Affinage

SMO

Spermine oxidase · UniProt Q9NWM0

Length
555 aa
Mass
61.8 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMO (Smoothened) is a seven-transmembrane signal transducer that operates as the central relay of the Hedgehog (Hh) pathway, propagating the signal from the Patched receptor to downstream Gli transcription factors (PMID:16229832, PMID:25448692). Productive signaling requires SMO localization to the primary cilium, an event dependent on intraflagellar transport; loss of the retrograde IFT motor disrupts SMO ciliary accumulation and abolishes both Gli activator and repressor output, including Gli3 proteolytic processing (PMID:16229832). Once active in the cilium, SMO requires the Evc/Evc2 complex, with which it physically associates, to drive recruitment of Gli3 to ciliary tips and dissociation of Sufu/Gli3 complexes, shifting the balance toward Gli activator forms (PMID:23026747). SMO activity is gated by graded C-tail phosphorylation: in Drosophila, sequential PKA/CK1 priming enables GRK2 (Gprk2) phosphorylation of Ser741/Thr742 and kinase-independent GRK2 binding that stabilizes the active conformation in a positive feedback loop, while PP4 phosphatase and the Fused–Costal2 complex counteract this to restrain surface accumulation and signaling (PMID:17671093, PMID:19088085, PMID:20844016). SMO abundance and trafficking are further controlled by ubiquitin-dependent mechanisms: Smurf E3 ligases (regulated by GRK2 and PKA phosphorylation) and the ESCRT-II component Vps36 mediate ubiquitin-dependent surface clearance in the Hh-off state, HERC4 promotes SMO degradation, and TMED2 retains SMO in the ER/Golgi prior to activation (PMID:29438012, PMID:23843610, PMID:31010679, PMID:35353806). In humans, activating somatic and mosaic mutations such as L412F constitutively activate the pathway and drive Curry-Jones syndrome and multiple cancers, whereas bi-allelic loss-of-function variants cause developmental anomalies including hypothalamic hamartoma and polydactyly (PMID:24859340, PMID:27236920, PMID:32413283). Beyond canonical ciliary signaling, SMO engages non-canonical roles, including PTCH1-loss-dependent nuclear localization that activates GLI1 refractory to SMO antagonists and association with an IGF-IR/PI3K p85 complex (PMID:29463581, PMID:21618536).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2005 High

    Established that SMO must traffic to the primary cilium to transduce Hedgehog signal, defining the subcellular site of pathway activation.

    Evidence Mouse retrograde IFT motor mutants with SMO ciliary immunofluorescence and Gli3 processing assays

    PMID:16229832

    Open questions at the time
    • Did not define the activating conformational change SMO undergoes in the cilium
    • Mechanism linking ciliary SMO to Gli processing left open
  2. 2006 High

    Identified the Fused–Costal2 complex as a direct regulator of SMO phosphorylation and surface accumulation, showing SMO activity is set by an upstream kinase/scaffold network.

    Evidence Drosophila genetics, reciprocal co-IP, phosphorylation-site mapping

    PMID:17671093

    Open questions at the time
    • Demonstrated in Drosophila; mammalian conservation not addressed
    • Did not link Cos2 binding to downstream Gli output directly
  3. 2008 High

    Showed that PP4 phosphatase opposes kinase-driven SMO phosphorylation, revealing reversible phosphorylation as the switch controlling SMO accumulation.

    Evidence In vivo Drosophila RNAi screen, domain-deletion mutagenesis, co-IP

    PMID:19088085

    Open questions at the time
    • PP4 target residues on SMO not mapped
    • Drosophila context; mammalian PP4–SMO link untested
  4. 2010 High

    Resolved the kinase hierarchy by placing GRK2/Gprk2 phosphorylation downstream of PKA/CK1 priming and uncovering a kinase-independent stabilization feedback loop for high-level signaling.

    Evidence Drosophila genetics, phospho-site and kinase-dead mutagenesis, co-IP, epistasis

    PMID:20844016

    Open questions at the time
    • Structural basis of GRK2-stabilized active conformation not determined
    • Conservation of Ser741/Thr742 phosphorylation in mammals untested
  5. 2010 Medium

    Connected active SMO to a TGFβ2 effector arm, showing SMO drives tumor growth partly through downstream TGFβ signaling in skin.

