SHH (Sonic Hedgehog)
SHH (Sonic hedgehog) is a secreted morphogen that organizes embryonic patterning and maintains adult stem-cell compartments; its pathway reappears as a cancer pathway when reactivated in adult tissue.
Function
SHH is lipid- and cholesterol-modified, which shapes it into multimeric particles that spread through tissue as a gradient. Cells receiving SHH through the PTCH1 receptor release SMO from inhibition, and GLI transcription factors (GLI1/2 as activators, GLI3 as repressor) convert the graded signal into positional identity - the mechanism by which the embryonic neural tube, limb buds, and gut are patterned. In adult tissue, SHH signaling maintains stem cells in skin, gut, and brain.
In cancer
Reactivated SHH signaling causes two distinct cancer classes. Loss-of-function mutations in PTCH1 (a negative regulator of the pathway) cause basal cell carcinoma and medulloblastoma - the receptor’s loss mimics ligand presence, and the pathway runs constitutively; this is the “ligand-independent” mode, and SMO inhibitors (vismodegib, sonidegib) work here. In pancreatic, prostate, and lung cancers, tumor and stromal cells produce SHH ligand itself, recruiting a fibrotic, immunosuppressive stroma - the “ligand-dependent” mode, which SMO inhibitors failed to treat and which requires targeting the GLI transcription factors downstream.
Notes
- Human gene symbol: SHH; UniProt Q15465; 462 amino acids (precursor); Hedgehog family.
- Named for the mutant-wing phenotype in Drosophila; the mammalian homologs are named for hedgehog species.