ライフサイエンスコーパス: SMO

1 mplex relieves Ptc inhibition on Smoothened (Smo).

2 degib are targeted inhibitors of Smoothened (SMO).

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

4 Ptch1) and the pathway activator smoothened (Smo).

5 tream G-protein-coupled receptor Smoothened (SMO).

6 intracellular signaling through Smoothened (Smo).

7 st notably through inhibition of Smoothened (SMO).

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

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

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

11 f the canonical Hh pathway operating through Smo.

12 n cell surface localization of both Gish and Smo.

13 interaction of the compounds at the level of Smo.

14 ly outcompete cells containing the wild-type SMO.

15 that preferentially interact with activated Smo.

16 signaling by the G protein-coupled receptor SMO.

17 compounds that block simultaneously MET and SMO.

18 ion, consistent with it acting downstream of Smo.

19 n, particularly those that act downstream of Smo.

20 it Ptc and thereby relieve its repression of Smo.

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

22 tely change the cell surface accumulation of Smo.

23 ver, this activity is largely independent of SMO.

24 nto how Hh morphogen progressively activates 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 1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh si

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

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

30 n Receptor 3 (SSTR3, a GPCR) and Smoothened (Smo, a Hedgehog signal transducer) in the ciliary membra

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

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

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

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

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

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

37 calcium concentration and thereby modifying SMO-activated GLI2 translocation and GLI1 expression.

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

39 Ptch1-mediated inhibition of Smo, leading to Smo activation and subsequent cell-autonomous activation

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

41 Hh/Smo activation enables transiently divided clusters of S

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

43 ell autonomously inhibit the consequences of Smo activation, it can inhibit the Shh response non-cell

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

45 g pocket residues, which could contribute to SMO activation.

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

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

48 1), and these phosphorylation events elevate Smo activity in vivo.

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

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

51 utations at some sites also increasing basal SMO activity.

52 /2 and c-src independently of its control of smo activity.

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

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

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

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

57 inical trials for cancer, and small-molecule Smo agonists may have therapeutic interests in regenerat

58 We show that a frequently occurring SMO alteration encoding p.Leu412Phe is an activating mut

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

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

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

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

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

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

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

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

67 ve aPKC elevates basolateral accumulation of Smo and promotes Hh signaling.

68 ins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immuno

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

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

71 In summary, SMO and/or PTCH1 mutations are present at low frequency

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

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

74 2, p-ERK, p-PLCr1/2), hedgehog (Gli1, Ptch1, SMO), and mTOR (pS6K1) signaling pathways to determine t

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

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

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

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

79 SMO antagonists can suppress the growth of some tumours;

80 3R is required for the therapeutic effect of SMO antagonists in AML samples and restoration of GLI3R

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

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

83 fect on cell differentiation is inhibited by Smo antagonists, such as MRT-83, SANT-1, LDE225, and M25

84 tial effects of chemoresistance mutations on SMO antagonists.

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

86 Recent studies identify Smo as a G-protein coupled receptor (GPCR)-like protein

87 his regard, we evaluate here the efficacy of Smo as it relates to the activation of G(i), by comparin

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

89 The aPKC-mediated phosphorylation of Smo at Ser680 promotes Ser683 phosphorylation by casein

90 f aPKC by either RNAi or a mutation inhibits Smo basolateral accumulation and attenuates Hh target ge

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

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

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

94 we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the

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

96 l the structural basis for the modulation of SMO by small molecules.

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

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

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

100 basal cell carcinoma, acquired mutations in Smo can result in rapid relapse.

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

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

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

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

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

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

107 cause defects in primary cilium elongation, Smo ciliary translocation, and Sonic Hedgehog (Shh) sign

108 Acquired Smoothened mutations, including SMO(D477G), confer resistance to these inhibitors.

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

110 Smo-deleted fibroblasts had higher expression of transfo

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

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

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

114 lized to the nucleus upon Hh activation in a Smo-dependent manner, and loss of Miz1 prevents the nucl

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

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

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

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

119 cell autonomously, activation of Smoothened (Smo) drastically increases Hhip internalization and degr

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

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

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

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

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

125 Depletion of Smo from osteoblastoid cells is associated with profound

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

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

128 ing at levels distinct from those inhibiting SMO function.

