ライフサイエンスコーパス: SMO

1 y accumulation and activation of smoothened (Smo).

2 ch block the HH pathway effector Smoothened (SMO).

3 moresistance due to mutations in smoothened (SMO).

4 mplex relieves Ptc inhibition on Smoothened (Smo).

5 degib are targeted inhibitors of Smoothened (SMO).

6 d receptor (GPCR)-family protein Smoothened (Smo).

7 onsists of 10 FZD paralogues and Smoothened (SMO).

8 compounds that block simultaneously MET and SMO.

9 e Fused (FU), a known downstream effector of SMO.

10 tely change the cell surface accumulation of Smo.

11 ver, this activity is largely independent of SMO.

12 nto how Hh morphogen progressively activates Smo.

13 s the pool of PI(4)P associated with Ptc and Smo.

14 level of Hh than PKA-site phosphorylation on Smo.

15 f the canonical Hh pathway operating through Smo.

16 n cell surface localization of both Gish and Smo.

17 interaction of the compounds at the level of Smo.

18 ly outcompete cells containing the wild-type SMO.

19 that preferentially interact with activated Smo.

20 signaling by the G protein-coupled receptor SMO.

21 HH pathway: the HH ligand, DISP1, PTCH1, and SMO.

22 rmal activation of the pathway downstream of SMO.

23 a G(i)-coupled activation mechanism of human SMO.

24 obic tunnel), which drives the activation of SMO.

25 mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 x 10(-8)) and SUFU, 8%) and in TP53 (6

26 to modulation of the function of Smoothened (Smo), a 7-pass integral membrane protein, has defied sta

27 The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzle

28 1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh si

29 loping small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that re

30 Using cell type-specific deletion of Smo, a gene required in SHH-receiving cells, we found th

31 alian cells induces ciliary translocation of Smo-a key step in pathway activation-in the absence of H

32 Upon stimulation, Smo accumulates on the cell surface in Drosophila or pri

33 SUMO isoform in Drosophila) by RNAi prevents Smo accumulation and alters Smo activity in the wing.

34 ed, which counteracts its inhibitory role on Smo accumulation in the wing.

35 tin 2, inhibits Smo sumoylation and prevents Smo accumulation through Krz regulatory domain.

36 nhance the effects of the PKA/CKI kinases on SMO accumulation, its localization at the plasma membran

37 l from the cell and that calcitriol inhibits Smo action and ciliary translocation by acting on a site

38 opposed to an accumulation of 7DHC, impairs SMO activation and its localization to the primary ciliu

39 her, we have uncovered a novel mechanism for Smo activation by sumoylation that is regulated by Hh an

40 Hh/Smo activation enables transiently divided clusters of S

41 a cholesterol molecule that is critical for SMO activation is bound deep within the seven-transmembr

42 in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to n

43 ponent for enriching PI(4)P and facilitating Smo activation.

44 ane protein Patched, which in turn regulates SMO activation.

45 Our findings suggest a bifurcation of Smo activity in Hh response, with a Dlg5-independent arm

46 by RNAi prevents Smo accumulation and alters Smo activity in the wing.

47 This Hh/Smo activity is driven by epidermal Sonic hedgehog a (Sh

48 racellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in choles

49 utations at some sites also increasing basal SMO activity.

50 gnaling, the GPCR-family protein Smoothened (Smo) acts as a signal transducer that is regulated by ph

51 lated Tgfa expression in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the

52 ps), SUFU (infants, including germline), and SMO (adults).

53 ts inhibition of the oncoprotein Smoothened (SMO) after binding the HH ligand, triggering downstream

54 Depleting Intu blocked Smo agonist-induced Hh pathway activation, whereas the e

55 negative regulators converged on Smoothened (SMO), an oncoprotein that transduces the Hh signal acros

56 signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across

57 t is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.

58 i-RhoA-stress fibre signalling by increasing Smo and Galphai binding.

59 ciation with abnormal ciliary trafficking of SMO and GLI2, and impaired processing of Gli transcripti

60 show that both Dnchc2 and Wdr34 act between Smo and Gli2/Gli3 in the Hh pathway.

