Smoothened, frizzled class receptor (SMO) (SMO)

Smoothened, frizzled class receptor (SMO) is a Class F G protein-coupled receptor that serves as a critical transducer in the Hedgehog signaling pathway [3, 10]. In the absence of Hedgehog ligands, SMO activity is constitutively repressed by the transmembrane protein Patched-1 (PTCH1) [9, 16]. Upon ligand binding to PTCH1, this inhibition is relieved, allowing SMO to translocate to the primary cilium and activate downstream GLI transcription factors, which regulate genes involved in cell growth and differentiation [13, 16]. Dysregulation of this pathway, often through loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO, is a primary driver of several malignancies, most notably basal cell carcinoma and medulloblastoma [3, 12]. Consequently, SMO has become a validated therapeutic target, with several FDA-approved small-molecule antagonists like vismodegib, sonidegib, and glasdegib used to treat advanced basal cell carcinoma or acute myeloid leukemia [4, 12]. However, clinical utility is often limited by the emergence of drug resistance, frequently caused by secondary mutations in the SMO receptor that prevent drug binding [4, 10].

Other names

SMOSMOHFrizzled family receptorFrizzled class receptorFZD11Protein GxSeven transmembrane helix receptorSmoothened homolog (Drosophila)

Small-molecule antagonist/inhibitor of the Hedgehog signaling pathway