Affinage

SMO

Protein smoothened · UniProt Q99835

Length
787 aa
Mass
86.4 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMO (Smoothened) is a seven-transmembrane signal transducer of the Hedgehog (Hh) pathway that functions downstream of Patched receptors to regulate Gli/Ci transcription factors, with vertebrate signaling requiring primary cilia-dependent trafficking (PMID:16339192, PMID:25908617). SMO activity is controlled by a balance of phosphorylation (promoted by Fu kinase, opposed by PP4 phosphatase) and ubiquitylation (mediated by Smurf and HERC4 E3 ligases, read by ESCRT-II/Vps36), which together govern its cell-surface accumulation and endosomal sorting; TMED2 retains SMO in the ER/Golgi, while WDR35/IFT-A directs its ciliary entry (PMID:17671093, PMID:19088085, PMID:29438012, PMID:23843610, PMID:35353806, PMID:25908617). SMO signals through heterotrimeric G proteins and can also translocate to the nucleus to activate GLI1 through a non-canonical mechanism that escapes conventional SMO inhibitors (PMID:19211052, PMID:29463581). Activating somatic mutations such as L412F cause Curry-Jones syndrome and drive medulloblastoma, ameloblastoma, and basal cell carcinoma, while biallelic loss-of-function variants cause developmental anomalies with disrupted ciliary Hh transduction (PMID:27236920, PMID:32413283).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 High

    Establishing SMO as the obligate signal transducer between Patched and Gli/Ci resolved the core pathway architecture and revealed that vertebrate Hh signaling uniquely requires primary cilia.

    Evidence Genetic epistasis and cell biological studies across Drosophila and vertebrate models

    PMID:16339192

    Open questions at the time
    • Precise mechanism by which cilia enable SMO signaling was unknown
    • Identity of intracellular effectors coupling SMO to Gli in vertebrates was unclear
  2. 2007 High

    Demonstrating that the Fu-Cos2 complex regulates SMO phosphorylation and surface accumulation in Drosophila defined the first feedback circuit controlling SMO activation state.

    Evidence Genetic epistasis with fu mutant clones, Cos2 domain mapping, and Ser572 phosphorylation site mutagenesis in Drosophila

    PMID:17671093

    Open questions at the time
    • Whether an analogous Fu-Cos2-like complex operates on vertebrate SMO
    • Full complement of kinases phosphorylating SMO C-tail was not defined
  3. 2008 High

    Identification of PP4 phosphatase as a direct Smo dephosphorylating enzyme revealed that SMO activation is set by a kinase–phosphatase balance, not kinase activity alone.

    Evidence In vivo RNAi screen, PP4-interaction domain deletion (aa 626–678), co-immunoprecipitation in Drosophila

    PMID:19088085

    Open questions at the time
    • Vertebrate phosphatase counterpart not identified
    • Structural basis of PP4-Smo interaction unknown
  4. 2009 Medium

    Evidence that Smo couples to heterotrimeric G proteins established it as a functional GPCR-like receptor, bridging Hh signal transduction to classical G protein cascades.

    Evidence Review citing direct experimental evidence for G protein coupling to Smo

    PMID:19211052

    Open questions at the time
    • Specific Gα subtype selectivity not fully resolved
    • Relative contribution of G protein vs. non-G-protein SMO signaling unclear
  5. 2013 High

    Showing that ESCRT-II/Vps36 recognizes ubiquitin on SMO to direct it away from the plasma membrane in the absence of Hh linked the ubiquitin code to SMO trafficking decisions.

    Evidence Genetic analysis, ubiquitylation assays, and ESCRT-II mutant trafficking assays in Drosophila

    PMID:23843610

    Open questions at the time
    • Identity of the E3 ligase(s) responsible was not yet established
    • Whether mammalian SMO uses the same ESCRT sorting mechanism
  6. 2014 Medium

    Functional characterization of the SMO L412F activating mutation and identification of vismodegib-resistance mutations (G497W, D473Y) linked specific structural features to constitutive activation and drug escape.

    Evidence In vitro Hh pathway assays for L412F, patient BCC sequencing plus molecular modeling for G497W/D473Y

    PMID:24859340 PMID:25306392

    Open questions at the time
    • No crystal structure of mutant SMO with drug bound
    • In vitro reconstitution of resistance mutations not performed for G497W
  7. 2015 High

    Demonstration that WDR35/IFT-A is required specifically for SMO ciliary entry, and that Notch signaling promotes SMO ciliary accumulation independently of Shh, identified two distinct inputs governing SMO access to cilia.

