Preferred Label : Sonic Hedgehog Pathway;
NCIt related terms : Sonic Hedgehog (Shh) Pathway;
Alternative definition : BIOCARTA: Sonic Hedgehog (Shh) is one of a family of three secreted proteins, including
Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh), that play distinct and crucial roles
in development. The morphogenic signal Shh provides in the developing CNS induces
proliferation of neuronal precursor cells in the developing cerebellum and other tissues.
Proliferative signaling by Shh is involved in the development of cancer, including
specific brain and skin cancers such as basal cell carcinomas, while activation of
Shh signaling in neurons may also provide a means to induce neuronal regeneration.
Mitogenic Shh signaling does not appear to involve Map kinase pathways, but may involve
induction of Cyclin D1 expression to maintain Rb in the hyperphosphorylated state
and allow progression through the G1 phase of the cell cycle. Activation of myc may
be one mechanism by which Shh induces cell cycle progression. Activation of Shh proliferative
signaling occurs through binding to a receptor complex including Patched (Ptc-1) and
Smoothened, a G-protein coupled receptor. Patched is an integral membrane protein
with twelve transmembrane domains that acts as an inhibitor of Smoothened activation.
Patched has been classified as a tumor suppressor due to its inhibition of Smoothened
and the presence of inactivated Ptc-1 mutations in some cancers. One possibility is
that Ptc-1, which resembles transmembrane channels, may not directly associate with
Smoothened but may repress Smoothened signaling by transporting an endogenous Smoothened
inhibitor across the plasma membrane into the cytoplasm. Small non-peptide agonists
and antagonists of the Shh pathway have been identified and appear to act at the level
of the Smoothened receptor, providing pharmacological tools to study Shh signaling.
The pathway downstream of the Smoothened receptor has remained somewhat unclear, but
involves the Gli family of transcriptional activators, including Gli-1, Gli-2, and
Gli-3, homologs of the drosophila gene cubitis interruptis. Kinases including GSK-3
and PKA oppose activation of the Shh pathway, perhaps by regulating the stability
of Shh pathway intermediate signaling factors transcription factors. Suppressor of
Fused (SUFU) interacts directly with Gli proteins, repressing Shh signaling while
Dyrk1 is a kinase that acts by a distinct pathway to stimulate Gli1 activation of
transcription. The multiplicity of factors involved in Shh signaling creates many
opportunities for therapeutic intervention in the treatment of cancer and possibly
neurodegenerative diseases. (This definition may be outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_shhPathway;
Origin ID : C39231;
UMLS CUI : C1519425;
Semantic type(s)
- concept_is_in_subset
- has_gene_product_element
- is_target
- pathway_has_gene_element
