Human Gene SHH (R17645) Description and Page Index
  Description: sonic hedgehog preproprotein
RefSeq Summary (NM_000193): This gene encodes a protein that is instrumental in patterning the early embryo. It has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. Of three human proteins showing sequence and functional similarity to the sonic hedgehog protein of Drosophila, this protein is the most similar. The protein is made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the developing embryo. Defects in this protein or in its signalling pathway are a cause of holoprosencephaly (HPE), a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres. HPE is manifested by facial deformities. It is also thought that mutations in this gene or in its signalling pathway may be responsible for VACTERL syndrome, which is characterized by vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia, cardiac anomalies, and limb abnormalities. Additionally, mutations in a long range enhancer located approximately 1 megabase upstream of this gene disrupt limb patterning and can result in preaxial polydactyly. [provided by RefSeq, Jul 2008].
Transcript (Including UTRs)
   Position: hg17 chr7:155,095,034-155,104,443 Size: 9,410 Total Exon Count: 3 Strand: -
Coding Region
   Position: hg17 chr7:155,095,070-155,104,292 Size: 9,223 Coding Exon Count: 3 

Page IndexSequence and LinksUniProtKB CommentsCTDMicroarray ExpressionRNA Structure
Protein StructureOther SpeciesGO AnnotationsmRNA DescriptionsPathwaysOther Names
Methods
Data last updated: 2005-06-03

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr7:155,095,034-155,104,443)mRNA (may differ from genome)Protein (462 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
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PubMedReactomeStanford SOURCEUniProtKB

-  Comments and Description Text from UniProtKB
  ID: SHH_HUMAN
DESCRIPTION: RecName: Full=Sonic hedgehog protein; Short=SHH; AltName: Full=HHG-1; Contains: RecName: Full=Sonic hedgehog protein N-product; Contains: RecName: Full=Sonic hedgehog protein C-product; Flags: Precursor;
FUNCTION: Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTC represses the constitutive signaling activity of SMO. Also regulates another target, the gli oncogene. Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction (By similarity).
SUBUNIT: Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH N-terminus. N-product is active as a multimer (By similarity).
SUBCELLULAR LOCATION: Sonic hedgehog protein C-product: Secreted, extracellular space (By similarity). Note=The C-terminal peptide diffuses from the cell (By similarity).
SUBCELLULAR LOCATION: Sonic hedgehog protein N-product: Cell membrane; Lipid-anchor (By similarity). Note=The N-product either remains associated with lipid rafts at the cell surface, or forms freely diffusible active multimers with its hydrophobic lipid- modified N- and C-termini buried inside (By similarity).
TISSUE SPECIFICITY: Expressed in fetal intestine, liver, lung, and kidney. Not expressed in adult tissues.
PTM: The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N- terminal fragment (N-product). The N-product is the active species in both local and long-range signaling, whereas the C-product has no signaling activity.
PTM: Cholesterylation is required for N-product targeting to lipid rafts and multimerization (By similarity).
PTM: N-palmitoylation of Cys-24 by HHAT is required for N-product multimerization and full activity (By similarity).
MASS SPECTROMETRY: Mass=19.560; Method=Electrospray; Range=24-197; Note=Soluble N-product, purified from insect cells; Source=PubMed:9593755;
MASS SPECTROMETRY: Mass=20.167; Method=Electrospray; Range=24-197; Note=Membrane-bound N-product, purified from insect cells; Source=PubMed:9593755;
DISEASE: Defects in SHH are the cause of microphthalmia isolated with coloboma type 5 (MCOPCB5) [MIM:611638]. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, cataract and other abnormalities like cataract may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure).
DISEASE: Defects in SHH are the cause of holoprosencephaly type 3 (HPE3) [MIM:142945]. Holoprosencephaly (HPE) [MIM:236100] is the most common structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of HPE3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. Interestingly, up to 30% of obligate carriers of HPE3 gene in autosomal dominant pedigrees are clinically unaffected.
DISEASE: Defects in SHH are a cause of solitary median maxillary central incisor (SMMCI) [MIM:147250]. SMMCI is a rare dental anomaly characterized by the congenital absence of one maxillary central incisor.
DISEASE: Defects in SHH are the cause of triphalangeal thumb- polysyndactyly syndrome (TPTPS) [MIM:174500]. TPTPS is an autosomal dominant syndrome characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. TPTPS mutations have been mapped to the 7q36 locus in the LMBR1 gene which contains in its intron 5 a long-range cis-regulatory element of SHH expression.
SIMILARITY: Belongs to the hedgehog family.
WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/SHHID378.html";
WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SHH";
WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/shh/";