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

130 narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1

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

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

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

134 The structure of Smo implies interactions with heterotrimeric G proteins,

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

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

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

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

139 urprisingly, whereas conditional ablation of Smo in postnatal glial fibrillary acidic protein-express

140 P), we demonstrate that RGS5 is present with Smo in primary cilia.

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

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

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

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

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

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

147 umors by specifically activating Smoothened (Smo) in both Hh-producing and -responsive cell lineages

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

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

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

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

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

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

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

155 e Gli activity is activated in a Smoothened (Smo)-independent fashion, consistent with it acting down

156 Arhgap36 acts in a Smoothened (Smo)-independent manner to inhibit Gli repressor formati

157 Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observati

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

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

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

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

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

163 To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunoh

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

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

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

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

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

169 tify two distinct paradigms of resistance to Smo inhibition.

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

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

172 side comparison between Gli and Smoothened (Smo) inhibition was conducted in vitro using siRNA and s

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

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

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

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

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

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

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

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

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

182 Clinical trials with the SMO inhibitor, vismodegib, showed remarkable efficacy in

183 to treatment despite institution of a second SMO inhibitor.

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

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

186 ibitor, ICI 182780 but is not blocked by the smo-inhibitor, SANT-1.

187 lastomas that acquire resistance to chemical Smo inhibitors and that ARHGAP36 isoforms capable of Gli

188 s of disease refractory to oral therapy with SMO inhibitors have been reported in patients with Gorli

189 on that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of

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

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

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

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

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

195 Phytocannabinoids are also potent Smo inhibitors.

196 intain Hedgehog signaling in the presence of SMO inhibitors.

197 a patient with metastatic BCC refractory to SMO inhibitors.

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

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

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

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

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

203 ted to be extremely sensitive to Smoothened (SMO) inhibitors, a novel targeted therapy against the He

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

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

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

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

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

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

210 excellent candidate for transmission of Ptch/Smo interaction.

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

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

213 in Hh signaling, but how the localization of Smo is controlled remains poorly understood.

214 i) fused to the C terminus of each receptor, Smo is equivalent to the 5-HT(1A) receptor in the assay

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

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

217 Cell surface/cilium accumulation of Smo is thought to play an important role in Hh signaling

218 Smoothened (Smo) is a 7-transmembrane protein essential to the activ

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

220 Smoothened (Smo) is a member of the Frizzled (FzD) class of G-protei

221 Smoothened (Smo) is essential for transduction of the Hedgehog (Hh)

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

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

224 the release of Ptch1-mediated inhibition of Smo, leading to Smo activation and subsequent cell-auton

225 lation of the serpentine protein Smoothened (Smo) leads to Ci activation, whereas PKA-dependent phosp

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

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

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

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

230 ntial germline polymorphisms, we found three SMO missense mutations, and one PTCH1 frameshift mutatio

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

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

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

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

235 a clinically relevant, vismodegib -resistant Smo mutant, as well as the Gli activity resulting from l

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

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

238 Furthermore, we show that smo mutants exhibit perturbations in the Rab11 trafficki

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

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

241 SMO mutations either directly impaired drug binding or a

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

243 his interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rat

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

245 Somatic SMO mutations that result in constitutive activation hav

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

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

248 cells are not able to give rise to eRMS upon Smo or Gli1/2 overactivation in vivo, suggesting that Hh

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

250 oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evid

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

252 monstrate that atypical PKC (aPKC) regulates Smo phosphorylation and basolateral accumulation in Dros

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

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

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

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

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

258 Although the SMO receptor shares the seven-transmembrane helical fold

259 The smoothened (SMO) receptor, a key signal transducer in the hedgehog s

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

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

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

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

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

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

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

267 ity is sensitive to lipid binding at several Smo sites, suggesting mechanisms for tuning by multiple

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

269 f instant velocities revealed that SSTR3 and Smo spent less than a third of their time undergoing act

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

271 ese effects are unclear because the relevant Smo structural determinants are unknown.

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

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

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

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

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

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

278 We also inactivated Smo, the common Hh receptor, in neural tube progenitors.

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

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

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 Ptch mutations permit transposition of SMO to the primary cilium followed by enhanced expressio

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

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

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

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

289 The expression of Gli2, Ptch1 and Smo was consistently detected in other types of pluripot

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

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

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

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

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

295 icular, Hh signalling increases the level of Smo, which then outcompetes Ci for association with PKA

296 ates to the activation of G(i), by comparing Smo with the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor

297 uses PKA to switch its substrates from Ci to Smo within the Hh signalling complex (HSC).

298 , and in which the relative levels of Ci and Smo within the HSC determine differential activation and

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