    Evidence K14cre/R26SmoM2 transgenic mice, expression analysis, TGFβ receptor inhibitor rescue

    PMID:20858897

    Open questions at the time
    • Whether TGFβ2 induction is a direct or Gli-dependent transcriptional output unclear
    • Single lab; single tissue context
  6. 2011 Medium

    Demonstrated ligand-independent pathway activation via transcriptional upregulation of SMO under hypoxia, decoupling SMO from upstream Shh.

    Evidence siRNA knockdown of Smo vs Shh, qRT-PCR, invasion assays under hypoxia

    PMID:21338440

    Open questions at the time
    • Transcription factor driving hypoxic SMO induction not identified
    • Single lab; pancreatic context only
  7. 2012 Medium

    Uncovered a non-canonical SMO role in IGF-I/PI3K signaling, showing SMO associates with IGF-IR and p85 independent of classical Gli output.

    Evidence Smo conditional knockout myoblasts, cyclopamine, co-IP of Smo–p85–IGF-IR, phospho-westerns

    PMID:21618536

    Open questions at the time
    • Direct vs indirect nature of SMO–IGF-IR association not resolved
    • Single lab
  8. 2012 High

    Placed the Evc/Evc2 complex downstream of SMO ciliary entry, identifying the step at which SMO triggers Sufu/Gli3 dissociation at the cilium tip.

    Evidence Mouse genetics, Smo–Evc/Evc2 co-IP, ciliary immunofluorescence, Sufu-/- epistasis

    PMID:23026747

    Open questions at the time
    • Molecular mechanism by which active SMO engages Evc/Evc2 unknown
    • Restricted to chondrocyte context
  9. 2013 High

    Defined ubiquitin-dependent control of SMO surface levels through Smurf E3 ligases and the ESCRT-II component Vps36, linking phosphorylation state to SMO trafficking and degradation.

    Evidence Drosophila genetics, ubiquitylation assays, co-IP, phospho-site mutagenesis

    PMID:23843610 PMID:29438012

    Open questions at the time
    • Mammalian conservation of Smurf/Vps36 regulation of SMO untested
    • Ubiquitin chain types directing trafficking vs degradation not distinguished
  10. 2014 High

    Established L412F as a constitutively activating SMO mutation driving Hedgehog-dependent tumors and pharmacologically targetable by arsenic trioxide.

    Evidence Reporter assays with mutant SMO, ATO inhibition in ameloblastoma cells

    PMID:24859340

    Open questions at the time
    • Structural basis of L412F constitutive activation not resolved here
    • ATO mechanism of inhibition not defined
  11. 2014 Low

    Defined the basis of vismodegib resistance, attributing it to mutations that alter drug-binding-site geometry rather than pathway rewiring.

    Evidence Clinical sequencing of pre/post-treatment BCC, in silico molecular modeling

    PMID:25306392

    Open questions at the time
    • In silico only — no in vitro reconstitution or mutagenesis functional assay
    • Predicted conformational effects not biochemically validated
  12. 2014 Medium

    Showed Ptch2 acts as a functional Shh receptor controlling SMO localization, expanding the receptor input regulating SMO beyond Ptch1.

    Evidence In vitro SMO localization assay, Ptch1/Ptch2 double-mutant mouse epistasis

    PMID:25448692

    Open questions at the time
    • Relative contribution of Ptch1 vs Ptch2 to SMO regulation in different tissues unclear
    • Single lab
  13. 2016 Medium

    Linked the recurrent mosaic L412F activating substitution to a defined human developmental disorder, Curry-Jones syndrome, unifying its tumor and germline phenotypes.

    Evidence Targeted/Sanger sequencing for mosaicism across tissues with cross-reference to functional tumor data

    PMID:27236920

    Open questions at the time
    • No new in vitro reconstitution in this study
    • Mechanism of mosaic-stage-dependent phenotype not addressed
  14. 2017 Medium

    Identified Arl13b as a SMO-binding GTPase controlling SMO stability and ciliary localization in a cancer context.