    Evidence Wdr35−/− mouse fibroblasts with SMO immunofluorescence; Notch1 overexpression with live cilia imaging in neuroepithelial cells

    PMID:25908617 PMID:25995356

    Open questions at the time
    • Whether Notch acts on SMO directly or via cilia length/structure
    • How WDR35 selectively recognizes SMO cargo
  8. 2016 Medium

    Discovery that somatic mosaic SMO L412F causes Curry-Jones syndrome and that biallelic SMO loss-of-function causes developmental anomalies established SMO as a Mendelian disease gene with both gain- and loss-of-function phenotypes.

    Evidence Whole exome sequencing with mosaicism quantification; patient-derived cells with ciliary SMO/GLI2 localization assays

    PMID:27236920 PMID:32413283

    Open questions at the time
    • Genotype–phenotype spectrum across different SMO loss-of-function alleles incomplete
    • Whether nuclear SMO function contributes to Curry-Jones pathology
  9. 2018 High

    Identification of Smurf E3 ligases as SMO ubiquitylating enzymes, regulated by Gprk2 and PKA phosphorylation, completed the ubiquitin-mediated arm of SMO trafficking control and explained how Hh reciprocally shifts Smurf from Smo to Ptc.

    Evidence Co-immunoprecipitation, ubiquitylation assays, phosphorylation site mutagenesis, and genetic analysis in Drosophila

    PMID:29438012

    Open questions at the time
    • Mammalian Smurf-SMO axis not validated
    • Quantitative contribution of Smurf vs. HERC4 to total SMO ubiquitylation unknown
  10. 2018 Medium

    Discovery that SMO can translocate to the nucleus via a nuclear/nucleolar localization signal and activate GLI1 through a mechanism insensitive to conventional SMO inhibitors revealed a non-canonical signaling mode with therapeutic implications.

    Evidence Nuclear fractionation, immunohistochemistry of human BCC, N(o)LS mutagenesis in PTCH1-silenced keratinocytes

    PMID:29463581

    Open questions at the time
    • Nuclear SMO effector mechanism beyond GLI1 induction not defined
    • Whether nuclear SMO engages G proteins or other partners unknown
    • Independent replication needed
  11. 2022 High

    Identification of TMED2 as an ER/Golgi retention factor for SMO resolved how SMO is kept from the plasma membrane prior to Hh stimulation, providing the earliest known checkpoint in SMO trafficking.

    Evidence Haploid ESC genetic screen, super-resolution microscopy, co-immunoprecipitation, TMED2 mutation analysis, neural differentiation assays

