SUFU Gene: Suppressor of Fused Homolog – Function, Mutations & Disease

SUFU encodes a negative regulator of the Hedgehog (Hh) signaling pathway. The protein binds to GLI transcription factors and sequesters them in the cytoplasm, preventing their nuclear translocation and target gene activation. SUFU also plays a role in primary cilium function and cell proliferation. Loss-of-function mutations in SUFU lead to constitutive Hh pathway activation and are associated with medulloblastoma, basal cell carcinoma, and Gorlin syndrome.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Hedgehog signaling pathway (Reactome: R-HSA-5358351)

• GLI protein processing (Reactome: R-HSA-5610785)

• Signaling by Hedgehog (Reactome: R-HSA-5358346)

SUFU is a 484-amino-acid protein that acts as a scaffold in the Hedgehog pathway. It directly binds GLI transcription factors (GLI1, GLI2, GLI3) and recruits protein kinases (e.g., PKA, GSK3β, CK1) to promote GLI phosphorylation and proteasomal processing. In the absence of Hh ligand, SUFU retains GLI in the cytoplasm and facilitates its conversion to repressor forms. Upon Hh stimulation, SUFU dissociates from GLI, allowing GLI activators to enter the nucleus. SUFU also localizes to the primary cilium, where it modulates signal transduction. Loss of SUFU function mimics Hh pathway activation and drives tumorigenesis.