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  Microarray Expression Data
 
Expression ratio colors:

GNF Expression Atlas 2 Data from U133A and GNF1H Chips

      
      
      
     
    
     
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-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -53.10151-0.352 Picture PostScript Text
3' UTR -9.5036-0.264 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR001657 - Hedgehog
IPR009045 - Hedgehog_sig/DD-Pept_Zn-bd_dom
IPR000320 - Hedgehog_signaling_dom
IPR001767 - Hint_dom
IPR003586 - Hint_dom_C
IPR003587 - Hint_dom_N
IPR006141 - Intein_splice_site

Pfam Domains:
PF01085 - Hedgehog amino-terminal signalling domain
PF01079 - Hint module

Protein Data Bank (PDB) 3-D Structure
MuPIT help

3HO5
- X-ray

3M1N
- X-ray

3MXW
- X-ray


ModBase Predicted Comparative 3D Structure on Q15465
FrontTopSide
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserNo orthologNo orthologGenome BrowserGenome BrowserNo ortholog
Gene DetailsGene Details Gene DetailsGene Details 
Gene SorterGene Sorter Gene SorterGene Sorter 
MGIRGDEnsemblFlyBaseWormBase 
Protein Sequence  Protein SequenceProtein Sequence 
Alignment  AlignmentAlignment 

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0005113 patched binding
GO:0005509 calcium ion binding
GO:0005515 protein binding
GO:0005539 glycosaminoglycan binding
GO:0008233 peptidase activity
GO:0008270 zinc ion binding
GO:0016015 morphogen activity
GO:0016787 hydrolase activity
GO:0043237 laminin-1 binding
GO:0046872 metal ion binding