    PMID:35353806

    Open questions at the time
    • Structural basis of TMED2-SMO interaction not determined
    • How Hh signaling relieves TMED2 retention is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and quantitative model integrating SMO's phosphorylation code, ubiquitin signals, ciliary trafficking, nuclear translocation, and G protein coupling into a single activation framework remains to be established.
  • No integrated structural model of full-length SMO with all regulatory modifications
  • Relative flux through canonical (ciliary/Gli) vs. non-canonical (nuclear) SMO pathways unquantified
  • Vertebrate equivalents of Drosophila Fu-Cos2-PP4 regulatory circuit not fully identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005929 cilium 3 GO:0005634 nucleus 1 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3
Partners
ARL13BCOS2FUPTCH1SMURFTMED2VPS36WDR35
Complex memberships
Fu-Cos2-Smo complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SMO (Smoothened) acts as the key signal transducer downstream of Patched in the Hedgehog pathway, relaying signals to Ci/Gli transcription factors; fundamental differences exist between Drosophila and vertebrates in how signals are transduced from SMO to Gli, including vertebrate-specific roles of intraflagellar transport proteins linking Hh signaling to primary cilia. Genetic and cell biological studies in Drosophila and vertebrate model organisms; review of epistasis and pathway placement experiments Development (Cambridge, England) High 16339192
2007 In Drosophila, the Fu-Cos2 intracellular signaling complex regulates Smo phosphorylation and cell-surface accumulation: Cos2 interacts with Smo via its C-terminal domain to block Hh-induced Smo phosphorylation, while Fu promotes Smo phosphorylation by phosphorylating Cos2 at Ser572, attenuating the Cos2-Smo interaction and promoting Cos2 instability. Genetic epistasis (fu mutant clones, dominant-negative Fu), overexpression of Cos2, domain mapping of Cos2-Smo interaction, phosphorylation site mutagenesis (Ser572) Genes & development High 17671093
2008 In Drosophila, PP4 phosphatase regulates Hh signaling by dephosphorylating Smo: RNAi knockdown of PP4 elevates Smo phosphorylation and accumulation, increasing Hh signaling; deletion of the PP4-interaction domain (amino acids 626-678) in Smo promotes Smo phosphorylation and signaling; Hh downregulates the Smo-PP4 interaction mediated by Cos2. In vivo RNAi screen, domain deletion mutagenesis, phosphorylation assays, co-immunoprecipitation (Smo-PP4 interaction mediated by Cos2) Development (Cambridge, England) High 19088085
2013 In Drosophila, Vps36 of the ESCRT-II complex controls Smo trafficking by recognizing ubiquitin signals on Smo in the absence of Hh; in the absence of Hh, Smo is ubiquitylated on its cytoplasmic part (internal loops and C-tail), targeting it away from the plasma membrane. Genetic analysis in Drosophila, ubiquitylation assays, trafficking assays with ESCRT-II mutants Journal of cell science High 23843610
2015 Notch signaling promotes accumulation of Smoothened (Smo) within primary cilia and elevates full-length Gli3 levels in a Shh-independent manner; activated Notch1 also promotes longer primary cilia, thereby augmenting the cellular response to Shh. Live imaging and immunofluorescence of primary cilia in neuroepithelial cells; activated Notch1 overexpression; in vitro and in vivo experiments Development (Cambridge, England) Medium 25995356
2015 Loss of primary cilia (via ciliogenesis gene mutations) confers resistance to SMO inhibitors in Hedgehog pathway-dependent medulloblastoma, maintaining a 'persister' state with low Hedgehog output; paradoxically, cilia loss protects tumor cells from SMO inhibitor susceptibility. Transposon mutagenesis screen in medulloblastoma, functional validation with ciliogenesis gene knockouts, clinical patient dataset analysis Cancer discovery High 28923910
2015 WDR35/IFT121 (a retrograde intraflagellar transport protein) is specifically required for SMO entry into the ciliary compartment; in Wdr35-/- cells, SMO fails to localize to cilia, causing Hedgehog signaling defects similar to those of Evc/Evc2 mutants. Knockout mouse fibroblasts (Wdr35-/-, Dync2h1-/-), immunofluorescence/localization of SMO in cilia, rescue experiments with disease cDNAs Human molecular genetics High 25908617
2018 Smurf family E3 ubiquitin ligases mediate Smo ubiquitylation and cell-surface clearance in Drosophila; Gprk2-mediated phosphorylation of Smurf promotes Smo ubiquitylation by increasing Smurf recruitment to Smo, whereas PKA-mediated phosphorylation of Smo causes Smurf to dissociate from Smo, inhibiting Smo ubiquitylation; Hh promotes reciprocal trafficking of Ptc and Smo by shifting Smurf binding from Smo to Ptc. Co-immunoprecipitation, ubiquitylation assays, phosphorylation site mutagenesis, genetic analysis in Drosophila Science signaling High 29438012
2018 SMO can localize to the nucleus via a putative nuclear/nucleolar localization signal (N(o)LS); in PTCH1-silenced keratinocytes, nuclear SMO activates GLI1 through a mechanism that escapes pharmacological SMO inhibitors; mutational inactivation of the N(o)LS ablated nuclear SMO accumulation and suppressed GLI1 induction. siRNA silencing, pharmacological inhibition, nuclear fractionation, immunohistochemistry of human/mouse BCC, N(o)LS mutagenesis Cancer research Medium 29463581