    Evidence Co-IP (Arl13b–Smo), stability and trafficking assays in gastric cancer cells

    PMID:28611043

    Open questions at the time
    • Whether Arl13b–SMO regulation is general or cancer-specific unknown
    • Single lab
  15. 2018 High

    Established TMED2 as an ER/Golgi retention factor that limits SMO surface delivery, defining a pre-ciliary checkpoint on signal strength.

    Evidence Haploid ESC genetic screen, TMED2–SMO co-IP, super-resolution microscopy, neural differentiation assay

    PMID:35353806

    Open questions at the time
    • How Hh stimulation overcomes TMED2 retention not defined
    • Relationship to Patched-mediated inhibition unclear
  16. 2018 Medium

    Revealed a non-canonical nuclear SMO that activates GLI1 in a manner refractory to SMO antagonists, defining a drug-resistant signaling mode.

    Evidence siRNA silencing, SMO inhibition, N(o)LS mutagenesis, immunofluorescence in BCC

    PMID:29463581

    Open questions at the time
    • Mechanism of SMO nuclear import and GLI1 activation not biochemically defined
    • Single lab
  17. 2018 Medium

    Showed SMO transcription is directly activated by the Wnt/β-catenin–TCF4 complex, providing cross-talk input that sets SMO expression levels.

    Evidence ChIP, yeast one-hybrid, β-catenin/TCF4 overexpression and siRNA, RT-qPCR

    PMID:30186446

    Open questions at the time
    • Physiological contexts where Wnt drives SMO not established
    • Single lab
  18. 2019 Medium

    Identified HERC4 as an E3 ligase that destabilizes the SMO oncoprotein, adding a degradation arm restraining SMO levels in lung cancer.

    Evidence Drosophila modifier screen, reciprocal HERC4–Smo co-IP, degradation assays

    PMID:31010679

    Open questions at the time
    • HERC4 ubiquitylation sites on SMO not mapped
    • Single lab
  19. 2020 High

    Demonstrated that bi-allelic loss-of-function SMO variants cause human developmental anomalies and that SMO regulates basal GLI2 ciliary trafficking even when the pathway is off.

    Evidence Human genetics in 7 individuals, patient-derived cell functional assays, immunofluorescence

    PMID:32413283

    Open questions at the time
    • Whether trafficking vs downstream-activation defects dominate per variant not fully resolved
    • Basal GLI2 trafficking mechanism not detailed
  20. 2021 Medium

    Placed SMO downstream of CD47–SIRPα in macrophages, extending SMO signaling into innate immune/inflammatory regulation via Gli1–NICD interaction.

    Evidence Myeloid-specific SMO deletion, ischemia/reperfusion model, Gli1–NICD co-IP, NLRP3 assays

    PMID:33765345

    Open questions at the time
    • Direct SMO partner linking CD47 to SMO not identified
    • Single lab
  21. 2022 Medium

    Connected SMO to Hippo signaling through a SMO–LATS1 interaction regulated by FGF18, implicating SMO in fibrosis via YAP control.

    Evidence SMO–LATS1 co-IP, FGF18 manipulation in vivo, CCl4 fibrosis model

    PMID:35202822

    Open questions at the time
    • Mechanism by which SMO modulates LATS1 activity unknown
    • Single lab
  22. 2022 Medium

    Showed SMO expression is post-transcriptionally controlled by ALYREF-mediated m5C-dependent mRNA export, adding an RNA-level layer to SMO regulation in myogenesis.

    Evidence RNA bisulfite sequencing, ALYREF binding, nuclear/cytoplasmic fractionation, differentiation assays

