A Hedgehog-Induced BTB Protein Modulates Hedgehog Signaling by Degrading Ci/Gli Transcription Factor

Zhang, Qing; Zhang, Lei; Wang, Bing; Ou, Chan-Yen; Chien, Ching‐Te; Jen, Jin

doi:10.1016/j.devcel.2006.05.004

Cited by 206 publications

(353 citation statements)

References 37 publications

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“…SPOP is a substrate adaptor of a cullin‐3‐RING ubiquitin ligase (CRL3) and serves to recruit substrates to the CRL3 (Zhuang et al , 2009) for subsequent ubiquitination and degradation (Hernández‐Muñoz et al , 2005; Kent et al , 2006; Kwon et al , 2006; Zhang et al , 2006; Li et al , 2008). The Drosophila melanogaster homolog of SPOP, Roadkill/HIB, is essential for early development (Kent et al , 2006).…”

Section: Introductionmentioning

confidence: 99%

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

et al. 2016

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Membrane‐less organelles in cells are large, dynamic protein/protein or protein/RNA assemblies that have been reported in some cases to have liquid droplet properties. However, the molecular interactions underlying the recruitment of components are not well understood. Herein, we study how the ability to form higher‐order assemblies influences the recruitment of the speckle‐type POZ protein (SPOP) to nuclear speckles. SPOP, a cullin‐3‐RING ubiquitin ligase (CRL3) substrate adaptor, self‐associates into higher‐order oligomers; that is, the number of monomers in an oligomer is broadly distributed and can be large. While wild‐type SPOP localizes to liquid nuclear speckles, self‐association‐deficient SPOP mutants have a diffuse distribution in the nucleus. SPOP oligomerizes through its BTB and BACK domains. We show that BTB‐mediated SPOP dimers form linear oligomers via BACK domain dimerization, and we determine the concentration‐dependent populations of the resulting oligomeric species. Higher‐order oligomerization of SPOP stimulates CRL3SPOP ubiquitination efficiency for its physiological substrate Gli3, suggesting that nuclear speckles are hotspots of ubiquitination. Dynamic, higher‐order protein self‐association may be a general mechanism to concentrate functional components in membrane‐less cellular bodies.

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Section: Introductionmentioning

confidence: 99%

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

et al. 2016

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“…Usually the BTB domain interacts with the Cul family member Cul3 and the MATH domain recognizes the substrates for the 26S proteasome degradation [64]. Our previous study showed that HIB interacts with Cul3 to form an E3 ligase complex that mediates Ci degradation [39,43]. We therefore tested whether HIB acts in conjunction with Cul3 to regulate Su(fu).…”

Section: Regulation Of Su(fu) Level By Hib Depends On E3 Ligase Cul3mentioning

confidence: 99%

“…To verify this hypothesis, we knocked down smo and ci by expressing UASsmo-RNAi and UAS-ci-RNAi, respectively, with MS1096 and found that the level of Su(fu) near A/P boundary increased to the level similar to that outside the A/P boundary ( Figure 1D-1E''). Furthermore, MS1096-driven overexpression of UAS-Ci -3P , which is one active form of Ci with three mutated PKA kinase sites [39], downregulated Su(fu) in both A and P compartments ( Figure 1F-1F''). Taken together, these results support the notion that Hh signal transduction is both necessary and sufficient for downregulating Su(fu).…”

Section: Hh Signaling Downregulates Su(fu)mentioning

confidence: 99%

“…hib is a target gene of Hh signaling pathway and its upregulation overlaps with low Su(fu) domain, as indicated by LacZ staining from the hib-lacZ enhancer trap line, which mimics endogenous hib expression pattern ( Figure 2A-2A''') [39]. HIB could function as a substrate recognition component of Cul3-based E3 ubiquitin ligase to promote ubiquitination and proteasome-mediated degradation of its target proteins [39]. These observations prompted us to test whether HIB mediates the reduction of Su(fu) induced by Hh signaling.…”

Section: Hh Signaling Downregulates Su(fu) Through Its Target Hibmentioning

confidence: 99%

“…HIB contains an N-terminal MATH domain and a Cterminal BTB domain [39]. Usually the BTB domain interacts with the Cul family member Cul3 and the MATH domain recognizes the substrates for the 26S proteasome degradation [64].…”

Section: Regulation Of Su(fu) Level By Hib Depends On E3 Ligase Cul3mentioning

confidence: 99%

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Hedgehog signaling downregulates Suppressor of Fused through the HIB/SPOP-Crn axis in Drosophila

et al. 2014

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Hedgehog (Hh) signaling plays vital roles in animal development and tissue homeostasis, and its misregulation causes congenital diseases and several types of cancer. Suppressor of Fused (Su(fu)) is a conserved inhibitory component of the Hh signaling pathway, but how it is regulated remains poorly understood. Here we demonstrate that in Drosophila Hh signaling promotes downregulation of Su(fu) through its target protein HIB (Hh-induced BTB protein). Interestingly, although HIB-mediated downregulation of Su(fu) depends on the E3 ubiquitin ligase Cul3, HIB does not directly regulate Su(fu) protein stability. Through an RNAi-based candidate gene screen, we identify the spliceosome factor Crooked neck (Crn) as a regulator of Su(fu) level. Epistasis analysis indicates that HIB downregulates Su(fu) through Crn. Furthermore, we provide evidence that HIB retains Crn in the nucleus, leading to reduced Su(fu) protein level. Finally, we show that SPOP, the mammalian homologue of HIB, can substitute HIB to downregulate Su(fu) level in Drosophila. Our study suggests that Hh regulates both Ci and Su(fu) levels through its target HIB, thus uncovering a novel feedback mechanism that regulates Hh signal transduction. The dual function of HIB may provide a buffering mechanism to fine-tune Hh pathway activity.

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Hedgehog signaling update

Cohen

2010

American J of Med Genetics Pt A

110

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In vertebrate hedgehog signaling, hedgehog ligands are processed to become bilipidated and then multimerize, which allows them to leave the signaling cell via Dispatched 1 and become transported via glypicans and megalin to the responding cells. Hedgehog then interacts with a complex of Patched 1 and Cdo/Boc, which activates endocytic Smoothened to the cilium. Patched 1 regulates the activity of Smoothened (1) via Vitamin D3, which inhibits Smoothened in the absence of hedgehog ligand or (2) via oxysterols, which activate Smoothened in the presence of hedgehog ligand. Hedgehog ligands also interact with Hip1, Patched 2, and Gas1, which regulate the range as well as the level of hedgehog signaling. In vertebrates, Smoothened is shortened at its C-terminal end and lacks most of the phosphorylation sites of importance in Drosophila. Cos2, also of importance in Drosophila, plays no role in mammalian transduction, nor do its homologs Kif7 and Kif27. The cilium may provide a function analogous to that of Cos2 by linking Smoothened to the modulation of Gli transcription factors. Disorders associated with the hedgehog signaling network follow, including nevoid basal cell carcinoma syndrome, holoprosencephaly, Smith-Lemli-Opitz syndrome, Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, Carpenter syndrome, and Rubinstein-Taybi syndrome.

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A Hedgehog-Induced BTB Protein Modulates Hedgehog Signaling by Degrading Ci/Gli Transcription Factor

Cited by 206 publications

References 37 publications

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

Hedgehog signaling downregulates Suppressor of Fused through the HIB/SPOP-Crn axis in Drosophila

Hedgehog signaling update

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