2022 TMED2 binds to SMO and retains it in the endoplasmic reticulum and Golgi compartments, preventing SMO localization to the plasma membrane; mutation of TMED2 allows SMO accumulation at the plasma membrane, recapitulating early events after Hh stimulation; this interaction is physiologically relevant in neural differentiation where TMED2 represses Hh signal strength. Genetic screen in haploid ESCs, super-resolution microscopy, co-immunoprecipitation (TMED2-SMO binding), TMED2 mutation analysis, neural differentiation assays PLoS biology High 35353806
2017 The small GTPase Arl13b is a novel binding partner and regulator of Smo: Arl13b regulates Smo stability, trafficking, and localization in gastric cancer cells, and stimulates proliferation, migration, and invasion through Hh pathway activation. Co-immunoprecipitation (Arl13b-Smo), knockdown/overexpression assays, in vitro and in vivo functional assays, clinical specimen analysis Cancer research Medium 28611043
2021 SMO-193aa, a novel protein encoded by circular SMO (circ-SMO), is required for Shh-induced SMO activation: it interacts with SMO, enhances SMO cholesterol modification, and releases SMO from Patched inhibition; a positive feedback loop exists: Shh/Gli1/FUS/SMO-193aa sustains Hedgehog signaling in glioblastoma. Co-immunoprecipitation (SMO-193aa with SMO), RNA interference, cholesterol modification assays, in vitro and in vivo glioblastoma models Genome biology Medium 33446260
2019 HERC4 E3 ubiquitin ligase interacts with Smo and destabilizes it; depletion of HERC4 increases Smo protein levels and activates Hh pathway; initially identified via a modifier screen in Drosophila (dHerc4 degrades dSmo), validated in non-small cell lung cancer cells. Drosophila modifier screen, co-immunoprecipitation (HERC4-Smo), knockdown assays, protein stability assays in NSCLC cells Biochemical and biophysical research communications Medium 31010679
2010 TGFβ2 is a major Hh-regulated gene downstream of SMO activation; TGFβ signaling is required for SMO-mediated carcinogenesis, as demonstrated by inhibition of TGFβ receptor I (SD208) significantly reducing tumor area in K14cre/R26SmoM2 mice; SMO-activated tumors show elevated phospho-SMAD2/3 in both tumor and stroma. Mouse model (K14cre/R26SmoM2), TGFβ receptor inhibitor treatment, gene expression analysis, immunohistochemistry for phospho-SMAD2/3, loss-of-function assays The Journal of biological chemistry Medium 20858897
2014 The SMO L412F mutation is an activating mutation that constitutively activates Hedgehog pathway signaling; its effect can be inhibited by arsenic trioxide (ATO), identifying a mechanism of pharmacological intervention. In vitro functional assay of Hedgehog pathway activity with L412F SMO variant, pharmacological inhibition with ATO Nature genetics Medium 24859340
2016 Biallelic loss-of-function variations in SMO in humans cause developmental anomalies; affected patient cells show normal ciliogenesis but severely altered Hh-signal transduction due to either altered primary cilium (PC) trafficking or abnormal pathway activation downstream of SMO; SMO also has a function in regulating basal ciliary trafficking of GLI2 when the pathway is off. Human genetics (patient-derived cells), ciliogenesis assays, immunofluorescence of SMO and GLI2 in primary cilia, Hh signaling assays American journal of human genetics Medium 32413283
2018 The Wnt3a-activated β-catenin/TCF4 transcriptional complex directly binds to SMO and GLI1 promoters (two binding sites for SMO, one for GLI1) and activates their transcription, establishing a direct cross-talk mechanism between Wnt and Hedgehog signaling pathways. Chromatin immunoprecipitation (ChIP), yeast one-hybrid assay, promoter reporter assays, siRNA knockdown of β-catenin, RT-qPCR Experimental and therapeutic medicine Medium 30186446
2009 Smoothened (Smo) is structurally similar to G protein-coupled receptors and directly relies on heterotrimeric G proteins to transduce the Hedgehog signal, providing evidence for GPCR-like signaling mechanism. Review of direct experimental evidence for G protein coupling to Smo Current biology : CB Medium 19211052
2007 Constitutive expression of activated human SMO (SmoM2) in mouse mammary glands increases proliferation, alters differentiation, causes ductal dysplasia, and increases mammosphere-forming efficiency of primary mammary epithelial cells; however, limiting-dilution transplantation showed a decrease in regenerative stem cell frequency, suggesting SMO promotes survival of division-competent cells rather than expanding stem cells. MMTV-SmoM2 transgenic mouse model, mammosphere assay, limiting-dilution transplantation, Ki67 co-localization Development (Cambridge, England) Medium 17287253
2011 Hypoxia activates Hedgehog signaling in pancreatic cancer cells in a ligand-independent manner by transcriptionally upregulating Smo; silencing of Smo (not Shh) decreases Gli1 and MMP9 transcription and reduces PDAC invasiveness, placing Smo as the essential node for hypoxia-driven Hh pathway activation. siRNA knockdown of Smo and Shh, RT-PCR, invasion assays in pancreatic cancer cell lines under hypoxic conditions Cancer science Medium 21338440