    PMID:35962235

    Open questions at the time
    • Generality beyond myogenic/adipogenic balance untested
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse phosphorylation, ubiquitylation, trafficking, and non-canonical inputs are integrated into a single conformational switch in the mammalian ciliary SMO remains unresolved.
  • No unified structural model connecting C-tail phosphorylation to active conformation in mammals
  • Mechanistic link between canonical ciliary SMO and non-canonical nuclear/IGF-IR/Hippo functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005929 cilium 3 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-9609507 Protein localization 2
Partners
ARL13BEVC2HERC4IGF1RLATS1PTCH1PTCH2TMED2
Complex memberships
Evc/Evc2 complexFused–Costal2 complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Localization of Smo to primary cilia is required for Hedgehog signal transduction; loss of the retrograde IFT motor (Dnchc2) disrupts Smo ciliary localization and prevents both Gli activator and repressor function, as well as effective proteolytic processing of Gli3. Mouse genetics (retrograde IFT motor mutants), immunofluorescence localization of Smo to primary cilia, Gli3 processing assay Developmental biology High 16229832
2006 Fused (Fu) and Costal2 (Cos2) form a complex that regulates Smo phosphorylation and cell-surface accumulation in Drosophila: Cos2 binds Smo C-terminal domain to block Hh-induced phosphorylation, while Fu phosphorylates Cos2 at Ser572 to attenuate Cos2–Smo interaction and promote Smo surface accumulation. Drosophila genetics (fu mutant clones, dominant-negative Fu), co-immunoprecipitation, epistasis analysis, phosphorylation mapping Genes & development High 17671093
2008 PP4 phosphatase counteracts kinase-mediated phosphorylation of Smo in Drosophila: RNAi knockdown of PP4 elevates Smo phosphorylation and accumulation, increasing Hh signaling; deletion of a PP4-interaction domain (aa 626–678) in Smo promotes Smo phosphorylation and signaling; Hh downregulates the Smo–PP4 interaction, which is mediated by Cos2. In vivo RNAi screen in Drosophila, domain-deletion mutagenesis, co-immunoprecipitation, Hh pathway activity assays Development (Cambridge, England) High 19088085
2010 GRK2 (Gprk2) promotes high-level Hedgehog signaling in Drosophila by phosphorylating Smo C-tail at Ser741/Thr742, facilitated by prior PKA and CK1 phosphorylation; additionally, Gprk2 dimerizes/oligomerizes and binds Smo C-tail in a kinase-independent manner to stabilize the active Smo conformation, forming a positive feedback loop downstream of PKA and CK1. Drosophila genetics, phosphorylation-site mutagenesis, co-immunoprecipitation, kinase-dead constructs, epistasis analysis Genes & development High 20844016
2012 The Evc/Evc2 complex co-precipitates with Smo and is required for Hh signaling downstream of Smo ciliary translocation in chondrocytes: Smo translocation to the cilium is normal in Evc2-deficient cells after SAG treatment, but Gli3 recruitment to cilia tips and Sufu/Gli3 dissociation are impaired, and Evc silencing in Sufu−/− cells attenuates Hh output. Mouse genetic models, co-immunoprecipitation (Smo–Evc/Evc2), immunofluorescence (ciliary localization), Sufu−/− epistasis Human molecular genetics High 23026747
2013 Smurf family E3 ubiquitin ligases ubiquitylate Smo and mediate its cell-surface clearance in Drosophila; GRK2-mediated phosphorylation of Smurf promotes Smo ubiquitylation by recruiting Smurf to Smo, whereas PKA-mediated phosphorylation of Smo causes Smurf to dissociate, inhibiting ubiquitylation; Smo and Ptc compete for the same Smurf pool, so Hh promotes Ptc ubiquitylation/degradation by displacing Smurf from Smo. Drosophila genetics, co-immunoprecipitation, ubiquitylation assays, phosphorylation-site mutagenesis, epistasis Science signaling High 29438012
