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FLASH GENE
Symbol SMO contributors: mct/pgu - updated : 28-08-2020
HGNC name smoothened homolog (Drosophila)
HGNC id 11119
Corresponding disease
CJS Curry-Jones syndrome
PHLS
Location 7q32.1      Physical location : 128.828.712 - 128.853.383
Synonym name
  • smoothened
  • seven transmembrane helix receptor
  • Gx protein
  • frizzled family member 11
  • seven transmembrane helix receptor
  • Synonym symbol(s) SMOH, Gx, FZD11
    DNA
    TYPE functioning gene
    STRUCTURE 24.67 kb     12 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 - 3772 86.2 787 - 1998 9628830
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Hearing/Equilibriumearinnercochlea highly
    Nervousbrainlimbic systemhippocampus   Rattus norvegicusFetal
     brainlimbic systemhippocampus   Rattus norvegicusAdult
     brainhindbraincerebellum highly Rattus norvegicusAdult
     brainhindbraincerebellum   Rattus norvegicusFetal
    Reproductivefemale systemovary  highly
     female systembreastmammary gland  
     male systemtestis    Homo sapiens
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow   
    Connectivebone   
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron Rattus norvegicus
    NervousPurkinje cell Rattus norvegicus
    Reproductivespermatocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • seven transmembrane segments spanning protein
  • one frizzled (FZ) domain
  • two extracellular loops EC1 and EC2, playing a regulatory role in control of Hedgehog pathway activation
  • Smo auto-inhibitory domain (SAID domain, Smo C-tail amino acids 661–818) contains several arginine motifs, which can block the phosphorylation of their adjacent target sites
  • secondary structure heptahelical structure required for binding of cyclopamine that is the target for ortho- and allosteric G protein–coupled receptor (GPCR) modulators
    HOMOLOGY
    interspecies homolog to Drosophila segment polarity gene Smoothened
    homolog to rattus Smo (93.6pc)
    homolog to murine Smo (93.4pc)
    Homologene
    FAMILY
  • G-protein coupled receptor Fz/Smo family
  • class F family of G-protein coupled receptors
  • CATEGORY regulatory , protooncogene , receptor membrane G
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule
    basic FUNCTION
  • positive regulator of HH signaling pathway
  • G protein-coupled receptor probably associated with the patched protein (PTCH) to transduce the hedgehog's proteins signal
  • involved in the primary cilium
  • serpentine receptor
  • PTCH1 and SMO are present in the processes and growth cones of immature neurons
  • as a membrane protein of HH pathway central components, SMO plays a crucial role in transducing the HH signal across the cell plasma membrane
  • SMO is likely ubiquitylated in the absence of HH, and then recognized by VPS36 for its trafficking and endocytosis
  • is the essential transducer of Sonic hedgehog (Shh) signaling, which regulates cell fate and proliferation during embryogenesis
  • likely the highest levels of vertebrate Hedgehog signaling activity require efficient SMO ciliary enrichment
  • encodes a G protein-coupled receptor that functions in Hedgehog signal transduction, an essential step during eye development
  • contribute to the maintenance of healthy ocular development
  • potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development
    text regulating of left-right (L/R) asymetry
    PATHWAY
    metabolism
    signaling signal transduction
  • SHH signaling pathway
  • SMO signaling, acting through CCND2, is critical for the proper development and maturation of the neocortex
  • a component
  • critical component of the Hedgehog (Hh) signaling pathway
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting normally with PTCH
  • activating GLI1
  • interaction with KIF3A is mediated by beta-arrestins
  • Sertoli cells coordinate DHH-dependent spermatogenesis events via PTCH1 and SMO prior to the first meiotic division and in postmeiotic (haploid) cells, particularly during the first half of spermiogenesis
  • USP8 interacting with SMO (overexpression of USP8 prevents SMO ubiquitination and elevates SMO accumulation, leading to increased HH signaling activity)
  • EVC/EVC2 complex interacts with SMO and is required for signal transduction events
  • SMO activates trimeric G proteins and CARD11-associated signaling complex, leading to NFKB1 activation, contributing to the survival of DLBCL
  • ESCRT-II complex, especially VPS36, has a special role in controlling HH signaling by targeting the membrane protein SMO for its trafficking in the absence of HH, thereby regulating HH signaling activity
  • in the absence of HH, VPS36 interacts with ubiquitylated SMO, thereby negatively regulating the accumulation of SMO on plasma membrane
  • interaction between SMO and VPS36 is mediated by the VPS36 GLUE domain, and regulated by the HH signal and SMO C-tail phosphorylation
  • bifurcation of SMO activity in HH response, with a DLG5-independent arm for suppression of GLI repressor formation and a second arm involving SMO interaction with DLG5 for GLI activation
  • activated NOTCH1 leads to pronounced accumulation of SMO within primary cilia and elevated levels of full-length GLI3
  • DYRK1B is a critical positive regulator of HH/GLI signaling downstream of SMO
  • PTCH1/PTCH2 mediate likely secretion of a SMO-inhibitory cholesterol precursor
  • SUMO pathway promotes HH signaling by regulating SMO subcellular localization , suggesting on how sumoylation regulates membrane protein trafficking
  • HH reciprocally controls trafficking of SMO and PTC through the SMURF family of E3 ubiquitin ligases
  • HERC4 acts as a tumor suppressor via destabilizing the oncoprotein Smo
  • inactivation of PTCH1 by HH likely allows a transmembrane sterol to access this seven-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO
  • cell & other
    REGULATION
    activated by after loss of PTCH1 function
    Other targetting numerous genes, HOX, BMP
    multi-monoubiquitinated and its ubiquitination is inhibited by HH and by phosphorylation
    ASSOCIATED DISORDERS
    corresponding disease(s) CJS , PHLS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    in basal cell carcinoma (BCC) of the skin
    tumoral       gain of function
    by somatic mutation in sporadic nevoid basal cell carcinoma syndrome (NBCCS) and primitive neuroectodermal tumors genes (HOX,BMP..)
    tumoral        
    loss of SMO impairs haematopoietic stem cell renewal and decreases induction of chronic myelogenous leukemia by the BCR-ABL1 oncoprotein
    tumoral     --other  
    constitutively active SMO augments CML stem cells and accelerate disease
    tumoral somatic mutation      
    in meningiomas
    tumoral     --over  
    is a mechanism for the activation of Hedgehog signaling in human pancreatic cancer-associated stromal fibroblasts
    tumoral     --low  
    by promoter methylation in colorectal cancer patients
    constitutional germinal mutation      
    in a patient with both anterior segment dysgenesis (congenital corneal opacity, cataract) and morning glory syndrome
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerdigestivepancreas
    stromal cells may be a therapeutic target for SMO antagonists in pancreatic cancer
    cancerbrain 
    acquired mutations in SMO can serve as a mechanism of drug resistance in human cancer (in medulloblastoma)
    cancerbone 
    inactivation of SMO may be a useful approach to the treatment of patients with osteosarcoma
    ANIMAL & CELL MODELS
    Smo-/-mutant have developmental defects with failure to turn,arresting at stages with a small heart tube,an open gut and cyclopia