Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

Cherry, Amy L.; Finta, Csaba; Karlström, Mikael; Jin, Qianren; Schwend, Thomas; Astorga‐Wells, Juan; Zubarev, Roman A.; Campo, Mark Del; Criswell, Angela; Sanctis, Daniele de; Jovine, Luca; Toftgárd, Rune

doi:10.1107/s0907444913028473

Cited by 58 publications

(72 citation statements)

References 86 publications

(100 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The conformation of Sufu is regulated by Gli binding and Sufu–Gli interaction requires an intact tertiary structure of Sufu (Cherry et al , 2013; Zhang et al , 2013). Thus, we asked whether Gli1 acts as a cofactor modulating the interaction between Fbxl17 and Sufu in vivo .…”

Section: Resultsmentioning

confidence: 99%

“…Ptch1 +/+ , Ptch1 +/− , and Ptch1 −/− MEFs were assessed after 24 h of maintenance in serum‐starved in serum‐reduced medium. SHH‐conditioned medium was generated as described previously (Cherry et al , 2013). After 24 h of incubation with the appropriate Hh pathway agonists, antagonist, or control vehicle, cell cultures were harvested for real‐time PCR or Western blotting.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

Self Cite

View full text Add to dashboard Cite

Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Targeted resequencing was performed on a Solid 5500xL platform using the TargetSeq Custom Enrichment System (ThermoFisher Scientific), as previously reported. 36 In Silico Modeling of SUFU Missense Variants Atomic coordinates of SUFU, in complex with GLI3, were obtained from the Protein Data Bank 38 (PDB: 4BLD) and used for Molecular Dynamics (MD) simulations. The residues of the considered PDB file correspond to residues 28-285 and 345-480 of SUFU and residues 333-340 of GLI3.…”

Section: Sequencing and Data Analysismentioning

confidence: 99%

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Mori

Romani²,

D’Arrigo

et al. 2017

The American Journal of Human Genetics

View full text Add to dashboard Cite

The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild ''molar tooth sign''), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.

show abstract

“…Additionally, the protein suppressor of fused (SUFU, encoded by the SUFU gene), part of a corepressor complex, provides additional negative regulation of GLI factors through direct binding [14]. When a hedgehog ligand (members include the proteins Indian hedgehog, desert hedgehog, and the most common sonic hedgehog (SHH) [13]) binds to PTCH1, SMO becomes hyperphosphorylated and in turn allows GLI to relocalize to the nucleus.…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)

Bresler

Padwa

Granter

2016

Head and Neck Pathol

113

108

View full text Add to dashboard Cite

Nevoid basal cell carcinoma syndrome, or basal cell nevus syndrome (Gorlin syndrome), is a rare autosomal dominantly inherited disorder that is characterized by development of basal cell carcinomas from a young age. Other distinguishing clinical features are seen in a majority of patients, and include keratocystic odontogenic tumors (formerly odontogenic keratocysts) as well as dyskeratotic palmar and plantar pitting. A range of skeletal and other developmental abnormalities are also often seen. The disorder is caused by defects in hedgehog signaling which result in constitutive pathway activity and tumor cell proliferation. As sporadic basal cell carcinomas also commonly harbor hedgehog pathway aberrations, therapeutic agents targeting key signaling constituents have been developed and tested against advanced sporadically occurring tumors or syndromic disease, leading in 2013 to FDA approval of the first hedgehog pathway-targeted small molecule, vismodegib. The elucidation of the molecular pathogenesis of nevoid basal cell carcinoma syndrome has resulted in further understanding of the most common human malignancy.

show abstract

Structural basis of SUFU–GLI interaction in human Hedgehog signalling regulation

Cited by 58 publications

References 86 publications

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)

Contact Info

Product

Resources

About