptus. J Biol Chem, 285(48): 37218–37226
|
| 48 |
Jia H, Liu Y, Yan W, Jia J (2009). PP4 and PP2A regulate Hedgehog signaling by controlling Smo and Ci phosphorylation. Development, 136(2): 307–316
|
| 49 |
Jia J (2012). Phosphorylation regulation of Hedgehog signaling. Vitam Horm, 88: 253–272
|
| 50 |
Jia J, Amanai K, Wang G, Tang J, Wang B, Jiang J (2002). Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature, 416(6880): 548–552
|
| 51 |
Jia J, Jiang J (2006). Decoding the Hedgehog signal in animal development. Cell Mol Life Sci, 63(11): 1249–1265
|
| 52 |
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(21): 2709–2720
|
| 53 |
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(7020): 1045–1050
|
| 54 |
Jiang J (2006). Regulation of Hh/Gli signaling by dual ubiquitin pathways. Cell Cycle, 5(21): 2457–2463
|
| 55 |
Jiang J, Hui C C (2008). Hedgehog signaling in development and cancer. Dev Cell, 15(6): 801–812
|
| 56 |
Jiang J, Struhl G (1995). Protein kinase A and hedgehog signaling in Drosophila limb development. Cell, 80(4): 563–572
|
| 57 |
Jiang J, Struhl G (1998). Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature, 391(6666): 493–496
|
| 58 |
Jiang K, Liu Y, Fan J, Epperly G, Gao T, Jiang J, Jia J (2014). Hedgehog-regulated atypical PKC promotes phosphorylation and activation of Smoothened and Cubitus interruptus in Drosophila. Proc Natl Acad Sci USA, 111(45): E4842–E4850
|
| 59 |
Jiang K, Liu Y, Fan J, Zhang J, Li X, Evers B M, Zhu H, Jia J (2016). PI(4)P promotes phosphorylation and conformational change of Smoothened through interaction with its C-terminal tail. PLoS Biol, 14(1): e1002375
|
| 60 |
Khaliullina H, Panáková D, Eugster C, Riedel F, Carvalho M, Eaton S (2009). Patched regulates Smoothened trafficking using lipoprotein-derived lipids. Development, 136(24): 4111–4121
|
| 61 |
Kim J, Hsia E Y, Brigui A, Plessis A, Beachy P A, Zheng X (2015). The role of ciliary trafficking in Hedgehog receptor signaling. Sci Signal, 8(379): ra55
|
| 62 |
Kool M, Jones D T, Jäger N, Northcott P A, Pugh T J, Hovestadt V, Piro R M, Esparza L A, Markant S L, Remke M, Milde T, Bourdeaut F, Ryzhova M, Sturm D, Pfaff E, Stark S, Hutter S, Seker-Cin H, Johann P, Bender S, Schmidt C, Rausch T,Shih D , Reimand J, Sieber L, Wittmann A,Linke L , Witt H, Weber U D, Zapatka M, König R, Beroukhim R, Bergthold G, van Sluis P, Volckmann R, Koster J,Versteeg R , Schmidt S, Wolf S, Lawerenz C,Bartholomae C C , von Kalle C, Unterberg A, Herold-Mende C, Hofer S, Kulozik A E, von Deimling A, Scheurlen W, Felsberg J, Reifenberger G, Hasselblatt M, Crawford J R, Grant G A, Jabado N, Perry A, Cowdrey C, Croul S, Zadeh G, Korbel J O, Doz F, Delattre O, Bader G D, McCabe M G, Collins V P, Kieran M W, Cho Y J, Pomeroy S L, Witt O, Brors B, Taylor M D, Schüller U, Korshunov A, Eils R, Wechsler-Reya R J, Lichter P, Pfister S M, and the ICGC PedBrain Tumor Project (2014). Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell, 25(3): 393–405
|
| 63 |
Kovacs J J, Whalen E J, Liu R, Xiao K, Kim J, Chen M, Wang J, Chen W, Lefkowitz R J (2008). Beta-arrestin-mediated localization of smoothened to the primary cilium. Science, 320(5884): 1777–1781
|
| 64 |
Kuzhandaivel A, Schultz S W, Alkhori L, Alenius M (2014). Cilia-mediated hedgehog signaling in Drosophila. Cell Reports, 7(3): 672–680
|
| 65 |
Li S, Chen Y, Shi Q, Yue T, Wang B, Jiang J (2012). Hedgehog-regulated ubiquitination controls smoothened trafficking and cell surface expression in Drosophila. PLoS Biol, 10(1): e1001239
