PTCH1 inhibits accumulation of SMO in the primary cilium in the absence of Hh signal

Stable Identifier
Reaction [BlackBoxEvent]
Homo sapiens
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In the absence of Hh ligand, the Hh receptor PTCH inhibits signaling by negatively regulating the activity of SMO, a candidate member of the GPCR superfamily that transduces the Hh signal to downstream pathway components (reviewed in Ayers and Therond, 2010; Briscoe and Therond, 2013). Neither the mechanism by which SMO activates Hh signaling nor the manner in which PTCH represses this activty are fully elucidated, but these may involve regulation of putative SMO ligand(s) or changes in cellular localization, protein conformation and phosphorylation status, among other possibilities (reviewed in Briscoe and Therond, 2013; Ayers and Therond; 2010).
PTCH is a 7 transmembrane protein that is localized to the primary cilium in the absence of Hh ligand (Rohatgi et al, 2007). PTCH regulates SMO in a non-stoichiometric manner and there is little evidence that endogenous PTCH and SMO interact directly (Taipale et al, 2002; reviewed in Huangfu and Anderson, 2006). PTCH has a sterol sensing domain (SSD) and structural similarity to bacterial RND transporters. Mutation in conserved motifs in the RND domain abrogate the ability of PTCH to negatively regulate SMO activity (Taipale et al, 2002). The transmembrane heptahelical domain of SMO has been shown to bind to a number of natural and synthetic molecules, many of which are structurally related to sterols, and this binding can activate or repress SMO activity (Mas et al, 2010; Dwyer et al, 2007; Nachtergaele et al, 2012; Corcoran et al, 2006). Together, these data suggest a speculative model where PTCH regulates SMO activity by controlling the flux of sterol-related SMO agonists and/or antagonists, although this has not been fully substantiated (Khaliullina et al, 2009; reviewed in Rohatgi and Scott, 2007; Briscoe and Therond, 2013).
In the absence of Hh signal, SMO is largely found in intracellular vesicles, with a fraction localized to the plasma membrane (Milenkovic et al, 2009; Huangfu et al, 2006; Corbit et al, 2005; Rohatgi et al, 2007; Wang et al, 2009; Wilson et al, 2009). Like GLI2, 3 and SUFU, however, SMO may traffic through the cilium in the absence of ligand (Wilson et al, 2009; Kim et al, 2009). SMO and PTCH appear to have opposing localizations in both the 'off' and 'on' state, with PTCH exiting and SMO entering the cilium upon Hh pathway activation (Denef et al, 2000; Rohatgi et al, 2007; reviewed in Goetz and Anderson, 2010; Hui and Angers, 2011). Clearance of PTCH from the ciliary membrane in the presence of Hh is promoted by its ubiquitination by the E3 ligase SMURF (Huang et al, 2013; Yue et al, 2014)
Like the Drosophila homologue, vertebrate SMO appears to exists as a constitutive dimer. Dimerization is mediated by the N-terminal Cys-rich domain (CRD) and is required for function (Zhao et al, 2007). The C-terminal tail of SMO has arginine-rich clusters that appear to regulate the conformation of the tails in the dimer, maintaining the SMO dimer in an inactive state. In Drosophila, the inhibitory effect of the arginine-rich region is counteracted upon Hh pathway activation by PKA-mediated phosphorylation of adjacent serine residues. This promotes an open tail conformation that is required for cell surface accumulation and signaling (Zhao et al, 2007; Chen et al, 2010). These consensus PKA motifs are not conserved in the vertebrate SMO C-terminal tail, and a role for PKA-mediated phosphorylation and direct activation of SMO appears not to hold true in mammalian cells (Zhao et al, 2007; Tuson et al, 2011). A similar activating phosphorylation of vertebrate SMO may be CK1 or GRK2-dependent (Chen et al, 2011).

Literature References
PubMed ID Title Journal Year
20207148 Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling Trends Cell Biol. 2010
21695114 Sonic Hedgehog dependent phosphorylation by CK1? and GRK2 is required for ciliary accumulation and activation of smoothened PLoS Biol. 2011
20412786 Small molecule modulation of HH-GLI signaling: current leads, trials and tribulations Biochem. Pharmacol. 2010
10966113 Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened Cell 2000
23719536 The mechanisms of Hedgehog signalling and its roles in development and disease Nat. Rev. Mol. Cell Biol. 2013
19365551 Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium PLoS ONE 2009
20844016 G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila Genes Dev. 2010
17200122 Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells J. Biol. Chem. 2007
24925320 Requirement of Smurf-mediated endocytosis of Patched1 in Sonic Hedgehog signal reception Elife 2014
24302888 Activation of Smurf E3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover PLoS Biol. 2013
22231273 Oxysterols are allosteric activators of the oncoprotein Smoothened Nat. Chem. Biol. 2012
12192414 Patched acts catalytically to suppress the activity of Smoothened Nature 2002
21801010 Gli proteins in development and disease Annu. Rev. Cell Dev. Biol. 2011
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
16707575 Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells Proc. Natl. Acad. Sci. U.S.A. 2006
16136078 Vertebrate Smoothened functions at the primary cilium Nature 2005
19196978 Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation Proc. Natl. Acad. Sci. U.S.A. 2009
19948480 Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium J. Cell Biol. 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
19906846 Patched regulates Smoothened trafficking using lipoprotein-derived lipids Development 2009
16339192 Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates Development 2006
20395968 The primary cilium: a signalling centre during vertebrate development Nat. Rev. Genet. 2010
17762891 Patching the gaps in Hedgehog signalling Nat. Cell Biol. 2007
17960137 Hedgehog regulates smoothened activity by inducing a conformational switch Nature 2007
17641202 Patched1 regulates hedgehog signaling at the primary cilium Science 2007
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