SUFU

SUFU encodes a component of the Sonic hedgehog (SHH; MIM 600725)/Patched (PTCH; MIM 601309) signaling pathway. Mutations in genes encoding components of this pathway are deleterious for normal development and are associated with cancer-predisposing syndromes (e.g., HPE3, MIM 142945; BCNS, MIM 109400; and GCPS, MIM 175700).[supplied by OMIM

Full Name

suppressor of fused homolog (Drosophila)

Function

Negative regulator in the hedgehog/smoothened signaling pathway (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:12068298, PubMed:12975309, PubMed:27234298, PubMed:15367681, PubMed:22365972, PubMed:24217340, PubMed:24311597, PubMed:28965847).
Down-regulates GLI1-mediated transactivation of target genes (PubMed:15367681, PubMed:24217340, PubMed:24311597).
Down-regulates GLI2-mediated transactivation of target genes (PubMed:24311597, PubMed:24217340).
Part of a corepressor complex that acts on DNA-bound GLI1. May also act by linking GLI1 to BTRC and thereby targeting GLI1 to degradation by the proteasome (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:24217340).
Sequesters GLI1, GLI2 and GLI3 in the cytoplasm, this effect is overcome by binding of STK36 to both SUFU and a GLI protein (PubMed:10559945, PubMed:10564661, PubMed:10806483, PubMed:24217340).
Negative regulator of beta-catenin signaling (By similarity).
Regulates the formation of either the repressor form (GLI3R) or the activator form (GLI3A) of the full-length form of GLI3 (GLI3FL) (PubMed:24311597, PubMed:28965847).
GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state (PubMed:24311597, PubMed:28965847).
Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R (PubMed:24311597, PubMed:28965847).
When Hh signaling is initiated, SUFU dissociates from GLI3FL and the latter translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A) (PubMed:24311597, PubMed:28965847).
Required for normal embryonic development (By similarity).
Required for the proper formation of hair follicles and the control of epidermal differentiation (By similarity).

Biological Process

Biological Process aorta developmentIEA:Ensembl
Biological Process coronary vasculature developmentIEA:Ensembl
Biological Process cytoplasmic sequestering of transcription factorManual Assertion Based On ExperimentIBA:GO_Central
Biological Process heart loopingIEA:Ensembl
Biological Process negative regulation of DNA-binding transcription factor activityManual Assertion Based On ExperimentTAS:BHF-UCL
Biological Process negative regulation of hh target transcription factor activityManual Assertion Based On ExperimentIDA:ComplexPortal
Biological Process negative regulation of osteoblast differentiationManual Assertion Based On ExperimentTAS:BHF-UCL
Biological Process negative regulation of protein import into nucleusManual Assertion Based On ExperimentTAS:BHF-UCL
Biological Process negative regulation of smoothened signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterningIEA:Ensembl
Biological Process negative regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:MGI
Biological Process negative regulation of ubiquitin-dependent protein catabolic processIEA:Ensembl
Biological Process neural tube closureIEA:Ensembl
Biological Process regulation of DNA-templated transcriptionManual Assertion Based On ExperimentTAS:UniProtKB
Biological Process signal transductionManual Assertion Based On ExperimentTAS:ProtInc
Biological Process skin developmentIEA:Ensembl
Biological Process smoothened signaling pathway involved in dorsal/ventral neural tube patterningIEA:Ensembl
Biological Process smoothened signaling pathway involved in spinal cord motor neuron cell fate specificationIEA:Ensembl
Biological Process smoothened signaling pathway involved in ventral spinal cord interneuron specificationIEA:Ensembl
Biological Process ventricular septum developmentIEA:Ensembl

Cellular Location

Cytoplasm
Nucleus

Involvement in disease

Medulloblastoma (MDB):
Malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.
Joubert syndrome 32 (JBTS32):
A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS32 inheritance is autosomal recessive.
Basal cell nevus syndrome (BCNS):
An autosomal dominant disease characterized by nevoid basal cell carcinomas and developmental abnormalities such as rib and craniofacial alterations, polydactyly, syndactyly, and spina bifida. In addition, the patients suffer from a multitude of tumors like basal cell carcinomas, fibromas of the ovaries and heart, cysts of the skin, jaws and mesentery, as well as medulloblastomas and meningiomas.

PTM

Polyubiquitinated at Lys-257 by the SCF(FBXL17) complex, leading to its subsequent degradation and allowing the release of GLI1 for proper hedgehog/smoothened signal transduction (PubMed:27234298).
Ubiquitination is impaired by phosphorylation at Ser-342, Ser-346, Ser-352 and Thr-353 (PubMed:27234298).
Phosphorylation at Ser-342, Ser-346, Ser-352 and Thr-353 prevents ubiquitination by the SCF(FBXL17) complex.