2021 STAT3 is required for Smo-dependent Shh signaling in medulloblastoma: STAT3 activity is necessary for expression of Hck proto-oncogene downstream of Smo; STAT3 is reciprocally regulated by Shh signaling; dual Smo + STAT3 inhibition results in synergistic killing and overcomes resistance in vitro; STAT3 inhibitor prevents in vivo tumor formation in genetically engineered Shh MB mice. siRNA knockdown, pharmacological inhibition, colony formation assays, in vivo mouse model (genetically engineered Shh MB mice) Molecular oncology Medium 34482626
2020 Smo-specific deletion in macrophage/osteoclast lineage in mice attenuates age-related trabecular bone loss, demonstrating that Smo-GLI1/2 signaling mediates osteoclastogenesis; Smo inhibition (cyclopamine) significantly inhibits RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Conditional Smo knockout mice (macrophage/osteoclast-specific), RANKL-induced osteoclast differentiation assays, cyclopamine pharmacological inhibition International journal of molecular sciences Medium 32326611
2003 Purified recombinant human PAOh1/SMO (spermine oxidase) preferentially oxidizes spermine (Km=1.6 μM) and N1-acetylspermine (Km=51 μM) but not spermidine; specific oligamine analogues are potent inhibitors of spermine oxidation by SMO. Purification of recombinant enzyme, in vitro enzymatic kinetics assays, inhibition studies Biochemical and biophysical research communications High 12727196
2005 SMO(PAOh1) (spermine oxidase), not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine analogue-treated breast cancer cells; stable knockdown of SMO(PAOh1) reduces sensitivity of MDA-MB-231 cells to BENSpm and eliminates H2O2 production from analogue-induced catabolism. Stable siRNA knockdown of SMO(PAOh1) and SSAT, H2O2 measurement, cell growth inhibition assays, enzyme activity assays The Journal of biological chemistry High 16207710
2005 Induction of SMO(PAOh1) spermine oxidase by polyamine analogues occurs at the level of new mRNA synthesis and protein translation; CPENSpm treatment increases transcription (~30-90% via promoter reporter assays) and significantly stabilizes SMO(PAOh1) mRNA (half-life increased from 8.8 h to 17.1 h); protein stabilization does not play a significant role. Actinomycin D and cycloheximide inhibition studies, mRNA half-life determination, promoter reporter assays, enzyme activity assays The Biochemical journal High 15496143
2022 m5C mRNA modification of SMO promotes SMO mRNA export from nucleus to cytoplasm via ALYREF, increasing SMO protein expression and promoting myogenesis; this ALYREF-m5C-SMO mechanism is distinct from its role in adipogenesis. RNA bisulfite sequencing (m5C profiling), ALYREF co-immunoprecipitation with m5C-modified SMO mRNA, SMO protein expression assays, in vitro differentiation assays Cellular and molecular life sciences : CMLS Medium 35962235
2022 FGF18 attenuates liver fibrosis by suppressing SMO; the interaction between SMO and LATS1 (Hippo kinase) is crucial for FGF18-induced protective effects; FGF18 treatment activates Hippo signaling by suppressing SMO, identifying SMO as a negative regulator of LATS1 in hepatic stellate cells. Co-immunoprecipitation (SMO-LATS1 interaction), in vivo mouse model (CCl4-induced fibrosis), HSC-specific FGF18 knockout, in vitro FGF18 treatment Pharmacological research Medium 35202822
2014 Vismodegib resistance in basal cell carcinoma is mediated by secondary SMO mutations (G497W and D473Y): in silico modeling demonstrates G497W causes conformational rearrangement partially obstructing drug entry site (primary resistance mechanism), while D473Y disrupts a stabilizing hydrogen bond network at the binding site (secondary resistance mechanism). DNA sequencing of patient BCC samples, molecular modeling/in silico analysis of SMO protein structure Molecular oncology Medium 25306392
2016 Somatic mosaic SMO L412F mutation causes Curry-Jones syndrome by constitutively activating SMO in the absence of Hh signaling; the identical mutation is found in medulloblastoma, ameloblastoma, and basal cell carcinoma, establishing that this substitution activates SMO constitutively. Whole exome sequencing, tissue-specific mosaicism quantification, functional studies showing constitutive SMO activation American journal of human genetics Medium 27236920
2014 Ptch2 is a functional Shh receptor that regulates Smo localization and activity in vitro; Ptch1 and Ptch2 co-operate in regulating cellular responses to Shh during mouse limb development, with Ptch2 loss exacerbating limb outgrowth defects in limb-specific Ptch1 knockouts. In vitro Smo localization assays, conditional Ptch1 knockout mice, Ptch2 knockout mice, double mutant genetic analysis Developmental biology Medium 25448692
2018 LncRNA-MEG3 directly interacts with SMO protein to inhibit Hedgehog-mediated EMT and HSC activation in liver fibrosis; this interaction was confirmed by RNA immunoprecipitation and deletion-mapping analysis. RNA immunoprecipitation (RIP), deletion-mapping analysis of MEG3-SMO protein interaction, MEG3 overexpression in liver fibrosis models Cell death & disease Low 30282972