2013 The ESCRT-II component Vps36 regulates Smo trafficking between cytosol and plasma membrane by recognizing ubiquitin on Smo in the absence of Hh; Smo is ubiquitylated on its cytoplasmic loops and C-tail in the Hh-off state. Drosophila genetics, co-immunoprecipitation, ubiquitylation assays, plasma membrane accumulation assays Journal of cell science High 23843610
2014 Ptch2 functions as a functional Shh receptor that regulates Smo localization and activity in vitro, sharing overlapping function with Ptch1; loss of Ptch2 exacerbates limb outgrowth defects in Ptch1 limb-specific knockouts in vivo. In vitro Smo localization assay, mouse genetic epistasis (Ptch1/Ptch2 double mutants), limb bud phenotype analysis Developmental biology Medium 25448692
2014 The SMO L412F mutation is an activating mutation that constitutively activates Hedgehog pathway signaling and its effect can be inhibited by arsenic trioxide (ATO). Functional reporter assay for Hedgehog pathway activity with mutant SMO constructs, ATO inhibition in ameloblastoma cells Nature genetics High 24859340
2016 Recurrent somatic mosaic SMO c.1234C>T (p.Leu412Phe) substitution constitutively activates SMO in the absence of Hh signaling and causes Curry-Jones syndrome; the same mutation is the most common activating SMO mutation found in medulloblastoma, ameloblastoma, and BCC. Targeted sequencing/Sanger sequencing across multiple tissues for mosaicism, cross-referencing with functional activation data from tumor studies American journal of human genetics Medium 27236920
2017 Arl13b, a small GTPase, binds Smo and regulates its stability, trafficking, and ciliary localization, which are required for Hedgehog signaling activation in gastric cancer cells. Co-immunoprecipitation (Arl13b–Smo), protein stability assays, Smo trafficking/localization assays, in vitro and in vivo functional assays Cancer research Medium 28611043
2018 TMED2 binds to SMO and retains it in the ER and Golgi compartments, preventing SMO localization to the plasma membrane; mutation of TMED2 allows SMO accumulation at the plasma membrane, recapitulating early events of HH stimulation; TMED2 functions to repress HH signal strength during neural differentiation. Genetic screen in haploid ESCs, co-immunoprecipitation (TMED2–SMO), super-resolution microscopy (ER/Golgi localization), TMED2 mutant functional analysis, neural differentiation assay PLoS biology High 35353806
2018 In PTCH1-silenced keratinocytes, SMO localizes to the nucleus via a putative nuclear/nucleolar localization signal (N(o)LS), and this nuclear SMO activates GLI1 through a mechanism that is unresponsive to pharmacological SMO inhibitors; mutational inactivation of the N(o)LS ablates nuclear SMO localization and suppresses GLI1 induction. siRNA silencing, pharmacological SMO inhibition, immunofluorescence/immunohistochemistry (nuclear SMO), N(o)LS mutagenesis, gene expression analysis Cancer research Medium 29463581
2019 HERC4 E3 ubiquitin ligase binds Smo, promotes its degradation, and destabilizes the Smo oncoprotein; depletion of HERC4 increases Smo protein levels and activates Hh pathway in non-small cell lung cancer cells. Drosophila modifier screen (dHerc4/dSmo), reciprocal co-immunoprecipitation (HERC4–Smo in NSCLC), protein stability/degradation assays, Hh pathway activity readout Biochemical and biophysical research communications Medium 31010679
2020 Bi-allelic loss-of-function variants in SMO in humans cause developmental anomalies (hypothalamic hamartoma, heart defects, polydactyly, aganglionosis); patient-derived cells show normal ciliogenesis but severely altered Hh signal transduction due to either altered primary cilium trafficking or abnormal downstream activation; SMO also regulates basal ciliary trafficking of GLI2 when the pathway is off. Human genetics (bi-allelic SMO variants in 7 individuals), patient-derived cell functional assays (ciliogenesis, Hh signaling, PC trafficking of SMO/GLI2), immunofluorescence American journal of human genetics High 32413283