61 A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulatio

62 treatment increases the interaction between Smo and PI(4)P but decreases the interaction between Ptc

63 minantly through mutation of the drug target SMO and to a lesser extent through concurrent copy numbe

64 z likely facilitates the interaction between Smo and Ulp1 because knockdown of Krz by RNAi attenuates

65 These factors include smoothened (SMO) and patched, which constitute the core reception sy

66 associated Shh signal transducer Smoothened (Smo) and the transcription factor Gli, which induces the

67 epends on the pathway transducer Smoothened (Smo) and the transcription factor Gli1.

68 2, p-ERK, p-PLCr1/2), hedgehog (Gli1, Ptch1, SMO), and mTOR (pS6K1) signaling pathways to determine t

69 s and the GPCR Smoothened (SMO) reveals that SMO, and likely also other GPCR cargoes, must release th

70 he ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, i

71 thway through loss of PTCH1 or activation of SMO, and SMO inhibitors, such as vismodegib, are effecti

72 potential biomarker for patient selection in SMO antagonist clinical trials.

73 ere, we report that the Smoothened receptor (Smo) antagonist cyclopamine acts as a potent and selecti

74 SMO antagonists can suppress the growth of some tumours;

75 for therapeutics, exemplified by the use of SMO antagonists for the treatment of basal cell carcinom

76 3R is required for the therapeutic effect of SMO antagonists in AML samples and restoration of GLI3R

77 combinations of hypomethylating agents with SMO antagonists in clinical trials.

78 culture and in vivo Addition of SHH ligand, SMO antagonists, or other Hedgehog pathway agonists did

79 Mutations in SMO (encoding Smoothened, SMO) are common in ameloblastomas of the maxilla, wherea

80 of the Hedgehog signal mediator Smoothened (Smo) as well as by systemic administration of the Smo in

81 The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coup

82 Ptch), reduced the affinity and frequency of Smo binding at the base.

83 Smo blocks transcriptional expression of miR-378a-3p by

84 cryo-electron microscopy structure of human SMO bound to 24(S),25-epoxycholesterol and coupled to a

85 report the crystal structure of active mouse SMO bound to both the agonist SAG21k and to an intracell

86 crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC11

87 the critical signaling component Smoothened (SMO), but preclinical research has identified additional

88 Blocking ubiquitination of Smo by an E1 ligase inhibitor or by mutating two lysine

89 ansducer and GPCR-family protein Smoothened (Smo) by inducing Smo phosphorylation, but whether Smo is

90 n kinase A (PKA)-mediated phosphorylation of Smo C-tail and depends on cell surface localization of b

91 tic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO)

92 re, enhanced Shh signaling through activated Smo cannot overcome impaired cerebellar cell generation,

93 uster (CL-II) in the juxtamembrane region of Smo carboxyl-terminal intracellular tail (C-tail).

94 rmal tissues, Hh pathway activation via PTCH/SMO causes an increase in the downstream transcriptional

95 in parallel with phosphorylation to promote Smo cell-surface expression and Hh signaling.

96 way response without a significant impact on Smo ciliary accumulation.

97 s canonical Hh-Gli signalling via disrupting Smo ciliary localization, but elevates non-canonical Hh-

98 Repression of Hh-signaling through Smo co-mutation in Tbx5 heterozygotes rescued the limb d

99 of NsM in cases with targetable mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and MET Our results indi

100 h2/Gas1 and Ptch1/Boc mediate the process of Smo de-repression with different kinetics, through disti

101 Smo-deleted fibroblasts had higher expression of transfo

102 ion in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the growth of Kras(G1

103 lineage tracing approaches and the effect of Smo deletion was examined in the injured entheses.

104 th conditional global or epithelium-specific Smo deletions and observed similar effects.

105 ting Gli3 and its expression is regulated by Smo-dependent NF-kappaB signalling, suggesting miR-378a-

106 tic mutations of pathway components or other Smo-dependent or independent mechanisms, all triggering

107 The Smo-dependent OR transport route works in parallel with

108 ein-borne Hh pathway inhibitors required for Smo destabilization.

