SMO

SMO (Smoothened) is a 787-amino-acid, seven-pass class-F G protein-coupled receptor and the obligate signal-transducing membrane component of vertebrate Hedgehog signaling. In the pathway-off state, PTCH1 or PTCH2 restricts SMO access to activating sterols. Hedgehog binding to Patched relieves this inhibition, allowing cholesterol and oxysterols to bind SMO's extracellular cysteine-rich domain and transmembrane sterol-binding sites, stabilize an active conformation, and promote accumulation of SMO in the primary-cilium membrane. Active SMO can couple to heterotrimeric Gi, lowering cAMP, and also directly binds and inhibits the catalytic subunit of protein kinase A through a C-terminal pseudosubstrate/PKI motif. These mechanisms prevent inhibitory phosphorylation and processing of GLI transcription factors and permit GLI-dependent transcription. SMO therefore functions principally at the plasma membrane and the membrane of non-motile primary cilia, with context-dependent roles in embryonic patterning, organogenesis, tissue homeostasis, and cell proliferation. Germline biallelic loss-of-function variants cause pleiotropic developmental anomalies through impaired Hedgehog signaling, whereas activating somatic or mosaic variants drive tumors and Curry-Jones syndrome.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

• hedgehog_pathway_activation via Basal Cell Carcinoma