A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes

Tukachinsky, Hanna; Lopez, Lyle V.; Salic, Adrian

doi:10.1083/jcb.201004108

Cited by 347 publications

(401 citation statements)

References 57 publications

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“…Indeed, Fbxl17 overexpression induced Sufu degradation and Gli1 release, whereas the depletion of Fbxl17 in MEFs Ptch1 −/− led to an accumulation of Sufu–Gli1 complexes (Fig 4E and Appendix Fig S1B). Since the polyubiquitylation of Sufu precedes degradation, this model is in accordance with previous findings on Sufu–Gli complex formation and dissociation (Tukachinsky et al , 2010). …”

Section: Resultssupporting

confidence: 93%

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

et al. 2016

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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.

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Section: Resultssupporting

confidence: 93%

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

et al. 2016

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“…It has been shown that Sufu retains Gli in the cytoplasm and promotes its proteolysis into a truncated repressor whereas activation of Smo in primary cilia upon Hh stimulation leads to recruitment of endogenous SufuGli complexes to the cilia and causes the dissociation of Sufu-Gli complex, allowing activated Gli proteins to enter the nucleus [40][41][42]. We found that Evc and Evc2 function upstream of Sufu to promote Gli activation.…”

Section: Discussionmentioning

confidence: 74%

Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

Yang

Chen

et al. 2012

Cell Res

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“…In the absence of Shh, Ptch1 normally represses the activity of Smoothened (Smo), the seven-pass transmembrane spanning receptor which is the major signaling component and switch in this pathway. The zinc-finger transcriptional factors of Glioma-associated oncogenes (Gli) family are inhibited by the cytoplasmic protein Suppressor of Fused (SuFu) (Tukachinsky et al, 2010). Conversely, in the presence of Shh binding to Ptch1, there is relief of the inhibition of Smo.…”

Section: Sonic Hedgehog Signaling: Components Routes and Mechanismmentioning

confidence: 99%

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou

Tan

Liu

2016

Sci. China Life Sci.

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The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog (Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease (CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelial-mesenchymal communication (EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.

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A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes

Abstract: Hedgehog signaling through the ciliary membrane protein Smoothened dissociates the Gli transcription factors from their inhibitor, Suppressor of Fused.

Cited by 347 publications

References 57 publications

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

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

Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

Sonic hedgehog signaling in kidney fibrosis: a master communicator

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