SHH

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]

Sonic Hedgehog

Sonic hedgehog protein
The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity (By similarity).
Both activities result in the cleavage of the full-length protein into two parts (ShhN and ShhC) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated ShhN (By similarity).
Both activities occur in the reticulum endoplasmic (By similarity).
Once cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity).
Sonic hedgehog protein N-product
The dually lipidated sonic hedgehog protein N-product (ShhNp) is a morphogen which is essential for a variety of patterning events during development. Induces ventral cell fate in the neural tube and somites (PubMed:24863049).
Involved in the patterning of the anterior-posterior axis of the developing limb bud (By similarity).
Essential for axon guidance (By similarity).
Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes (PubMed:10753901).
In the absence of SHH, PTCH1 represses the constitutive signaling activity of SMO (PubMed:10753901).

Biological Process alpha-beta T cell differentiationIEA:Ensembl
Biological Process androgen metabolic processISS:UniProtKB
Biological Process animal organ formationIEA:Ensembl
Biological Process apoptotic signaling pathwayISS:UniProtKB
Biological Process artery developmentIEA:Ensembl
Biological Process axon guidanceISS:UniProtKB
Biological Process Bergmann glial cell differentiationIEA:Ensembl
Biological Process blood coagulationIEA:Ensembl
Biological Process branching involved in blood vessel morphogenesisISS:UniProtKB
Biological Process branching involved in salivary gland morphogenesisIEA:Ensembl
Biological Process branching involved in ureteric bud morphogenesisISS:UniProtKB
Biological Process branching morphogenesis of an epithelial tubeISS:UniProtKB
Biological Process bud outgrowth involved in lung branchingIEA:Ensembl
Biological Process camera-type eye developmentIEA:Ensembl
Biological Process canonical Wnt signaling pathwayIEA:Ensembl
Biological Process CD4-positive or CD8-positive, alpha-beta T cell lineage commitmentManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process cell developmentISS:UniProtKB
Biological Process cell fate specificationISS:UniProtKB
Biological Process cell-cell signalingISS:UniProtKB
Biological Process cellular response to lithium ionIEA:Ensembl
Biological Process central nervous system developmentISS:UniProtKB
Biological Process cerebellar granule cell precursor proliferationISS:UniProtKB
Biological Process determination of left/right asymmetry in lateral mesodermISS:BHF-UCL
Biological Process dopaminergic neuron differentiationManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Biological Process dorsal/ventral neural tube patterningIEA:Ensembl
Biological Process dorsal/ventral pattern formationISS:UniProtKB
Biological Process ectoderm developmentIEA:Ensembl
Biological Process embryonic digestive tract morphogenesisIEA:Ensembl
Biological Process embryonic digit morphogenesisISS:UniProtKB
Biological Process embryonic foregut morphogenesisIEA:Ensembl
Biological Process embryonic forelimb morphogenesisIEA:Ensembl
Biological Process embryonic hindlimb morphogenesisIEA:Ensembl
Biological Process embryonic limb morphogenesisISS:UniProtKB
Biological Process embryonic pattern specificationManual Assertion Based On ExperimentTAS:BHF-UCL
Biological Process embryonic skeletal system developmentIEA:Ensembl
Biological Process endocytosisIEA:Ensembl
Biological Process epithelial cell proliferation involved in prostate gland developmentIEA:Ensembl
Biological Process epithelial cell proliferation involved in salivary gland morphogenesisIEA:Ensembl
Biological Process epithelial-mesenchymal signaling involved in prostate gland developmentManual Assertion Based On ExperimentIDA:MGI
Biological Process establishment of epithelial cell polarityIEA:Ensembl
Biological Process forebrain developmentISS:UniProtKB
Biological Process formation of anatomical boundaryIEA:Ensembl
Biological Process hair follicle morphogenesisIEA:Ensembl
Biological Process heart developmentISS:UniProtKB
Biological Process heart loopingISS:BHF-UCL
Biological Process hindbrain developmentISS:UniProtKB
Biological Process hindgut morphogenesisIEA:Ensembl
Biological Process inner ear developmentIEA:Ensembl
Biological Process intein-mediated protein splicingIEA:InterPro
Biological Process intermediate filament organizationIEA:Ensembl
Biological Process left lung developmentIEA:Ensembl
Biological Process limb bud formationIEA:Ensembl
Biological Process lung developmentISS:UniProtKB
Biological Process lung epithelium developmentIEA:Ensembl
Biological Process lung lobe morphogenesisIEA:Ensembl
Biological Process lung-associated mesenchyme developmentIEA:Ensembl
Biological Process lymphoid progenitor cell differentiationManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process male genitalia developmentISS:UniProtKB
Biological Process mesenchymal cell apoptotic processIEA:Ensembl
Biological Process mesenchymal cell proliferation involved in lung developmentIEA:Ensembl
Biological Process mesenchymal smoothened signaling pathway involved in prostate gland developmentIEA:Ensembl
Biological Process metanephric collecting duct developmentManual Assertion Based On ExperimentIEP:UniProtKB
Biological Process metanephric mesenchymal cell proliferation involved in metanephros developmentISS:UniProtKB
Biological Process metanephros developmentISS:UniProtKB
Biological Process midbrain developmentISS:UniProtKB
Biological Process myoblast differentiationIEA:Ensembl
Biological Process negative regulation of alpha-beta T cell differentiationIEA:Ensembl
Biological Process negative regulation of apoptotic processISS:UniProtKB
Biological Process negative regulation of canonical Wnt signaling pathwayIEA:Ensembl
Biological Process negative regulation of cell differentiationISS:UniProtKB
Biological Process negative regulation of cell migrationISS:UniProtKB
Biological Process negative regulation of cholesterol effluxISS:BHF-UCL
Biological Process negative regulation of dopaminergic neuron differentiationIEA:Ensembl
Biological Process negative regulation of gene expressionIEA:Ensembl
Biological Process negative regulation of kidney smooth muscle cell differentiationISS:UniProtKB