2010 SMO-mediated Hedgehog signaling requires TGFβ2 as a downstream effector: activated SMO (SmoM2) upregulates TGFβ2 in keratinocytes with activated TGFβ signaling (elevated pSMAD2/3) in both tumor and stroma; TGFβ receptor I inhibitor significantly reduces tumor area in K14cre/R26SmoM2 mice. Transgenic mouse model (K14cre/R26SmoM2), gene expression analysis (TGFβ2 as Hh-regulated gene), pharmacological inhibition of TGFβ receptor I (SD208), histology The Journal of biological chemistry Medium 20858897
2012 Smo activity is required for IGF-I-induced PI3K/Akt signaling in myoblasts: cyclopamine reduces IGF-I-induced Akt phosphorylation, Smo-conditional knockout myoblasts show markedly reduced IGF-I-induced Akt and MAPK phosphorylation, and immunoprecipitation reveals that tyrosine-phosphorylated proteins including the PI3K regulatory subunit p85 and IGF-IR associate with Smo in response to Shh and IGF-I. Smo conditional knockout mice (MCre;Smo flox/flox), cyclopamine inhibition, co-immunoprecipitation (Smo–p85–IGF-IR), phospho-western blots Journal of cellular physiology Medium 21618536
2021 CD47–SIRPα interaction activates Hedgehog/SMO/Gli1 signaling in macrophages; disruption of myeloid SMO increases liver inflammation with diminished Gli1; Gli1 interacts with Notch intracellular domain (NICD) and regulates target gene Dvl2 to inhibit NEK7/NLRP3 activity. Mouse ischemia/reperfusion model, myeloid-specific SMO deletion, MSC/macrophage co-culture, Co-IP (Gli1–NICD), nuclear translocation assays, NLRP3 activity measurement Hepatology (Baltimore, Md.) Medium 33765345
2022 mRNA m5C modification of SMO mRNA is recognized by ALYREF, which exports SMO mRNA from nucleus to cytoplasm, increasing SMO protein expression and promoting myogenesis; this ALYREF-m5C-SMO mechanism regulates the balance between adipogenesis and myogenesis. RNA bisulfite sequencing (m5C profiling), ALYREF binding assays, nuclear/cytoplasmic fractionation, SMO protein expression analysis, in vitro adipogenesis/myogenesis assays Cellular and molecular life sciences : CMLS Medium 35962235
2018 The Wnt3a-activated β-catenin/TCF4 complex directly binds to the SMO promoter (two binding sites within 1.5 kb) and transcriptionally activates SMO expression; siRNA knockdown of β-catenin reduces SMO mRNA even under Wnt3a treatment. Chromatin immunoprecipitation (TCF4 binding to Smo promoter), yeast one-hybrid assay, TCF4/β-catenin overexpression and siRNA knockdown, RT-qPCR, western blot Experimental and therapeutic medicine Medium 30186446
2014 SMO D473Y and G497W mutations confer resistance to vismodegib in BCC by distinct mechanisms: in silico modeling shows G497W causes partial obstruction of the drug entry site (conformational rearrangement), while D473Y disrupts a stabilizing hydrogen bond network at the binding site geometry. Clinical sequencing of pre/post-treatment BCC specimens, in silico molecular modeling (conformational and hydrogen bond analysis) Molecular oncology Low 25306392
2011 Hypoxia activates Hedgehog signaling in pancreatic cancer in a ligand-independent manner by upregulating Smo transcription; silencing Smo (but not silencing Shh) decreases Gli1 and MMP9 transcription and reduces PDAC invasiveness. siRNA knockdown of Smo (vs Shh), qRT-PCR, invasion assays in hypoxic vs normoxic conditions Cancer science Medium 21338440
2022 FGF18 attenuates liver fibrosis by suppressing SMO expression, and the interaction between SMO and LATS1 is crucial for FGF18-induced protective effects via the SMO–LATS1–YAP Hippo signaling axis. Co-immunoprecipitation (SMO–LATS1), FGF18 overexpression/HSC-specific deletion in vivo, western blot (SMO, pLATS1, YAP), CCl4 fibrosis model Pharmacological research Medium 35202822

