Smoothened transmembrane receptor (SMO)

The Smoothened transmembrane receptor (SMO) is a Class Frizzled (Class F) G protein-coupled receptor fundamental to the Hedgehog (Hh) signaling pathway, which mediates critical processes in embryonic development, tissue patterning, and homeostasis in vertebrates[1][2][3][4][7][8][9]. SMO is regulated by Patched (PTCH1), whose inhibition by Hedgehog ligands (such as Sonic Hedgehog) allows SMO to activate intracellular signaling cascades, ultimately influencing the activity of GLI transcription factors. SMO is an established therapeutic target: it is inhibited by FDA-approved drugs (vismodegib, sonidegib) for cancers driven by aberrant Hedgehog signaling, notably basal cell carcinoma and medulloblastoma[3][4][5][9]. Resistance to SMO-targeting drugs frequently arises due to mutations at the drug binding sites. The receptor features a unique structure with distinct transmembrane, hinge, and extracellular cysteine-rich domains, allowing for complex regulation by endogenous lipids (such as cholesterol) and small molecules. Mutations or dysregulation of SMO cause developmental abnormalities and drive oncogenesis, underlining its importance as a therapeutic target[1][2][3][4][7][8][9].

Other names

SmoothenedSMOSmoothened receptorSmoSmoothened GPCRSmoothened receptor protein

Antagonists inhibit Hedgehog signaling by binding to SMO and preventing signaling activation (e.g., vismodegib, sonidegib, cyclopamine, SANT1, LY2940680, Anta XV). Agonists activate SMO and stimulate downstream Hedgehog signaling (e.g., SAG1.5).