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science (New York, N.Y.) 706 23348505
2006 Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development (Cambridge, England) 386 16339192
1998 Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer research 335 9581815
2005 Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. The British journal of dermatology 313 15656799
2014 Identification of recurrent SMO and BRAF mutations in ameloblastomas. Nature genetics 265 24859340
2000 Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes, chromosomes & cancer 154 10564585
2007 Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia. Development (Cambridge, England) 147 17287253
2015 RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. Cancer research 137 26130651
2021 A novel protein encoded by circular SMO RNA is essential for Hedgehog signaling activation and glioblastoma tumorigenicity. Genome biology 134 33446260
2014 Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma. Molecular oncology 131 25306392
2018 Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis. Nature genetics 124 30374069
2003 Properties of purified recombinant human polyamine oxidase, PAOh1/SMO. Biochemical and biophysical research communications 105 12727196
2005 Spermine oxidase SMO(PAOh1), Not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine analogue-treated human breast cancer cell lines. The Journal of biological chemistry 104 16207710
2015 SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 100 26124204
2006 Hedgehog signalling: how to get from Smo to Ci and Gli. Trends in cell biology 99 16516476
2008 Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo). Breast cancer research and treatment 91 18563554
2011 Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer. Cancer science 84 21338440
2017 SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. Neuro-oncology 83 28082415
2015 A conserved role for Notch signaling in priming the cellular response to Shh through ciliary localisation of the key Shh transducer Smo. Development (Cambridge, England) 79 25995356
2018 LncRNA-MEG3 inhibits activation of hepatic stellate cells through SMO protein and miR-212. Cell death & disease 76 30282972
2013 Targeting of the signal transducer Smo links microRNA-326 to the oncogenic Hedgehog pathway in CD34+ CML stem/progenitor cells. International journal of cancer 73 23341351
2014 Targeting the SMO oncogene by miR-326 inhibits glioma biological behaviors and stemness. Neuro-oncology 71 25173582
2016 A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome. American journal of human genetics 69 27236920
2008 PP4 and PP2A regulate Hedgehog signaling by controlling Smo and Ci phosphorylation. Development (Cambridge, England) 69 19088085
2017 GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML. Blood 68 28487292
2020 Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis. Oncogene 65 32929154
2004 PTC gene mutations and expression of SHH, PTC, SMO, and GLI-1 in odontogenic keratocysts. International journal of oral and maxillofacial surgery 60 15308259
1999 The patched/hedgehog/smoothened signalling pathway in human breast cancer: no evidence for H133Y SHH, PTCH and SMO mutations. European journal of cancer (Oxford, England : 1990) 59 10505029
2018 Phase I Study of LY2940680, a Smo Antagonist, in Patients with Advanced Cancer Including Treatment-Naïve and Previously Treated Basal Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 58 29483143
2007 Fused-Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation. Genes & development 55 17671093
2010 Requirement of TGFbeta signaling for SMO-mediated carcinogenesis. The Journal of biological chemistry 54 20858897
2003 Induction of the PAOh1/SMO polyamine oxidase by polyamine analogues in human lung carcinoma cells. Cancer chemotherapy and pharmacology 54 12827295
2019 DNA-methylation-mediated silencing of miR-7-5p promotes gastric cancer stem cell invasion via increasing Smo and Hes1. Journal of cellular physiology 52 31517391
2016 Targeted sequencing of SMO and AKT1 in anterior skull base meningiomas. Journal of neurosurgery 52 27885953
2008 PTCH1 and SMO gene alterations in keratocystic odontogenic tumors. Journal of dental research 52 18502968
2017 A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors. Cancer discovery 50 28923910
1997 Patched (ptch)-associated preferential expression of smoothened (smoh) in human basal cell carcinoma of the skin. Cancer research 50 9354432
2015 Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium. Human molecular genetics 48 25908617
2021 CD47-Mediated Hedgehog/SMO/GLI1 Signaling Promotes Mesenchymal Stem Cell Immunomodulation in Mouse Liver Inflammation. Hepatology (Baltimore, Md.) 46 33765345