|
| 66 |
Li S, Ma G, Wang B, Jiang J (2014). Hedgehog induces formation of PKA-Smoothened complexes to promote Smoothened phosphorylation and pathway activation. Sci Signal, 7(332): ra62
|
| 67 |
Liu A, Wang B, Niswander L A (2005). Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development, 132(13): 3103–3111
|
| 68 |
Liu Y, Cao X, Jiang J, Jia J (2007). Fused-Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation. Genes Dev, 21(15): 1949–1963
|
| 69 |
Lum L, Beachy P A (2004). The Hedgehog response network: sensors, switches, and routers. Science, 304(5678): 1755–1759
|
| 70 |
Lum L, Zhang C, Oh S, Mann R K, von Kessler D P, Taipale J, Weis-Garcia F, Gong R, Wang B, Beachy P A (2003). Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol Cell, 12(5): 1261–1274
|
| 71 |
Marada S, Navarro G, Truong A, Stewart D P, Arensdorf A M, Nachtergaele S, Angelats E, Opferman J T, Rohatgi R, McCormick P J, Ogden S K (2015). Functional divergence in the role of N-linked glycosylation in Smoothened signaling. PLoS Genet, 11(8): e1005473
|
| 72 |
Méthot N, Basler K (2000). Suppressor of fused opposes hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development, 127(18): 4001–4010
|
| 73 |
Mukhopadhyay S, Wen X, Chih B, Nelson C D, Lane W S, Scales S J, Jackson P K (2010). TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia. Genes Dev, 24(19): 2180–2193
|
| 74 |
Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales S J, Jackson P K (2013). The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell, 152(1-2): 210–223
|
| 75 |
Myers B R, Sever N, Chong Y C, Kim J, Belani J D, Rychnovsky S, Bazan J F, Beachy P A (2013). Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response. Dev Cell, 26(4): 346–357
|
| 76 |
Nachtergaele S, Whalen D M, Mydock L K, Zhao Z, Malinauskas T, Krishnan K, Ingham P W, Covey D F, Siebold C, Rohatgi R (2013). Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. eLife, 2: e01340
|
| 77 |
Nüsslein-Volhard C, Wieschaus E (1980). Mutations affecting segment number and polarity in Drosophila. Nature, 287(5785): 795–801
|
| 78 |
Nybakken K, Vokes S A, Lin T Y, McMahon A P, Perrimon N (2005). A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway. Nat Genet, 37(12): 1323–1332
|
| 79 |
Ogden S K, Fei D L, Schilling N S, Ahmed Y F, Hwa J, Robbins D J (2008). G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature, 456(7224): 967–970
|
| 80 |
Oh S, Kato M, Zhang C, Guo Y, Beachy P A (2015). A comparison of Ci/Gli activity as regulated by Sufu in Drosophila and mammalian Hedgehog response. PLoS ONE, 10(8): e0135804
|
| 81 |
Pradhan-Sundd T, Verheyen E M (2015). The Myopic-Ubpy-Hrs nexus enables endosomal recycling of Frizzled. Mol Biol Cell, 26(18): 3329–3342
|
| 82 |
Price M A (2006). CKI, there’s more than one: casein kinase I family members in Wnt and Hedgehog signaling. Genes Dev, 20(4): 399–410
|
| 83 |
Price M A, Kalderon D (2002). Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell, 108(6): 823–835
|
| 84 |
Prulière G, Cosson J, Chevalier S, Sardet C, Chenevert J (2011). Atypical protein kinase C controls sea urchin ciliogenesis. Mol Biol Cell, 22(12): 2042–2053
|
| 85 |
Pusapati G V, Hughes C E, Dorn K V, Zhang D, Sugianto P, Aravind L, Rohatgi R (2014). EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia. Dev Cell, 28(5): 483–496
|
| 86 |
