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).
Organ Systems
integumentary
musculoskeletal
nervous
digestive
Pathway Steps
no SHH — PTCH1 active → SMO tonically inhibited — via PTCH1 keeps SMO out of primary cilium / dephosphorylated; net Hh OFF. In the resting (OFF) state the receptor PTCH1 keeps the transducer SMO inactive — catalytically pumping sterols to deny SMO its activating ligand and keeping it out of the primary cilium. That cilium is the essential compartment where vertebrate Hedgehog transduction is organized.
GLI3 / GLI2 cytoplasm → GLI-Rep (cleaved repressor) — via SUFU + KIF7 + PKA + GSK-3β + CK1 destruction complex (analogous to APC-Axin for Wnt). Without signal, a SUFU/KIF7/PKA/GSK-3β/CK1 complex (functionally analogous to Wnt’s destruction complex) processes the GLI transcription factors (GLI2/3) into truncated repressor forms (GLI-Rep) that actively silence target genes — so the default Hedgehog output is repression, not merely the absence of activation.
SHH ligand → PTCH1 binding + internalization — via SHH is palmitoylated + cholesterol-modified — diffuses as multimers. The SHH ligand is dually lipid-modified (N-palmitoylated and C-cholesterol-modified), which controls its release and multimeric spread. SHH binding to PTCH1 triggers their internalization, removing PTCH1’s inhibition of SMO. Sterol/cholesterol handling is therefore central to the pathway — and a drug-target node.
PTCH1 internalized → SMO derepression + ciliary accumulation — via oxysterol / cholesterol shift in primary cilium membrane activates SMO. With PTCH1 internalized, SMO is derepressed and accumulates in the primary cilium, activated by a shift in ciliary oxysterols/cholesterol. SMO is the target of the approved antagonists vismodegib and sonidegib (basal-cell carcinoma) — and the natural teratogen cyclopamine acts here.
SMO active → GLI dissociation from SUFU → nuclear — via GLI-Act drives target gene transcription. Active ciliary SMO blocks SUFU-mediated processing, so full-length GLI escapes as the activator form (GLI-Act) and enters the nucleus. The net GLI-Act vs GLI-Rep ratio — not a simple on/off — encodes the strength and duration of the signal, allowing morphogen-gradient readout.
GLI-Act (nucleus) → PTCH1 (feedback), GLI1, BCL2, cyclin D, FOXM1 transcription — via PTCH1 upregulation = negative-feedback; GLI1 = positive feedback. Nuclear GLI-Act transcribes proliferation/survival genes (cyclin D, BCL2, FOXM1), the amplifier GLI1 (positive feedback), and PTCH1 itself (negative feedback that limits the response). Inappropriate reactivation drives basal-cell carcinoma and medulloblastoma — the rationale for SMO/GLI-targeted therapy.
Known Modulators
itraconazole (inhibitor) — SMO (off-target, independent of antifungal CYP51 action). repurposing trials for BCC + Hh-driven tumors; not first-line vs vismodegib