2009 The immunoprofile of odontogenic keratocyst (keratocystic odontogenic tumor) that includes expression of PTCH, SMO, GLI-1 and bcl-2 is similar to ameloblastoma but different from odontogenic cysts. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 46 19473442
2010 Spermine oxidase (SMO) activity in breast tumor tissues and biochemical analysis of the anticancer spermine analogues BENSpm and CPENSpm. BMC cancer 43 20946629
2021 Smo-Shh signaling activator purmorphamine ameliorates neurobehavioral, molecular, and morphological alterations in an intracerebroventricular propionic acid-induced experimental model of autism. Human & experimental toxicology 42 33906504
2019 A Smo/Gli Multitarget Hedgehog Pathway Inhibitor Impairs Tumor Growth. Cancers 42 31601026
2016 Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors. Blood 41 27694322
2014 Development of a concise, asymmetric synthesis of a smoothened receptor (SMO) inhibitor: enzymatic transamination of a 4-piperidinone with dynamic kinetic resolution. Organic letters 40 24502520
2014 Ptch2 shares overlapping functions with Ptch1 in Smo regulation and limb development. Developmental biology 39 25448692
2021 MIRLET7BHG promotes hepatocellular carcinoma progression by activating hepatic stellate cells through exosomal SMO to trigger Hedgehog pathway. Cell death & disease 37 33771969
2022 mRNA m5C inhibits adipogenesis and promotes myogenesis by respectively facilitating YBX2 and SMO mRNA export in ALYREF-m5C manner. Cellular and molecular life sciences : CMLS 35 35962235
2017 Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway. Cancer research 35 28611043
2009 Hedgehog signaling: is Smo a G protein-coupled receptor? Current biology : CB 34 19211052
2009 The role of the polyamine catabolic enzymes SSAT and SMO in the synergistic effects of standard chemotherapeutic agents with a polyamine analogue in human breast cancer cell lines. Cancer chemotherapy and pharmacology 34 19727732
2006 The cell biology of Smo signalling and its relationships with GPCRs. Biochimica et biophysica acta 34 17094938
1989 Mutations at the smo genetic locus affect the shape of diverse cell types in the rice blast fungus. Genetics 34 17246498
2019 Glesatinib, a c-MET/SMO Dual Inhibitor, Antagonizes P-glycoprotein Mediated Multidrug Resistance in Cancer Cells. Frontiers in oncology 33 31106148
2018 Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold. European journal of medicinal chemistry 33 30025349
2022 Smo-Shh Agonist Purmorphamine Prevents Neurobehavioral and Neurochemical Defects in 8-OH-DPAT-Induced Experimental Model of Obsessive-Compulsive Disorder. Brain sciences 32 35326298
2018 Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases. Science signaling 32 29438012
2013 Drosophila Vps36 regulates Smo trafficking in Hedgehog signaling. Journal of cell science 32 23843610
2023 The role of Smo-Shh/Gli signaling activation in the prevention of neurological and ageing disorders. Biogerontology 31 37097427
2019 Circular RNA SMO sponges miR-338-3p to promote the growth of glioma by enhancing the expression of SMO. Aging 31 31895689
2018 Selective vulnerability of the primitive meningeal layer to prenatal Smo activation for skull base meningothelial meningioma formation. Oncogene 31 29789719
2013 Mutations in the hedgehog pathway genes SMO and PTCH1 in human gastric tumors. PloS one 31 23349881
1990 Genetic mapping with dispersed repeated sequences in the rice blast fungus: mapping the SMO locus. Molecular & general genetics : MGG 31 1980141
2013 Adenovirus vector-mediated Gli1 siRNA induces growth inhibition and apoptosis in human pancreatic cancer with Smo-dependent or Smo-independent Hh pathway activation in vitro and in vivo. Cancer letters 30 23791879
2005 Induction of human spermine oxidase SMO(PAOh1) is regulated at the levels of new mRNA synthesis, mRNA stabilization and newly synthesized protein. The Biochemical journal 30 15496143
2018 SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer. Frontiers in pharmacology 29 29456503
2019 Intraventricular meningiomas frequently harbor NF2 mutations but lack common genetic alterations in TRAF7, AKT1, SMO, KLF4, PIK3CA, and TERT. Acta neuropathologica communications 28 31470906
2014 NL-103, a novel dual-targeted inhibitor of histone deacetylases and hedgehog pathway, effectively overcomes vismodegib resistance conferred by Smo mutations. Pharmacology research & perspectives 28 25505589
2014 Molecular docking approaches in identification of High affinity inhibitors of Human SMO receptor. Bioinformation 28 25670876
2008 Increased spermine oxidase (SMO) activity as a novel differentiation marker of myogenic C2C12 cells. The international journal of biochemistry & cell biology 28 18852063
