Reactome: A Curated Pathway Database

phosphorylated GLI proteins bind SPOP:CUL3:RBX1

Stable Identifier
R-HSA-5635855
Type
Reaction
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

Full-length GLI proteins are labile transcription factors that are rapidly degraded after ubiquitination by the SPOP:CUL3:RBX1 E3 ligase (Ohlmeyer et al, 1998; Humke et al, 2010; Tukachinsky et al, 2010; Chen et al, 2009; Zhang et al, 2009; Wen et al, 2010). SPOP (Speckle-type POZ protein) is the vertebrate homologue of Drosophila Hib/Roadkill, which was identified as a negative regulator of Hh signaling (Ohlmeyer et al, 1998; Zhang et al, 2006; Kent et al, 2006). SPOP/Hib proteins contain BTB and MATH domains and function as the substrate-binding component of the E3 ligase complex, where they promote oligomerization (Zhang et al, 2009; Furukawa et al, 2003; Zhuang et al, 2009). SPOP has been shown to bind to GLI2 and GLI3 through multiple serine and threonine rich motifs in the transcription factors, but direct binding to GLI1 has not been demonstrated (Cheng et al, 2009; Zhang et al, 2009).
The stability of SPOP itself is regulated in an unknown manner by DZIP1, a regulator of Hh signaling best characterized in zebrafish for its positive role in promoting ciliogenesis (Sekimizu et al, 2004; Wolff et al, 2004; Glazer et al, 2010; Kim et al, 2010; Tay et al, 2010; Wang et al, 2013). More recently, DZIP1 has also been shown to act as a negative regulator of Hh signaling by preventing the ubiquitin- and proteasome-dependent degradation of SPOP, and in this way increasing the turnover of activated GLI proteins (Jin et al, 2011; Schwend et al, 2013).

Literature References
PubMed ID Title Journal Year
21878643 The antagonistic action of B56-containing protein phosphatase 2As and casein kinase 2 controls the phosphorylation and Gli turnover function of Daz interacting protein 1 J. Biol. Chem. 2011
20014402 The iguana/DZIP1 protein is a novel component of the ciliogenic pathway essential for axonemal biogenesis Dev. Dyn. 2010
16651542 Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus Development 2006
20154143 Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation Mol. Cell. Biol. 2010
23955340 Centrosomal protein DZIP1 regulates Hedgehog signaling by promoting cytoplasmic retention of transcription factor GLI3 and affecting ciliogenesis J. Biol. Chem. 2013
24072710 Stabilization of speckle-type POZ protein (Spop) by Daz interacting protein 1 (Dzip1) is essential for Gli turnover and the proper output of Hedgehog signaling J. Biol. Chem. 2013
19852954 The Zn finger protein Iguana impacts Hedgehog signaling by promoting ciliogenesis Dev. Biol. 2010
9874371 Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator Nature 1998
15198976 iguana encodes a novel zinc-finger protein with coiled-coil domains essential for Hedgehog signal transduction in the zebrafish embryo Genes Dev. 2004
19818708 Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases Mol. Cell 2009
19955409 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase Proc. Natl. Acad. Sci. U.S.A. 2009
20487519 Gli2a protein localization reveals a role for Iguana/DZIP1 in primary ciliogenesis and a dependence of Hedgehog signal transduction on primary cilia in the zebrafish BMC Biol. 2010
19684112 Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved Genes Dev. 2009
16740475 A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor Dev Cell 2006
20360384 The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins Genes Dev. 2010
20956384 A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes J. Cell Biol. 2010
15115751 The zebrafish iguana locus encodes Dzip1, a novel zinc-finger protein required for proper regulation of Hedgehog signaling Development 2004
14528312 Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases Nat Cell Biol 2003
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