Reactome: A Curated Pathway Database

GLI:SUFU dissociates

Stable Identifier
R-HSA-5635859
Type
Reaction
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

Hh signaling promotes the dissociation of the GLI:SUFU complex in the cilium downstream of SMO activation (Humke et al, 2010; Tukachinsky et al, 2010). This appears to divert the transcription factors away from the partial processing/degradation pathway and allow the full-length forms to translocate to the nucleus where they are converted to labile transcriptional activators (Humke et al, 2010; Tukachinsky et al, 2010; Pan et al, 2006; Kim et al, 2009). How the Hh signal is transmited from SMO to promote the dissociation of the GLI:SUFU complex is not clear, however it may involve changes in PKA activity as a result of lowered cAMP levels upon pathway stimulation. (Tukachinsky et al, 2010; Wen et al, 2010; Tuson et al, 2011; Barzi et al, 2010; reviewed in Briscoe and Therond, 2013). GPR161, which localizes to the cilium in a TULP3-dependent manner and which increases cAMP levels in the absence of ligand, is cleared from the cilium upon pathway activation, and deletion of GPR161 increases Hh-dependent signaling (Mukhopadhyay et al, 2010; Mukhopadhyay et al, 2013). These data suggest that removal of ciliary GPR161 upon Hh stimulation may contribute to pathway activity by downregulating PKA activity through cAMP levels (reviewed in Mukhopadhyay and Rohatgi, 2014).

Literature References
PubMed ID Title Journal Year
20154143 Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation Mol. Cell. Biol. 2010
19996169 Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus Proc. Natl. Acad. Sci. U.S.A. 2009
22007132 Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube Development 2011
23332756 The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling Cell 2013
16611981 Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation Mol. Cell. Biol. 2006
20889716 TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia Genes Dev. 2010
23719536 The mechanisms of Hedgehog signalling and its roles in development and disease Nat. Rev. Mol. Cell Biol. 2013
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
24845016 G-protein-coupled receptors, Hedgehog signaling and primary cilia Semin. Cell Dev. Biol. 2014
20016067 Sonic-hedgehog-mediated proliferation requires the localization of PKA to the cilium base J. Cell. Sci. 2010
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