2016 Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists. Journal of medicinal chemistry 27 27736063
2011 Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic mouse model of islet cell neoplasms. Annals of surgery 27 22042473
2022 Fibroblast growth factor 18 attenuates liver fibrosis and HSCs activation via the SMO-LATS1-YAP pathway. Pharmacological research 26 35202822
2014 SMO expression in colorectal cancer: associations with clinical, pathological, and molecular features. Annals of surgical oncology 26 25023548
2019 State of the art of Smo antagonists for cancer therapy: advances in the target receptor and new ligand structures. Future medicinal chemistry 25 30912670
2020 Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling. American journal of human genetics 24 32413283
2019 Tumor Priming by SMO Inhibition Enhances Antibody Delivery and Efficacy in a Pancreatic Ductal Adenocarcinoma Model. Molecular cancer therapeutics 24 31363010
2017 Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer. Journal of medicinal chemistry 23 28787156
2014 Sonic hedgehog signalling pathway regulates apoptosis through Smo protein in human umbilical vein endothelial cells. Rheumatology (Oxford, England) 23 25406358
2014 Protein and mRNA expression of Shh, Smo and Gli1 and inhibition by cyclopamine in hepatocytes of rats with chronic fluorosis. Toxicology letters 22 24388991
2020 Understanding Abnormal SMO-SHH Signaling in Autism Spectrum Disorder: Potential Drug Target and Therapeutic Goals. Cellular and molecular neurobiology 21 33206287
2024 Human umbilical cord mesenchymal stem cell-derived exosomes ameliorate renal fibrosis in diabetic nephropathy by targeting Hedgehog/SMO signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 38572590
2020 Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss. International journal of molecular sciences 19 32326611
2020 The inhibition of microRNA-326 by SP1/HDAC1 contributes to proliferation and metastasis of osteosarcoma through promoting SMO expression. Journal of cellular and molecular medicine 19 32743904
2017 Molecular modeling study on resistance of WT/D473H SMO to antagonists LDE-225 and LEQ-506. Pharmacological research 18 29175550
2010 ¹H nuclear magnetic resonance spectroscopy characterisation of metabolic phenotypes in the medulloblastoma of the SMO transgenic mice. British journal of cancer 17 20842126
2019 HERC4 exerts an anti-tumor role through destabilizing the oncoprotein Smo. Biochemical and biophysical research communications 16 31010679
2018 Overcoming the emerging drug resistance of smoothened: an overview of small-molecule SMO antagonists with antiresistance activity. Future medicinal chemistry 16 30557039
2006 Mutation in exon 7 of PTCH deregulates SHH/PTCH/SMO signaling: possible linkage to WNT. International journal of molecular medicine 16 16596257
2021 STAT3 is required for Smo-dependent signaling and mediates Smo-targeted treatment resistance and tumorigenesis in Shh medulloblastoma. Molecular oncology 15 34482626
2019 miR-370 inhibits the angiogenic activity of endothelial cells by targeting smoothened (SMO) and bone morphogenetic protein (BMP)-2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 30865837
2017 Combination treatment with dendrosomal nanocurcumin and doxorubicin improves anticancer effects on breast cancer cells through modulating CXCR4/NF-κB/Smo regulatory network. Molecular biology reports 15 28752270
2012 Discovery of novel hedgehog antagonists from cell-based screening: Isosteric modification of p38 bisamides as potent inhibitors of SMO. Bioorganic & medicinal chemistry letters 15 22704236
2022 TMED2 binding restricts SMO to the ER and Golgi compartments. PLoS biology 14 35353806
2020 Scutellariabarbata D. Don extraction selectively targets stemness-prone NSCLC cells by attenuating SOX2/SMO/GLI1 network loop. Journal of ethnopharmacology 14 32841701
2018 A Novel Mechanism for Activation of GLI1 by Nuclear SMO That Escapes Anti-SMO Inhibitors. Cancer research 14 29463581
2020 Design, synthesis and biological evaluation of anthranilamide derivatives as potent SMO inhibitors. Bioorganic & medicinal chemistry 13 32063403
2019 miR-135a Inhibits the Invasion and Migration of Esophageal Cancer Stem Cells through the Hedgehog Signaling Pathway by Targeting Smo. Molecular therapy. Nucleic acids 13 31981861
2018 Wnt3a-regulated TCF4/β-catenin complex directly activates the key Hedgehog signalling genes Smo and Gli1. Experimental and therapeutic medicine 13 30186446
2018 A familial syndrome of hypothalamic hamartomas, polydactyly, and SMO mutations: a clinical report of 2 cases. Journal of neurosurgery. Pediatrics 13 30497210