109 We found that disruption of Smo-Dlg5 interactions or depletion of endogenous Dlg5 le

110 rough compartmentalisation and modulation of Smo-downstream signalling.

111 ions in seven-transmembrane (7-TM) domain of Smo due to an additional 2-pyridylmethyl group than GDC-

112 ngs quantify activation-dependent changes in Smo dynamics in cilia and highlight a previously unknown

113 One proposed mechanism of SLOS involves SMO dysregulation by altered sterol levels, but the sali

114 vesicles from mouse mutants exhibiting loss (Smo(ecko) ) and gain (Shh-P1) of Shh signaling reveal a

115 Mutations in SMO (encoding Smoothened, SMO) are common in ameloblasto

116 The affinity of Smo for these binding sites was modulated by the Hh path

117 Depletion of Smo from osteoblastoid cells is associated with profound

118 s the exit of GPR161, SSTR3, and Smoothened (SMO) from cilia.

119 and depletion of the Hh effector Smoothened (Smo) from stromal cells is associated with the loss of o

120 Overall, our data provide evidence for a SMO/FU positive regulatory loop nested within a multikin

121 onsidered an alternative approach to inhibit SMO function and thus, Hedgehog signaling.

122 Thus, loss of SMO function results in abnormal PC dynamics of key comp

123 Of the Galphai proteins that can couple with Smo, G protein alpha Z (Gnaz) is found in enteric axons.

124 whether novel combinations of JAK2-STAT3 and SMO-GLI1/tGLI1 inhibitors synergistically target TNBC an

125 nhibitor of Hh pathway component smoothened (Smo) has shown promise in the treatment of various cance

126 rowth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects,

127 PTCH) or activating mutations in Smoothened (SMO) have been reported in basal cell carcinoma and medu

128 ty ligation experiments identified novel CB1-Smo heteromers, suggesting allosteric CB1-Smo interactio

129 It has remained unknown how PTCH1 modulates SMO, how SMO is stimulated to form a complex with hetero

130 mor responsiveness to Smoothened inhibitors (Smo(i)), resistance in advanced tumors remains common.

131 , whereas desumoylation by Ulp1 destabilizes Smo in a phosphorylation independent manner.

132 disrupt the primarily diffusive movement of Smo in cilia at an array of sites near the base.

133 activate or delete the SHH signal transducer Smo in either pp endoderm or NC mesenchyme.

134 ified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders an

135 individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when

136 rt bi-allelic loss-of-function variations in SMO in seven individuals from five independent families;

137 this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explana

138 ting that the histology might be mediated by Smo in the local stroma, with systemic Ptch1 required fo

139 ed a mouse model for conditional ablation of Smo in the osteoblastoid lineage.

140 Sumoylation of Smo in turn recruits a deubiquitinase UBPY/USP8 to antag

141 e samples from nonresponders and upstream of SMO in two of four patients with favorable responses.

142 ted either by pharmacochemical activation of Smo in vitro or by loss of Ptch1 in vivo.

143 d can trigger G-protein signalling via human SMO in vitro.

144 d receptor (GPCR) family protein Smoothened (Smo) in Drosophila, but how PKA activity is regulated re

145 as1) and its signaling component smoothened (Smo) in enteric neurons.

146 n EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells.

147 el the finding that depletion of Smoothened (Smo) in pancreatic stromal fibroblasts results in AKT ac

148 ignaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model

149 ulation of the signaling protein Smoothened (Smo) in the membrane of primary cilia is an essential st

150 HH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (

151 idence that GLI3R plays an essential role in SMO-independent Hh signaling in AML, and suggests that G

152 Cyclopamine inhibits hRSV through a novel, Smo-independent mechanism.

153 Deletion of Aspm in mice with Smo-induced medulloblastoma reduces tumor growth and inc

154 In turn, activation of SMO induces FU to act on its downstream targets.

155 The ciliary phenotype of Smo inhibition is haploinsufficient, cell autonomous, an

156 a proton driven antiporter, is required for Smo inhibition via an unknown mechanism.