Biological Process:
GO:0000122 negative regulation of transcription from RNA polymerase II promoter
GO:0001525 angiogenesis
GO:0001569 branching involved in blood vessel morphogenesis
GO:0001570 vasculogenesis
GO:0001656 metanephros development
GO:0001658 branching involved in ureteric bud morphogenesis
GO:0001708 cell fate specification
GO:0001755 neural crest cell migration
GO:0001822 kidney development
GO:0001942 hair follicle development
GO:0001944 vasculature development
GO:0001947 heart looping
GO:0002052 positive regulation of neuroblast proliferation
GO:0002053 positive regulation of mesenchymal cell proliferation
GO:0002076 osteoblast development
GO:0002320 lymphoid progenitor cell differentiation
GO:0003140 determination of left/right asymmetry in lateral mesoderm
GO:0006355 regulation of transcription, DNA-templated
GO:0006508 proteolysis
GO:0006897 endocytosis
GO:0007224 smoothened signaling pathway
GO:0007228 positive regulation of hh target transcription factor activity
GO:0007267 cell-cell signaling
GO:0007275 multicellular organism development
GO:0007368 determination of left/right symmetry
GO:0007389 pattern specification process
GO:0007398 ectoderm development
GO:0007405 neuroblast proliferation
GO:0007411 axon guidance
GO:0007417 central nervous system development
GO:0007418 ventral midline development
GO:0007442 hindgut morphogenesis
GO:0007507 heart development
GO:0007596 blood coagulation
GO:0008209 androgen metabolic process
GO:0008283 cell proliferation
GO:0008284 positive regulation of cell proliferation
GO:0009880 embryonic pattern specification
GO:0009949 polarity specification of anterior/posterior axis
GO:0009952 anterior/posterior pattern specification
GO:0009953 dorsal/ventral pattern formation
GO:0010463 mesenchymal cell proliferation
GO:0010468 regulation of gene expression
GO:0010469 regulation of receptor activity
GO:0010628 positive regulation of gene expression
GO:0010629 negative regulation of gene expression
GO:0014003 oligodendrocyte development
GO:0014706 striated muscle tissue development
GO:0014858 positive regulation of skeletal muscle cell proliferation
GO:0014902 myotube differentiation
GO:0016539 intein-mediated protein splicing
GO:0021513 spinal cord dorsal/ventral patterning
GO:0021522 spinal cord motor neuron differentiation
GO:0021794 thalamus development
GO:0021871 forebrain regionalization
GO:0021904 dorsal/ventral neural tube patterning
GO:0021924 cell proliferation in external granule layer
GO:0021930 cerebellar granule cell precursor proliferation
GO:0021938 smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation
GO:0021940 positive regulation of cerebellar granule cell precursor proliferation
GO:0021978 telencephalon regionalization
GO:0030010 establishment of cell polarity
GO:0030162 regulation of proteolysis
GO:0030177 positive regulation of Wnt signaling pathway
GO:0030178 negative regulation of Wnt signaling pathway
GO:0030323 respiratory tube development
GO:0030324 lung development
GO:0030326 embryonic limb morphogenesis
GO:0030336 negative regulation of cell migration
GO:0030539 male genitalia development
GO:0030850 prostate gland development
GO:0030878 thyroid gland development
GO:0030900 forebrain development
GO:0030901 midbrain development
GO:0030902 hindbrain development
GO:0031016 pancreas development
GO:0031069 hair follicle morphogenesis
GO:0032435 negative regulation of proteasomal ubiquitin-dependent protein catabolic process
GO:0033077 T cell differentiation in thymus
GO:0033089 positive regulation of T cell differentiation in thymus
GO:0033092 positive regulation of immature T cell proliferation in thymus
GO:0034244 negative regulation of transcription elongation from RNA polymerase II promoter
GO:0034504 protein localization to nucleus
GO:0035115 embryonic forelimb morphogenesis
GO:0035116 embryonic hindlimb morphogenesis
GO:0042127 regulation of cell proliferation
GO:0042130 negative regulation of T cell proliferation
GO:0042177 negative regulation of protein catabolic process
GO:0042307 positive regulation of protein import into nucleus
GO:0042475 odontogenesis of dentin-containing tooth
GO:0042476 odontogenesis
GO:0042481 regulation of odontogenesis
GO:0042733 embryonic digit morphogenesis
GO:0043010 camera-type eye development
GO:0043066 negative regulation of apoptotic process
GO:0043369 CD4-positive or CD8-positive, alpha-beta T cell lineage commitment
GO:0043588 skin development