Rana R, Carroll C E, Lee H J, Bao J, Marada S, Grace C R, Guibao C D, Ogden S K, Zheng J J (2013). Structural insights into the role of the Smoothened cysteine-rich domain in Hedgehog signalling. Nat Commun, 4: 2965
|
| 87 |
Ranieri N, Ruel L, Gallet A, Raisin S, Thérond P P (2012). Distinct phosphorylations on kinesin costal-2 mediate differential hedgehog signaling strength. Dev Cell, 22(2): 279–294
|
| 88 |
Ranieri N, Thérond P P, Ruel L (2014). Switch of PKA substrates from Cubitus interruptus to Smoothened in the Hedgehog signalosome complex. Nat Commun, 5: 5034
|
| 89 |
Robbins D J, Nybakken K E, Kobayashi R, Sisson J C, Bishop J M, Thérond P P (1997). Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2. Cell, 90(2): 225–234
|
| 90 |
Rohatgi R, Milenkovic L, Corcoran R B, Scott M P (2009). Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci USA, 106(9): 3196–3201
|
| 91 |
Rohatgi R, Milenkovic L, Scott M P (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science, 317(5836): 372–376
|
| 92 |
Rorick A M, Mei W, Liette N L, Phiel C, El-Hodiri H M, Yang J (2007). PP2A:B56epsilon is required for eye induction and eye field separation. Dev Biol, 302(2): 477–493
|
| 93 |
Rosenbaum J L, Witman G B (2002). Intraflagellar transport. Nat Rev Mol Cell Biol, 3(11): 813–825
|
| 94 |
Ruel L, Rodriguez R, Gallet A, Lavenant-Staccini L, Thérond P P (2003). Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nat Cell Biol, 5(10): 907–913
|
| 95 |
Sekulic A, Migden M R, Oro A E, Dirix L, Lewis K D, Hainsworth J D, Solomon J A, Yoo S, Arron S T, Friedlander P A, Marmur E, Rudin C M, Chang A L, Low J A, Mackey H M, Yauch R L, Graham R A, Reddy J C, Hauschild A (2012). Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med, 366(23): 2171–2179
|
| 96 |
Sharpe H J, Pau G, Dijkgraaf G J, Basset-Seguin N, Modrusan Z, Januario T, Tsui V, Durham A B, Dlugosz A A, Haverty P M, Bourgon R, Tang J Y, Sarin K Y, Dirix L, Fisher D C, Rudin C M, Sofen H, Migden M R, Yauch R L, de Sauvage F J (2015). Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell, 27(3): 327–341
|
| 97 |
Shi Q, Li S, Jia J, Jiang J (2011). The Hedgehog-induced Smoothened conformational switch assembles a signaling complex that activates Fused by promoting its dimerization and phosphorylation. Development, 138(19): 4219–4231
|
| 98 |
Sisson J C, Ho K S, Suyama K, Scott M P (1997). Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell, 90(2): 235–245
|
| 99 |
Su Y, Ospina J K, Zhang J, Michelson A P, Schoen A M, Zhu A J (2011). Sequential phosphorylation of smoothened transduces graded hedgehog signaling. Sci Signal, 4(180): ra43
|
| 100 |
Swanson K D, Tang Y, Ceccarelli D F, Poy F, Sliwa J P, Neel B G, Eck M J (2008). The Skap-hom dimerization and PH domains comprise a 3′-phosphoinositide-gated molecular switch. Mol Cell, 32(4): 564–575
|
| 101 |
Taipale J, Cooper M K, Maiti T, Beachy P A (2002). Patched acts catalytically to suppress the activity of Smoothened. Nature, 418(6900): 892–897
|
| 102 |
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 Jr (2012). Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med, 366(23): 2180–2188
|
| 103 |
Thérond P P, Knight J D, Kornberg T B, Bishop J M (1996). Phosphorylation of the fused protein kinase in response to signaling from hedgehog. Proc Natl Acad Sci USA, 93(9): 4224–4228
|
| 104 |
Tuson M, He M, Anderson K V (2011). Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development, 138(22): 4921–4930
|
| 105 |
Wang B, Fallon J F, Beachy P A (2000a). Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell, 100(4): 423–434