157 investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer mode

158 me cell or also mediates non-cell-autonomous Smo inhibition, we generated genetically mosaic neuraliz

159 arboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutatio

160 rongly synergizes with itraconazole (ITZ) in Smo inhibition, which did not result from elevated calci

161 , was not sufficient to sustain TB during HH/SMO inhibition.

162 tify two distinct paradigms of resistance to Smo inhibition.

163 Smoothened (Smo) inhibition by Patched (Ptch) is central to Hedgehog

164 proliferation was not blocked by smoothened (SMO) inhibition, suggesting a non-canonical function of

165 lecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberration

166 After SMO inhibitor therapy, almost all of his cutaneous tumor

167 metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic tr

168 as well as by systemic administration of the Smo inhibitor vismodegib, a clinically used anticancer d

169 Using BMS-833923, a uniquely effective Smo inhibitor, and high-resolution imaging, we show that

170 Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activ

171 In the presence of a SMO inhibitor, tumor cells containing either class of SM

172 ), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with niloti

173 g, but can develop mechanisms of Smoothened (SMO) inhibitor resistance.

174 cell carcinomas resistant to the Smoothened (SMO) inhibitor vismodegib frequently harbor SMO mutation

175 tance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (

176 inhibitors (ruxolitinib and pacritinib) with SMO inhibitors (vismodegib and sonidegib) synergisticall

177 erestingly, BCNS-BCCs are more responsive to SMO inhibitors than sporadic BCCs, with minimal developm

178 t of emerging drug resistance occurring with SMO inhibitors, is of high importance.

179 SMO that is inherently resistant to existing SMO inhibitors, prolonging the survival of the mice.

180 ough loss of PTCH1 or activation of SMO, and SMO inhibitors, such as vismodegib, are effective therap

181 taste dysgeusia in patients treated with HH/SMO inhibitors.

182 g why BCNS-BCCs lack intrinsic resistance to SMO inhibitors.

183 hway at sites distinct from those treated by SMO inhibitors.

184 enance of the Shh pathway in the presence of Smo inhibitors.

185 Phytocannabinoids are also potent Smo inhibitors.

186 intain Hedgehog signaling in the presence of SMO inhibitors.

187 which correlate with nMRTF and resistance to SMO inhibitors.

188 rategy for overcoming clinical resistance to SMO inhibitors.

189 Smoothened (SMO) inhibitors are under clinical investigation for the

190 However, Smoothened (SMO) inhibitors have failed to show clinical benefit in

191 Smoothened (SMO) inhibitors recently entered clinical trials for son

192 frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms.

193 odel in which Ptch1/2 mediate secretion of a Smo-inhibitory cholesterol precursor.

194 Ptch reverses this inhibition and activated Smo initiates the Hh response.

195 n by sumoylation that is regulated by Hh and Smo interacting proteins.

196 However, a direct Ptch/Smo interaction has been excluded, Smo modulators were i

197 pressor formation and a second arm involving Smo interaction with Dlg5 for Gli activation.

198 ts a possible endogenous transmitter of Ptch/Smo interaction.

199 excellent candidate for transmission of Ptch/Smo interaction.

200 B1-Smo heteromers, suggesting allosteric CB1-Smo interactions.

201 gh their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellula

202 by inducing Smo phosphorylation, but whether Smo is activated through other post-translational modifi

203 protein-coupled receptors, the activation of SMO is associated with subtle motions in the extracellul

204 nd binding, Ptch1 is removed from cilia, and Smo is derepressed and accumulates in cilia where it act

205 d high-resolution imaging, we show that Shha/Smo is functionally dedicated to ray branching during fi

206 In the NanoBRET-based binding assay, SMO is N terminally tagged with nanoluciferase (Nluc) an

207 However, it is not clear whether Smo is regulated by other post-translational modificatio

208 emained unknown how PTCH1 modulates SMO, how SMO is stimulated to form a complex with heterotrimeric

209 bsence of ligand-induced pathway activation, Smo is ubiquitinated and removed from cilia, and this pr

210 Smoothened (SMO) is a G-protein-coupled receptor-related protein req

211 Smoothened (SMO) is a GPCR that mediates hedgehog signaling.

212 time, the transmembrane protein Smoothened (SMO) is released of its inhibition by PTCH1 and accumula

213 d1 (Ptch)-mediated inhibition of Smoothened (Smo) is still an open question.

