SHH
entrez
6469
canonical
uniprot
Q15465
canonical
ensembl
ENSG00000164690
resolver
ensp
ENSP00000297261
resolver
ensp
ENSP00000396621
resolver
enst
ENST00000297261
resolver
genesymbol
SHH
resolver
hgnc
HGNC:10848
resolver
uniprot
A4D247
resolver
uniprot
Q75MC9
resolver
uniprot_entry
SHH_HUMAN
resolver
uniprot_sec
A4D247
resolver
uniprot_sec
Q75MC9
resolver
amino_acid_sequence
MLLLARCLLLVLVSSLLVCSGLACGPGRGFGKRRHPKKLTPLAYKQFIPNVAEKTLGASGRYEGKISRNSERFKELTPNYNPDIIFKDEENTGADRLMTQRCKDKLNALAISVMNQWPGVKLRVTEGWDEDGHHSEESLHYEGRAVDITTSDRDRSKYGMLARLAVEAGFDWVYYESKAHIHCSVKAENSVAAKSGGCFPGSATVHLEQGGTKLVKDLSPGDRVLAADDQGRLLYSDFLTFLDRDDGAKKVFYVIETREPRERLLLTAAHLLFVAPHNDSATGEPEASSGSGPPSGGALGPRALFASRVRPGQRVYVVAERDGDRRLLPAAVHSVTLSEEAAGAYAPLTAQGTILINRVLASCYAVIEEHSWAHRAFAPFRLAHALLAALAPARTDRGGDSGGGDRGGGGGRVALTAPGAADAPGAGATAGIHWYSQLLYQIGTWLLDSEALHPLGMAVKSS
uniprot
proteins
disease_involvement
DISEASE: Microphthalmia/Coloboma 5 (MCOPCB5) [MIM:611638]: 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). {ECO:0000269|PubMed:12503095}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Holoprosencephaly 3 (HPE3) [MIM:142945]: A form of holoprosencephaly, a structural anomaly of the brain in which the developing forebrain fails to correctly separate into right and left hemispheres. It is a genetically and clinically heterogeneous disorder with a wide spectrum of severity, ranging from alobar holoprosencephaly with severe facial abnormalities, such as cyclopia and proboscis, to mild forms that include lobar or microform holoprosencephaly, without cerebral malformations and with mild craniofacial defects. The majority of HPE3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. {ECO:0000269|PubMed:10441331, ECO:0000269|PubMed:10556296, ECO:0000269|PubMed:11479728, ECO:0000269|PubMed:15107988, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15942952, ECO:0000269|PubMed:15942953, ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:17001669, ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572, ECO:0000269|PubMed:9302262}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Solitary median maxillary central incisor (SMMCI) [MIM:147250]: Rare dental anomaly characterized by the congenital absence of one maxillary central incisor. {ECO:0000269|PubMed:11471164, ECO:0000269|PubMed:15103725}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Triphalangeal thumb with polysyndactyly (TPTPS) [MIM:190605]: 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. {ECO:0000269|PubMed:12837695, ECO:0000269|PubMed:18417549}. Note=The gene represented in this entry is involved in disease pathogenesis. SHH expression is altered due to disease-causing variants located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH.; DISEASE: Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal. {ECO:0000269|PubMed:12837695}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences (PubMed:12837695). {ECO:0000269|PubMed:12837695}.; DISEASE: Hypoplasia or aplasia of tibia with polydactyly (THYP) [MIM:188740]: An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly. {ECO:0000269|PubMed:19847792, ECO:0000269|PubMed:24965254}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences. {ECO:0000303|PubMed:19847792, ECO:0000303|PubMed:24965254}.; DISEASE: Laurin-Sandrow syndrome (LSS) [MIM:135750]: 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). {ECO:0000269|PubMed:24456159}. Note=The gene represented in this entry is involved in disease pathogenesis. Abnormal SHH limb expression with pathological consequences is caused by duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5 (PubMed:24456159).
