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

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Reaction [omitted]
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
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