Category: signaling
Hedgehog (Hh) signaling is a developmental morphogen pathway essential for embryonic patterning (limb, neural tube, somites) and adult stem-cell maintenance. Three mammalian ligands: Sonic (SHH — most studied), Indian (IHH — bone/cartilage), Desert (DHH — gonadal). Mechanism is unusual: when no ligand is present, the 12-pass transmembrane receptor PATCHED1 (PTCH1) tonically INHIBITS Smoothened (SMO, a 7-pass GPCR-like receptor that doesn't use a heterotrimeric G-protein in the canonical sense). PTCH1 likely transports oxysterols/cholesterol away from SMO to keep it inactive. When SHH binds PTCH1, PTCH1 internalizes → relieves SMO inhibition → SMO active → GLI transcription factors translocate to nucleus → activate Hh target genes (PTCH1 itself — feedback, GLI1, BCL2, cyclin D, FOXM1). In OFF state, GLI3 (and GLI2) are processed by a destruction complex (SUFU + KIF7 + PKA + GSK-3β + CK1) → cleaved to GLI3-Rep (repressor) — analogous to Wnt/β-catenin. Disease: gorlin syndrome (PTCH1 LOF — basal cell carcinoma + medulloblastoma); sporadic BCC (PTCH1 / SMO somatic mutations — most common human cancer); medulloblastoma (SMO + PTCH1); rhabdomyosarcoma. Therapeutics — SMO inhibitors: vismodegib (Erivedge) — first FDA-approved Hh inhibitor (2012, locally advanced/metastatic BCC); sonidegib (Odomzo, 2015); glasdegib (Daurismo, 2018 — AML in combination). Itraconazole is an off-target SMO inhibitor (independent of CYP51); arsenic trioxide inhibits GLI directly (APL secondary use). Resistance: SMO D473H mutation (vismodegib); downstream GLI activation bypassing SMO. Cross-links: [[wnt_beta_catenin]] (parallel developmental), [[notch_signaling]] (parallel), [[cell_cycle_cdk]] (cyclin D target).