uniprot
proteins
ec_number
3.1.-.-
uniprot
proteins
function
FUNCTION: [Sonic hedgehog protein]: Precursor of sonic hedgehog, a morphogen that activates the smoothened signaling pathway, and which is essential for a variety of patterning events during development (PubMed:29954986, PubMed:29995851, PubMed:30139912, PubMed:31127104, PubMed:31548691). The C-terminal part of the precursor displays an autoproteolysis and a cholesterol transferase activity, resulting (1) in the cleavage of the full-length protein into two parts, Sonic hedgehog protein N-product and C-product (ShhN and ShhC, respectively) and (2) covalent attachment of a cholesterol moiety to the C-terminus of the newly generated ShhN (By similarity). Both autoproteolysis and a cholesterol transferase activities occur in the endoplasmic reticulum (By similarity). Following additional lipidation, ShhN acts as a morphogen, while ShhC is degraded in the endoplasmic reticulum (By similarity). {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:29954986, ECO:0000269|PubMed:29995851, ECO:0000269|PubMed:30139912, ECO:0000269|PubMed:31127104, ECO:0000269|PubMed:31548691}.; FUNCTION: [Sonic hedgehog protein N-product]: The dually lipidated sonic hedgehog protein N-product (ShhN) is a morphogen that activates the smoothened signaling pathway, and which is essential for a variety of patterning events during development (PubMed:10753901, PubMed:24522195, PubMed:24863049, PubMed:29995851, PubMed:30139912, PubMed:31127104, PubMed:31548691, PubMed:31555730). Acts by binding to the patched receptor (PTCH1 or PTCH2), relieving smoothened (SMO) inhibition by patched, activating the smoothened signaling pathway and transcription of target genes (PubMed:10753901, PubMed:29995851, PubMed:31548691, PubMed:31555730). In the absence of SHH, patched represses the constitutive signaling activity of SMO (PubMed:10753901). ShhN is widely expressed and plays a key role in the patterning of the central nervous system and limb development (By similarity). Induces ventral cell fate in the neural tube and somites (By similarity). Involved in the patterning of the anterior-posterior axis of the developing limb bud (By similarity). Essential for axon guidance (By similarity). {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:10753901, ECO:0000269|PubMed:29995851, ECO:0000269|PubMed:30139912, ECO:0000269|PubMed:31127104, ECO:0000269|PubMed:31548691, ECO:0000269|PubMed:31555730, ECO:0000303|PubMed:24522195, ECO:0000303|PubMed:24863049}.
uniprot
proteins
mass_dalton
49607
uniprot
proteins
mutagenesis
MUTAGEN 24; /note="C->S,A: Abolishes palmitoylation, leading to impaired smoothened signaling pathway."; /evidence="ECO:0000269|PubMed:18534984, ECO:0000269|PubMed:29995851, ECO:0000269|PubMed:30139912, ECO:0000269|PubMed:31875564, ECO:0000269|PubMed:9593755"; MUTAGEN 44..45; /note="YK->AA: Impaired binding to PTCH1."; /evidence="ECO:0000269|PubMed:29954986"; MUTAGEN 77; /note="T->A: Does not affect binding to PTCH1."; /evidence="ECO:0000269|PubMed:29954986"; MUTAGEN 80; /note="Y->A: Reduced interaction with GAS1."; /evidence="ECO:0000269|PubMed:35231446"; MUTAGEN 89; /note="E->A: Reduced interaction with GAS1 and CDON."; /evidence="ECO:0000269|PubMed:35231446"; MUTAGEN 111..115; /note="ISVMN->ESVMK: Abolished binding to PTCH1."; /evidence="ECO:0000269|PubMed:29995851"; MUTAGEN 153; /note="R->E: Impaired binding to PTCH1."; /evidence="ECO:0000269|PubMed:29954986"; MUTAGEN 155; /note="R->E: Impaired binding to PTCH1."; /evidence="ECO:0000269|PubMed:29954986"; MUTAGEN 177..178; /note="SK->AA: Impaired binding to PTCH1."; /evidence="ECO:0000269|PubMed:29954986
uniprot
proteins
post_translational_modification
PTM: [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 endoplasmic reticulum (By similarity). {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:24522195, ECO:0000303|PubMed:26875496}.; PTM: [Sonic hedgehog protein N-product]: Dually lipidated: a cholesterol moiety is attached to its C-terminus following cleavage (By similarity). N-palmitoylated by HHAT following cholesterylation; palmitoylation is required for sonic hedgehog protein N-product multimerization and full activity (PubMed:34112694). It is a prerequisite for the membrane-proximal positioning (PubMed:24522195). The lipidated N- and C-terminal peptides of ShhN can be cleaved (shedding) (PubMed:24522195). The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub (CW) motif site (PubMed:24522195). The cleavage reduces the interactions with heparan sulfate and is enhanced by SCUBE2 (PubMed:23118222, PubMed:24522195). {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:23118222, ECO:0000269|PubMed:24522195, ECO:0000269|PubMed:34112694}.