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.) 721 23348505
2006 Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development (Cambridge, England) 387 16339192
2005 Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Developmental biology 346 16229832
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 269 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
2021 A novel protein encoded by circular SMO RNA is essential for Hedgehog signaling activation and glioblastoma tumorigenicity. Genome biology 138 33446260
2015 RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. Cancer research 137 26130651
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 126 30374069
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 105 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 101 26124204
2016 In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors. Oncotarget 99 26843616
2006 Hedgehog signalling: how to get from Smo to Ci and Gli. Trends in cell biology 99 16516476
2012 The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia. Human molecular genetics 94 23026747
2008 Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo). Breast cancer research and treatment 92 18563554
2010 G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila. Genes & development 85 20844016
2017 SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. Neuro-oncology 84 28082415
2011 Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer. Cancer science 84 21338440
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 72 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 70 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 66 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
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
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
1997 Patched (ptch)-associated preferential expression of smoothened (smoh) in human basal cell carcinoma of the skin. Cancer research 50 9354432
2021 CD47-Mediated Hedgehog/SMO/GLI1 Signaling Promotes Mesenchymal Stem Cell Immunomodulation in Mouse Liver Inflammation. Hepatology (Baltimore, Md.) 47 33765345
2012 Cooperation between Shh and IGF-I in promoting myogenic proliferation and differentiation via the MAPK/ERK and PI3K/Akt pathways requires Smo activity. Journal of cellular physiology 46 21618536
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
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 45 33906504
2010 Spermine oxidase (SMO) activity in breast tumor tissues and biochemical analysis of the anticancer spermine analogues BENSpm and CPENSpm. BMC cancer 44 20946629
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 42 27694322
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 36 35962235
2023 The role of Smo-Shh/Gli signaling activation in the prevention of neurological and ageing disorders. Biogerontology 35 37097427
2017 Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway. Cancer research 35 28611043
2019 Glesatinib, a c-MET/SMO Dual Inhibitor, Antagonizes P-glycoprotein Mediated Multidrug Resistance in Cancer Cells. Frontiers in oncology 34 31106148
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
2022 Smo-Shh Agonist Purmorphamine Prevents Neurobehavioral and Neurochemical Defects in 8-OH-DPAT-Induced Experimental Model of Obsessive-Compulsive Disorder. Brain sciences 33 35326298
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
2019 Circular RNA SMO sponges miR-338-3p to promote the growth of glioma by enhancing the expression of SMO. Aging 32 31895689
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
2013 Mutations in the hedgehog pathway genes SMO and PTCH1 in human gastric tumors. PloS one 31 23349881
2019 Intraventricular meningiomas frequently harbor NF2 mutations but lack common genetic alterations in TRAF7, AKT1, SMO, KLF4, PIK3CA, and TERT. Acta neuropathologica communications 30 31470906
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
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 29 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
2022 Fibroblast growth factor 18 attenuates liver fibrosis and HSCs activation via the SMO-LATS1-YAP pathway. Pharmacological research 27 35202822
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
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 20 38572590
2023 Enhancement of biochemical and genomic pathways through lycopene-loaded nano-liposomes: Alleviating insulin resistance, hepatic steatosis, and autophagy in obese rats with non-alcoholic fatty liver disease: Involvement of SMO, GLI-1, and PTCH-1 genes. Gene 20 37516284
2006 Antisense Smo under the control of the PTCH1 promoter delivered by an adenoviral vector inhibits the growth of human pancreatic cancer. Gene therapy 20 16826192
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 18 20842126
2018 Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts. Clinical oral investigations 17 29564556
2018 Overcoming the emerging drug resistance of smoothened: an overview of small-molecule SMO antagonists with antiresistance activity. Future medicinal chemistry 17 30557039
2019 HERC4 exerts an anti-tumor role through destabilizing the oncoprotein Smo. Biochemical and biophysical research communications 16 31010679
2006 Mutation in exon 7 of PTCH deregulates SHH/PTCH/SMO signaling: possible linkage to WNT. International journal of molecular medicine 16 16596257
2006 Aberrant expression of PTCH (patched gene) and Smo (smoothened gene) in human pancreatic cancerous tissues and its association with hyperglycemia. Pancreas 16 16804411
2022 TMED2 binding restricts SMO to the ER and Golgi compartments. PLoS biology 15 35353806
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
2018 Triazoles bind the C-terminal domain of SMO: Illustration by docking and molecular dynamics simulations the binding between SMO and triazoles. Life sciences 15 30543826
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
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
2023 Purmorphamine, a Smo-Shh/Gli Activator, Promotes Sonic Hedgehog-Mediated Neurogenesis and Restores Behavioural and Neurochemical Deficits in Experimental Model of Multiple Sclerosis. Neurochemical research 13 38160216
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

Missed literature

Know a paper Affinage missed for SMO? Flag it for the maintainers and the community.

No submissions yet.