Smoothened receptor (SMO) (SMO)

The Smoothened receptor (SMO) is a Class F G protein-coupled receptor that serves as a key transducer in the Hedgehog (Hh) signaling pathway (UniProt Q99835). In the absence of Hh ligands, the Patched-1 (PTCH1) receptor inhibits SMO activity; however, upon ligand binding to PTCH1, this inhibition is relieved, allowing SMO to signal downstream to GLI transcription factors (PubMed: 25639794). This pathway is essential for embryonic development, including limb patterning and organogenesis, and plays a critical role in adult tissue maintenance and repair (StatPearls: Hedgehog Signaling Pathway). Dysregulation of SMO, often through loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO itself, leads to constitutive pathway activation and is a primary driver of various malignancies, most notably basal cell carcinoma and medulloblastoma (PubMed: 24671011). Pharmacological targeting of SMO with small-molecule antagonists like vismodegib and sonidegib has proven effective in treating these cancers, although clinical utility is often limited by the emergence of drug-resistant mutations and significant side effects (FDA Label: Erivedge). Because of its fundamental role in development, SMO inhibitors are highly teratogenic and require strict pregnancy prevention measures (PubMed: 22683261).

Other names

SMOSMOHFrizzled family receptorG protein-coupled receptor class F memberSmoothened homologSmoothened receptor, 7TM heptahelical bundle

Antagonist of the Smoothened receptor that inhibits the Hedgehog signaling pathway by preventing the activation of GLI transcription factors (PubMed: 22683261).