SHH
GeneName
SHH
Summary
SHH, also known as Sonic hedgehog protein, is a 50kDa secreted protein that plays a pivotal role in embryonic development and tissue patterning. It is expressed in various tissues, including the developing brain, limbs, and other organs. SHH is involved in critical processes such as cell fate specification, limb and organ formation, and neural patterning. It functions through binding to the Patched receptor and modulating the activity of the Smoothened protein, thereby influencing the canonical Wnt signalling pathway and other developmental pathways. SHH is localised to the extracellular space and is associated with various cellular components, including the plasma membrane and endoplasmic reticulum.
Importance
SHH is relevant to: - Developmental biology, particularly in understanding limb and organ formation and patterning during embryogenesis. - Cancer research, as aberrant SHH signalling is implicated in various cancers, including basal cell carcinoma and medulloblastoma. - Neurodevelopmental disorders, given its role in central nervous system development and neuronal differentiation. - Regenerative medicine, due to its potential in promoting tissue repair and regeneration through its morphogen activity.
Top Products
For researchers investigating Sonic Hedgehog (SHH), we highly recommend the top-selling recombinant antibody, Anti-Sonic Hedgehog antibody [EP1190Y] (ab53281). This well-cited antibody has garnered 99 citations, reflecting its strong reputation in the field. It has been validated for use in a variety of applications, including Western blotting (WB), immunohistochemistry (IHC), immunocytochemistry (ICC), and flow cytometry (FC). Its recombinant nature ensures batch-to-batch consistency, making it an excellent choice for reliable SHH detection in your experiments. The Human Sonic Hedgehog ELISA Kit (ab100639), supported by 25 citations, is an excellent option for researchers looking to accurately measure SHH levels in their samples.
Abcam Product Citation Summary
The data indicates that SHH is being studied in various human tissues, including cerebrospinal fluid, liver, pancreatic cancer cells, lung tissue, and tumour samples. The applications of the antibodies include immunofluorescence, immunohistochemistry, and Western blotting, highlighting the importance of SHH in both normal and pathological conditions, particularly in relation to ALS and cancer.
Abcam Product Citation Table
Domain
Sonic hedgehog protein N-product
Binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain.
Sonic hedgehog protein N-product
The Cardin-Weintraub (CW) motif is required for heparan sulfate binding of the solubilized ShhNp (PubMed:23118222). The N-terminal palmitoylated peptide is cleaved at the heparan sulfate-binding Cardin-Weintraub (CW) motif site (PubMed:24522195). The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195).
Function
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 endoplasmic reticulum (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).
Involvement in disease
Microphthalmia/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).
None
The disease is caused by variants affecting the gene represented in this entry.
Holoprosencephaly 3
HPE3
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.
None
The disease is caused by variants affecting the gene represented in this entry.
Solitary median maxillary central incisor
SMMCI
Rare dental anomaly characterized by the congenital absence of one maxillary central incisor.
None
The disease is caused by variants affecting the gene represented in this entry.
Triphalangeal thumb with polysyndactyly
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.
None
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.
Preaxial polydactyly 2
PPD2
Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal.
None
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).
Hypoplasia or aplasia of tibia with polydactyly
THYP
An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly.
None
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.
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).
None
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).
Post-translational modifications
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).
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:23118222, PubMed:24522195).
Sequence Similarities
Belongs to the hedgehog family.
Cellular localization
- 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
- Lipid-anchor
- 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:24522195, PubMed:26875496).
Alternative names
Sonic hedgehog protein, SHH, HHG-1, Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains, ShhNC