GO:0045059 positive thymic T cell selection
GO:0045060 negative thymic T cell selection
GO:0045109 intermediate filament organization
GO:0045165 cell fate commitment
GO:0045445 myoblast differentiation
GO:0045596 negative regulation of cell differentiation
GO:0045597 positive regulation of cell differentiation
GO:0045880 positive regulation of smoothened signaling pathway
GO:0045893 positive regulation of transcription, DNA-templated
GO:0045944 positive regulation of transcription from RNA polymerase II promoter
GO:0046638 positive regulation of alpha-beta T cell differentiation
GO:0046639 negative regulation of alpha-beta T cell differentiation
GO:0048468 cell development
GO:0048538 thymus development
GO:0048546 digestive tract morphogenesis
GO:0048557 embryonic digestive tract morphogenesis
GO:0048568 embryonic organ development
GO:0048589 developmental growth
GO:0048598 embryonic morphogenesis
GO:0048617 embryonic foregut morphogenesis
GO:0048643 positive regulation of skeletal muscle tissue development
GO:0048645 animal organ formation
GO:0048646 anatomical structure formation involved in morphogenesis
GO:0048663 neuron fate commitment
GO:0048706 embryonic skeletal system development
GO:0048709 oligodendrocyte differentiation
GO:0048714 positive regulation of oligodendrocyte differentiation
GO:0048754 branching morphogenesis of an epithelial tube
GO:0048839 inner ear development
GO:0048856 anatomical structure development
GO:0048859 formation of anatomical boundary
GO:0048864 stem cell development
GO:0051146 striated muscle cell differentiation
GO:0051155 positive regulation of striated muscle cell differentiation
GO:0051781 positive regulation of cell division
GO:0060020 Bergmann glial cell differentiation
GO:0060021 palate development
GO:0060070 canonical Wnt signaling pathway
GO:0060173 limb development
GO:0060174 limb bud formation
GO:0060425 lung morphogenesis
GO:0060428 lung epithelium development
GO:0060438 trachea development
GO:0060439 trachea morphogenesis
GO:0060441 epithelial tube branching involved in lung morphogenesis
GO:0060442 branching involved in prostate gland morphogenesis
GO:0060445 branching involved in salivary gland morphogenesis
GO:0060447 bud outgrowth involved in lung branching
GO:0060458 right lung development
GO:0060459 left lung development
GO:0060463 lung lobe morphogenesis
GO:0060484 lung-associated mesenchyme development
GO:0060516 primary prostatic bud elongation
GO:0060523 prostate epithelial cord elongation
GO:0060662 salivary gland cavitation
GO:0060664 epithelial cell proliferation involved in salivary gland morphogenesis
GO:0060684 epithelial-mesenchymal cell signaling
GO:0060685 regulation of prostatic bud formation
GO:0060738 epithelial-mesenchymal signaling involved in prostate gland development
GO:0060768 regulation of epithelial cell proliferation involved in prostate gland development
GO:0060769 positive regulation of epithelial cell proliferation involved in prostate gland development
GO:0060782 regulation of mesenchymal cell proliferation involved in prostate gland development
GO:0060783 mesenchymal smoothened signaling pathway involved in prostate gland development
GO:0060840 artery development
GO:0060916 mesenchymal cell proliferation involved in lung development
GO:0061053 somite development
GO:0061189 positive regulation of sclerotome development
GO:0071285 cellular response to lithium ion
GO:0071542 dopaminergic neuron differentiation
GO:0072001 renal system development
GO:0072136 metanephric mesenchymal cell proliferation involved in metanephros development
GO:0090090 negative regulation of canonical Wnt signaling pathway
GO:0090370 negative regulation of cholesterol efflux
GO:0097190 apoptotic signaling pathway
GO:1900175 regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry
GO:1900180 regulation of protein localization to nucleus
GO:1904339 negative regulation of dopaminergic neuron differentiation
GO:1905327 tracheoesophageal septum formation
GO:2000062 negative regulation of ureter smooth muscle cell differentiation
GO:2000063 positive regulation of ureter smooth muscle cell differentiation
GO:2000357 negative regulation of kidney smooth muscle cell differentiation
GO:2000358 positive regulation of kidney smooth muscle cell differentiation
GO:2000729 positive regulation of mesenchymal cell proliferation involved in ureter development
GO:2001054 negative regulation of mesenchymal cell apoptotic process