Biological Process negative regulation of mesenchymal cell apoptotic processIEA:Ensembl
Biological Process negative regulation of proteasomal ubiquitin-dependent protein catabolic processIEA:Ensembl
Biological Process negative regulation of T cell differentiation in thymusIEA:Ensembl
Biological Process negative regulation of T cell proliferationIEA:Ensembl
Biological Process negative regulation of transcription by RNA polymerase IIISS:BHF-UCL
Biological Process negative regulation of transcription elongation by RNA polymerase IIIEA:Ensembl
Biological Process negative regulation of ureter smooth muscle cell differentiationISS:UniProtKB
Biological Process negative thymic T cell selectionISS:UniProtKB
Biological Process neural crest cell migrationISS:UniProtKB
Biological Process neuroblast proliferationISS:UniProtKB
Biological Process neuron fate commitmentISS:UniProtKB
Biological Process odontogenesis of dentin-containing toothIEA:Ensembl
Biological Process oligodendrocyte developmentIEA:Ensembl
Biological Process oligodendrocyte differentiationManual Assertion Based On ExperimentIBA:GO_Central
Biological Process osteoblast developmentIEA:Ensembl
Biological Process pancreas developmentIEA:Ensembl
Biological Process pattern specification processISS:UniProtKB
Biological Process polarity specification of anterior/posterior axisISS:UniProtKB
Biological Process positive regulation of alpha-beta T cell differentiationISS:UniProtKB
Biological Process positive regulation of astrocyte differentiationIEA:Ensembl
Biological Process positive regulation of cell divisionManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process positive regulation of cell population proliferationManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process positive regulation of DNA-templated transcriptionManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process positive regulation of epithelial cell proliferation involved in prostate gland developmentIEA:Ensembl
Biological Process positive regulation of gene expressionIEA:Ensembl
Biological Process positive regulation of hh target transcription factor activityISS:BHF-UCL
Biological Process positive regulation of immature T cell proliferation in thymusISS:BHF-UCL
Biological Process positive regulation of kidney smooth muscle cell differentiationISS:UniProtKB
Biological Process positive regulation of mesenchymal cell proliferation involved in ureter developmentISS:UniProtKB
Biological Process positive regulation of neuroblast proliferationIEA:Ensembl
Biological Process positive regulation of oligodendrocyte differentiationIEA:Ensembl
Biological Process positive regulation of protein import into nucleusIEA:Ensembl
Biological Process positive regulation of sclerotome developmentManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process positive regulation of skeletal muscle cell proliferationIEA:Ensembl
Biological Process positive regulation of skeletal muscle tissue developmentIEA:Ensembl
Biological Process positive regulation of smoothened signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of striated muscle cell differentiationIEA:Ensembl
Biological Process positive regulation of T cell differentiation in thymusISS:UniProtKB
Biological Process positive regulation of transcription by RNA polymerase IIISS:BHF-UCL
Biological Process positive regulation of ureter smooth muscle cell differentiationISS:UniProtKB
Biological Process positive regulation of Wnt signaling pathwayIEA:Ensembl
Biological Process positive thymic T cell selectionISS:UniProtKB
Biological Process primary prostatic bud elongationIEA:Ensembl
Biological Process prostate epithelial cord elongationIEA:Ensembl
Biological Process prostate gland developmentISS:UniProtKB
Biological Process protein autoprocessingIEA:InterPro
Biological Process protein import into nucleusIEA:Ensembl
Biological Process regulation of cell population proliferationISS:UniProtKB
Biological Process regulation of gene expressionManual Assertion Based On ExperimentIBA:GO_Central
Biological Process regulation of glial cell proliferationIEA:Ensembl
Biological Process regulation of mesenchymal cell proliferation involved in prostate gland developmentIEA:Ensembl
Biological Process regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry1 PublicationNAS:BHF-UCL
Biological Process regulation of odontogenesisISS:BHF-UCL
Biological Process regulation of prostatic bud formationIEA:Ensembl
Biological Process regulation of protein localization to nucleusManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process regulation of proteolysisISS:UniProtKB
Biological Process regulation of stem cell proliferationIEA:Ensembl
Biological Process right lung developmentIEA:Ensembl
Biological Process roof of mouth developmentIEA:Ensembl
Biological Process salivary gland cavitationIEA:Ensembl
Biological Process self proteolysisISS:UniProtKB
Biological Process skeletal muscle cell proliferationIEA:Ensembl
Biological Process skeletal muscle fiber differentiationIEA:Ensembl
Biological Process smooth muscle tissue developmentManual Assertion Based On ExperimentIEP:UniProtKB
Biological Process smoothened signaling pathwayManual Assertion Based On ExperimentIDA:FlyBase
Biological Process smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferationIEA:Ensembl
Biological Process somite developmentISS:BHF-UCL
Biological Process spinal cord dorsal/ventral patterningIEA:Ensembl
Biological Process spinal cord motor neuron differentiationIEA:Ensembl
Biological Process stem cell developmentISS:UniProtKB
Biological Process stem cell proliferationIEA:Ensembl
Biological Process striated muscle tissue developmentIEA:Ensembl
Biological Process T cell differentiation in thymusISS:BHF-UCL
Biological Process T cell proliferationIEA:Ensembl
Biological Process telencephalon regionalizationIEA:Ensembl
Biological Process thalamus developmentIEA:Ensembl
Biological Process thymus developmentISS:UniProtKB
Biological Process thyroid gland developmentIEA:Ensembl
Biological Process trachea morphogenesisIEA:Ensembl
Biological Process tracheoesophageal septum formationIEA:Ensembl
Biological Process trunk neural crest cell migrationIEA:Ensembl
Biological Process vasculogenesisISS:UniProtKB
Biological Process ventral midline developmentManual Assertion Based On ExperimentTAS:BHF-UCL