214 g (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (P

215 ompatible assay is superior to commonly used SMO ligand binding assays in the separation of specific

216 ing experiments using commercially available SMO ligands (SANT-1, cyclopamine-KAAD, SAG1.3 and purmor

217 Upon Shh stimulation, Smo localization to dendrites increases significantly.

218 gradient leads to graded phosphorylation of SMO, mainly by the PKA and CKI kinases.

219 Additionally, Smo-mediated signaling has proproliferative effects on p

220 FZDs coordinate wingless/Int-1 signaling and SMO mediates Hedgehog signaling.

221 The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathwa

222 All cases of severe maternal outcome (SMO, MNM cases and deaths) were prospectively identified

223 rect Ptch/Smo interaction has been excluded, Smo modulators were identified, but the endogenous signa

224 ransduction, yet the molecular mechanisms of Smo movement and localization are poorly understood.

225 PI(4)P also binds mouse Smo (mSmo) and promotes its phosphorylation and ciliary

226 that Shh stimulates sumoylation of mammalian Smo (mSmo) and that sumoylation promotes ciliary localiz

227 expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked c

228 itor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the

229 ot lumen opening, is impaired in smoothened (smo) mutants, indicating that fluid-driven lumen enlarge

230 RAF wild-type cases, 1 UAM showed a missense SMO mutation (p.L412F), whereas 2 NRAS (p.Q61R), 2 HRAS

231 The smo mutation was identified > 25 years ago, and affects

232 all tested Class F receptors (FZD(4,5,6,7,) SMO), mutation of the molecular switch confers an increa

233 ity, and harbor fewer functionally resistant SMO mutations at baseline, explaining why BCNS-BCCs lack

234 SMO mutations either directly impaired drug binding or a

235 Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and sh

236 (SMO) inhibitor vismodegib frequently harbor SMO mutations that limit drug binding, with mutations at

237 Somatic SMO mutations that result in constitutive activation hav

238 ear to harbor more frequently RAS, FGFR2, or SMO mutations.

239 ex catalysts onto semiconductor metal oxide (SMO) nanofibers (NFs) via electrospinning for markedly e

240 short interfering RNA-mediated knockdown of SMO or GLI1 led to decreased cell proliferation.

241 ible patched2 reporter, we resolve active Hh/Smo output to a narrow distal regenerate zone comprising

242 rough an arginine motif, which then triggers Smo phosphorylation and activation.

243 s localized at the primary cilium to promote Smo phosphorylation and Sonic hedgehog (Shh) pathway act

244 -family protein Smoothened (Smo) by inducing Smo phosphorylation, but whether Smo is activated throug

245 disc model in Drosophila, we identified new SMO phosphosites that enhance the effects of the PKA/CKI

246 pathway inhibitors targeting the Smoothened (SMO) protein are in clinical use.

247 ization of Hh, Patched (Ptc) and Smoothened (Smo) proteins tagged with GFP or mCherry and expressed a

248 er (NanoBRET)-based ligand binding assay for SMO providing a sensitive and high throughput-compatible

249 As previously observed for SMO, PTCH1 molecules in cilia predominantly move by diff

250 important downstream targets such as Gli-1, SMO, PTCH1/2, NF-kappaB, p-AKT, and cyclin D1.

251 th constitutive actvation of the Smoothened (Smo) receptor using a PerkinElmer G4 PET-X-Ray scanner.

252 ons-delineate the structural basis for PTCH1-SMO regulation, and suggest a strategy for overcoming cl

253 ts indicated that dual targeting of JAK2 and SMO resulted in synergistic suppression of breast cancer

254 Some with membranes and the GPCR Smoothened (SMO) reveals that SMO, and likely also other GPCR cargoe

255 These data provide a mechanism to control Smo's ciliary level during Hedgehog signaling by regulat

256 r GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antag

257 ized novel mESC lines in which Ptch1, Ptch2, Smo, Shh and 7dhcr were inactivated via gene editing in

258 geting the Shh pathway component Smoothened (Smo) show great therapeutic promise.