uniprot
proteins
protein_family
Hedgehog family
uniprot
proteins
pubmed
10441331
uniprot
proteins
pubmed
10556296
uniprot
proteins
pubmed
10753901
uniprot
proteins
pubmed
11471164
uniprot
proteins
pubmed
11479728
uniprot
proteins
pubmed
12503095
uniprot
proteins
pubmed
12690205
uniprot
proteins
pubmed
12837695
uniprot
proteins
pubmed
12853948
uniprot
proteins
pubmed
15103725
uniprot
proteins
pubmed
15107988
uniprot
proteins
pubmed
15221788
uniprot
proteins
pubmed
15942952
uniprot
proteins
pubmed
15942953
uniprot
proteins
pubmed
16282375
uniprot
proteins
pubmed
16335952
uniprot
proteins
pubmed
17001669
uniprot
proteins
pubmed
18417549
uniprot
proteins
pubmed
18534984
uniprot
proteins
pubmed
19561609
uniprot
proteins
pubmed
19603532
uniprot
proteins
pubmed
19847792
uniprot
proteins
pubmed
20504762
uniprot
proteins
pubmed
22677548
uniprot
proteins
pubmed
22902404
uniprot
proteins
pubmed
23118222
uniprot
proteins
pubmed
23154980
uniprot
proteins
pubmed
24342078
uniprot
proteins
pubmed
24456159
uniprot
proteins
pubmed
24522195
uniprot
proteins
pubmed
24863049
uniprot
proteins
pubmed
24965254
uniprot
proteins
pubmed
26875496
uniprot
proteins
pubmed
29954986
uniprot
proteins
pubmed
29995851
uniprot
proteins
pubmed
30139912
uniprot
proteins
pubmed
31127104
uniprot
proteins
pubmed
31548691
uniprot
proteins
pubmed
31555730
uniprot
proteins
pubmed
31875564
uniprot
proteins
pubmed
34112694
uniprot
proteins
pubmed
35231446
uniprot
proteins
pubmed
7590746
uniprot
proteins
pubmed
7720571
uniprot
proteins
pubmed
8896572
uniprot
proteins
pubmed
9302262
uniprot
proteins
pubmed
9593755
uniprot
proteins
sequence_length
462
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: [Sonic hedgehog protein]: Endoplasmic reticulum membrane {ECO:0000305|PubMed:18534984}. Golgi apparatus membrane {ECO:0000305|PubMed:18534984}. Note=Co-localizes with HHAT in the ER and Golgi membrane. {ECO:0000269|PubMed:18534984}.; SUBCELLULAR LOCATION: [Sonic hedgehog protein N-product]: Secreted {ECO:0000269|PubMed:24342078, ECO:0000269|PubMed:24522195, ECO:0000269|PubMed:35231446}. Cell membrane {ECO:0000269|PubMed:24522195}; Lipid-anchor {ECO:0000269|PubMed:24522195}. Note=The dual-lipidated sonic hedgehog protein N-product (ShhN) is firmly tethered to the cell membrane where it forms multimers (PubMed:24522195, PubMed:35231446). Further solubilization from the cell surface is achieved by SCUBE2 carrier, which promotes its release from producing cells, allowing it to act as a morphogen for distant signaling (PubMed:24522195, PubMed:35231446). ShhN is then transferred to the CDON-BOC heterodimer and GAS1 coreceptors to reach the patched receptor (PTCH1 or PTCH2) (PubMed:35231446). {ECO:0000269|PubMed:24522195, ECO:0000269|PubMed:35231446}.
uniprot
proteins