Sonic hedgehog protein
Endoplasmic reticulum membrane
Golgi apparatus membrane
Secreted
Co-localizes with HHAT in the ER and Golgi membrane.
Sonic hedgehog protein N-product
Cell membrane
The dual-lipidated sonic hedgehog protein N-product (ShhNp) is firmly tethered to the cell membrane where it forms multimers (PubMed:24522195).
Further solubilization and release from the cell surface seem to be achieved through different mechanisms, including the interaction with DISP1 and SCUBE2, movement by lipoprotein particles, transport by cellular extensions called cytonemes or by the proteolytic removal of both terminal lipidated peptides (PubMed:26875496, PubMed:24522195).

Microphthalmia, isolated, with coloboma, 5 (MCOPCB5):
A 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, and other abnormalities 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).
Holoprosencephaly 3 (HPE3):
A 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 holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described.
Solitary median maxillary central incisor (SMMCI):
Rare dental anomaly characterized by the congenital absence of one maxillary central incisor.
Triphalangeal thumb-polysyndactyly syndrome (TPTPS):
Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development.
Preaxial polydactyly 2 (PPD2):
Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal.
Hypoplasia or aplasia of tibia with polydactyly (THYP):
An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly.
Laurin-Sandrow syndrome (LSS):
A rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome).

Sonic hedgehog protein
The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity (By similarity).
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 (ShhN) (By similarity).
Cholesterylation is required for the sonic hedgehog protein N-product targeting to lipid rafts and multimerization (PubMed:24522195, PubMed:26875496).
ShhN is the active species in both local and long-range signaling, whereas the C-product (ShhC) is degraded in the reticulum endoplasmic (By similarity).
Sonic hedgehog protein N-product
N-palmitoylation by HHAT of ShhN is required for sonic hedgehog protein N-product multimerization and full activity (By similarity).
It is a prerequisite for the membrane-proximal positioning and the subsequent shedding of this N-terminal peptide (PubMed:24522195).
Sonic hedgehog protein N-product
The lipidated N- and C-terminal peptides of ShhNp can be cleaved (shedding)(PubMed:24522195).
The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub (CW) motif site (PubMed:24522195).
The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195, PubMed:23118222).