|
| 106 |
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 (2013). Structure of the human smoothened receptor bound to an antitumour agent. Nature, 497(7449): 338–343
|
| 107 |
Wang G, Amanai K, Wang B, Jiang J (2000b). Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus. Genes Dev, 14(22): 2893–2905
|
| 108 |
Wang Y, Zhou Z, Walsh C T, McMahon A P (2009). Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc Natl Acad Sci USA, 106(8): 2623–2628
|
| 109 |
Williams R L, Urbé S (2007). The emerging shape of the ESCRT machinery. Nat Rev Mol Cell Biol, 8(5): 355–368
|
| 110 |
Wilson C W, Chen M H, Chuang P T (2009). Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS ONE, 4(4): e5182
|
| 111 |
Wilson C W, Chuang P T (2010). Mechanism and evolution of cytosolic Hedgehog signal transduction. Development, 137(13): 2079–2094
|
| 112 |
Wollert T, Hurley J H (2010). Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature, 464(7290): 864–869
|
| 113 |
Xia R, Jia H, Fan J, Liu Y, Jia J (2012). USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization. PLoS Biol, 10(1): e1001238
|
| 114 |
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, de Sauvage F J (1998). Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature, 391(6662): 90–92
|
| 115 |
Yang C, Chen W, Chen Y, Jiang J (2012). Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2. Cell Res, 22(11): 1593–1604
|
| 116 |
Yang L, Xie G, Fan Q, Xie J (2010). Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene, 29(4): 469–481
|
| 117 |
Yang X, Mao F, Lv X, Zhang Z, Fu L, Lu Y, Wu W, Zhou Z, Zhang L, Zhao Y (2013). Drosophila Vps36 regulates Smo trafficking in Hedgehog signaling. J Cell Sci, 126(Pt 18): 4230–4238
|
| 118 |
Yavari A, Nagaraj R, Owusu-Ansah E, Folick A, Ngo K, Hillman T, Call G, Rohatgi R, Scott M P, Banerjee U (2010). Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev Cell, 19(1): 54–65
|
| 119 |
Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X (2005). A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature, 438(7069): 873–877
|
| 120 |
Zhang C, Williams E H, Guo Y, Lum L, Beachy P A (2004). Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc Natl Acad Sci USA, 101(52): 17900–17907
|
| 121 |
Zhang J, Du J, Lei C, Liu M, Zhu A J (2014). Ubpy controls the stability of the ESCRT-0 subunit Hrs in development. Development, 141(7): 1473–1479
|
| 122 |
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(2): 267–278
|
| 123 |
Zhang Y, Mao F, Lu Y, Wu W, Zhang L, Zhao Y (2011). Transduction of the Hedgehog signal through the dimerization of Fused and the nuclear translocation of Cubitus interruptus. Cell Res, 21(10): 1436–1451
|
| 124 |
Zhao X, Ponomaryov T, Ornell K J, Zhou P, Dabral S K, Pak E, Li W, Atwood S X, Whitson R J, Chang A L, Li J, Oro A E, Chan J A, Kelleher J F, Segal R A (2015). RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. Cancer Res, 75(17): 3623–3635
|
| 125 |
Zhao Y, Tong C, Jiang J (2007). Hedgehog regulates smoothened activity by inducing a conformational switch. Nature, 450(7167): 252–258
|
| 126 |
Zheng X, Mann R K, Sever N, Beachy P A (2010). Genetic and biochemical definition of the Hedgehog receptor. Genes Dev, 24(1): 57–71
|
| 127 |
Zwolak A, Yang C, Feeser E A, Ostap E M, Svitkina T, Dominguez R (2013). CARMIL leading edge localization depends on a non-canonical PH domain and dimerization. Nat Commun, 4: 2523
|
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