259 a physiologic, selective requirement for HH/SMO signaling in taste homeostasis that includes potenti

260 nscriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation

261 ffects of sonidegib treatment result from HH/SMO signaling inhibition, we studied mice with condition

262 biology and taste sensation that follows HH/SMO signaling inhibition.

263 Overactive SMO signaling is oncogenic and is therefore a clinically

264 Hedgehog/Smoothened (Hh/Smo) signaling has been variably proposed to stimulate o

265 Imaging was performed in tumor-bearing Smo/Smo medulloblastoma mice with constitutive actvation

266 Disrupting Intu in an oncogenic mutant Smo (SmoM2)-driven BCC mouse model prevented the formati

267 To determine whether Ptch inhibits Smo strictly in the same cell or also mediates non-cell-

268 pathway promotes Hh signaling by regulating Smo subcellular localization and shed light on how sumoy

269 ved mechanism whereby Hh induces a change in Smo subcellular localization to promote its association

270 rz, the Drosophila beta-arrestin 2, inhibits Smo sumoylation and prevents Smo accumulation through Kr

271 We find that Hh stimulates Smo sumoylation by dissociating it from a desumoylation

272 iology strategies for the discovery of novel SMO-targeting drugs.

273 uppressed medulloblastoma driven by a mutant SMO that is inherently resistant to existing SMO inhibit

274 ate levels of ATP and stabilizes Smoothened (Smo), the 7-pass transmembrane protein that transduces t

275 i-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors

276 functionally overlap in the sequestration of Smo, the spatiotemporal expression of Boc and Gas1 may d

277 We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo p

278 re we show that Hh stimulates the binding of Smo to a plasma membrane-associated kinase Gilgamesh (Gi

279 residues in intracellular loop three causes Smo to aberrantly accumulate in cilia without pathway ac

280 nents, including Ift27 and the BBSome, cause Smo to accumulate in cilia without pathway activation.

281 upting targeting of both the EvC complex and SMO to cilia.

282 hich pathway activation is communicated from Smo to Gli2 is not known.

283 How thresholds in HH morphogen regulate SMO to promote switch-like transcriptional responses is

284 directly impaired drug binding or activated SMO to varying levels.

285 n and Hh target gene expression by impairing SMO translocation to the cilium.

286 binding sites for BODIPY-cyclopamine on the SMO transmembrane core in live cells in real time.

287 Activation of Hedgehog signaling decreases Smo ubiquitination and ciliary removal, resulting in its

288 its a deubiquitinase UBPY/USP8 to antagonize Smo ubiquitination and degradation, leading to its cell-

289 because knockdown of Krz by RNAi attenuates Smo-Ulp1 interaction.

290 Finally, we show that both classes of SMO variants respond to aPKC-iota/lambda or GLI2 inhibit

291 e seven-transmembrane transducer Smoothened (SMO) via a mechanism that is poorly understood.

292 In the absence of Atthog, SMO was stabilized at the cell surface and concentrated

293 signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC.

294 NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, P

295 show that Hh-induced-sumoylation stabilizes Smo, whereas desumoylation by Ulp1 destabilizes Smo in a

296 hrough the transmembrane protein Smoothened (SMO), which localizes to the primary cilium of a cell on

297 uced Shh signaling by inhibiting Smoothened (Smo), while Shh mRNA or a CB1 receptor antagonist attenu

298 tablished a NanoBRET-based binding assay for SMO with superior sensitivity compared to fluorescence-b

299 ds to pronounced accumulation of Smoothened (Smo) within primary cilia and elevated levels of full-le

300 seven-pass transmembrane protein Smoothened (Smo) within the primary cilium and of the zinc finger tr

301 f the mesenchymal-epithelial interface (Nes, Smo, Wnt5a, Nog) and the deposition of the provisional e