Cellular Component:
GO:0005576 extracellular region
GO:0005615 extracellular space
GO:0005788 endoplasmic reticulum lumen
GO:0005829 cytosol
GO:0005886 plasma membrane
GO:0009986 cell surface
GO:0016020 membrane
GO:0045121 membrane raft


-  Descriptions from all associated GenBank mRNAs
  AY927455 - Homo sapiens mRNA sequence.
AY927454 - Homo sapiens mRNA sequence.
AY927452 - Homo sapiens mRNA sequence.
AY927453 - Homo sapiens mRNA sequence.
L38518 - Homo sapiens sonic hedgehog protein (SHH) mRNA, complete cds.
AB464234 - Synthetic construct DNA, clone: pF1KB7188, Homo sapiens SHH gene for sonic hedgehog homolog, without stop codon, in Flexi system.
BC111925 - Synthetic construct Homo sapiens clone IMAGE:40080739, MGC:133452 SHH protein (SHH) mRNA, encodes complete protein.
AY927450 - Homo sapiens mRNA sequence.
JD477918 - Sequence 458942 from Patent EP1572962.
JD336838 - Sequence 317862 from Patent EP1572962.
JD336358 - Sequence 317382 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04340 - Hedgehog signaling pathway
hsa05200 - Pathways in cancer
hsa05217 - Basal cell carcinoma

BioCarta from NCI Cancer Genome Anatomy Project
h_ptc1Pathway - Sonic Hedgehog (SHH) Receptor Ptc1 Regulates cell cycle
h_shhPathway - Sonic Hedgehog (Shh) Pathway

Reactome (by CSHL, EBI, and GO)

Protein Q15465 (Reactome details) participates in the following event(s):

R-NUL-5362406 mouse Disp2 binds SHH N-terminal fragment
R-HSA-5362437 C-terminal Hh fragments are bound by lectins
R-HSA-5358340 Autoproteolytic cleavage of Hh precursors
R-HSA-5358343 HHAT palmitoylates Hh N-terminal fragment
R-HSA-5362450 Hh processing variants bind lectins
R-HSA-5358336 P4HB forms mixed disulphides with Hh precursors
R-HSA-5362459 VCP-catalyzed ATP hydrolysis promotes the translocation of Hh-C into the cytosol
R-HSA-5362422 Hh-Np binds to DISP2
R-HSA-5362427 Hh-Np binds GPC5
R-HSA-5362793 Hh-Np is cleaved by ADAM17 to promote ligand shedding
R-HSA-445448 HHIP binds Hedgehog
R-HSA-5632649 Hh-Npp binds GAS1 and PTCH
R-HSA-5632652 Hh-Npp binds CDON and PTCH
R-HSA-5632653 Hh-Npp binds BOC:PTCH1
R-HSA-5387389 Hh processing variants are translocated to the cytosol in a VCP-dependent manner
R-HSA-5362551 Hh-Np binds SCUBE2 in the extracellular region to promote long-range signalling
R-HSA-5362553 NOTUM releases Hh-Np:GPC5 from the plasma membrane
R-HSA-5362441 C-terminal Hh fragments are recruited to SEL1:SYVN1 at the ER membrane
R-HSA-5387386 Hh processing variants are recruited to SEL1:SYVN at the ER membrane
R-HSA-5362412 SYVN1 ubiquitinates Hh C-terminal fragments
R-HSA-5483238 Hh processing variants are ubiquitinated
R-HSA-5358346 Hedgehog ligand biogenesis
R-HSA-5658034 HHAT G278V abrogates palmitoylation of Hh-Np
R-HSA-5362768 Hh mutants that don't undergo autocatalytic processing are degraded by ERAD
R-HSA-5362798 Release of Hh-Np from the secreting cell
R-HSA-5632681 Ligand-receptor interactions
R-HSA-5358351 Signaling by Hedgehog
R-HSA-5387390 Hh mutants abrogate ligand secretion
R-HSA-5632684 Hedgehog 'on' state
R-HSA-162582 Signal Transduction
R-HSA-5663202 Diseases of signal transduction
R-HSA-1643685 Disease

-  Other Names for This Gene
  Alternate Gene Symbols: HLP3, HPE3, L38518
UCSC ID: NM_000193
RefSeq Accession: NM_000193
Protein: Q15465 (aka SHH_HUMAN)
CCDS: CCDS5942.1

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.