Activation of SMO

Stable Identifier
Homo sapiens
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Activation of the transmembrane protein SMO in response to Hh stimulation is a major control point in the Hh signaling pathway (reviewed in Ayers and Therond, 2010; Jiang and Hui, 2008). In the absence of ligand, SMO is inhibited in an unknown manner by the Hh receptor PTCH. 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 may regulate 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).

PTCH-mediated inhibition of SMO is relieved upon ligand stimulation of PTCH, but the mechanisms for this relief are again unknown. 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). Activation of SMO involves a conserved phosphorylation-mediated conformational change in the C-terminal tails that destabilizes an intramolecular interaction and promotes the interaction between adjacent tails in the SMO dimer. In Drosophila, this phosphorylation is mediated by PKA and CK1, while in vertebrates it appears to involve ADRBK1/GRK2 and CSNK1A1. Sequential phosphorylations along multiple serine and threonine motifs in the SMO C-terminal tail appear to allow a graded response to Hh ligand concentration in both flies and vertebrates (Zhao et al, 2007; Chen et al, 2010; Chen et al, 2011). In flies, Smo C-terminal tail phosphorylation promotes an association with the Hedgehog signaling complex (HSC) through interaction with the scaffolding kinesin-2 like protein Cos2, activating the Fu kinase and ultimately releasing uncleaved Ci from the complex (Zhang et al, 2005; Ogden et al, 2003; Lum et al, 2003; reviewed in Mukhopadhyay and Rohatgi, 2014). In vertebrates, SMO C-terminal tail phosphorylation and conformational change is linked to its KIF7-dependent ciliary accumulation (Chen et al, 2011; Zhao et al, 2007; Chen et al, 2010). In the cilium, SMO is restricted to a transition-zone proximal region known as the EvC zone (Yang et al, 2012; Blair et al, 2011; Pusapati et al, 2014; reviewed in Eggenschwiler 2012). Both SMO phosphorylation and its ciliary localization are required to promote the Hh-dependent dissociation of the GLI:SUFU complex, ultimately allowing full-length GLI transcription factors to translocate to the nucleus to activate Hh-responsive genes (reviewed in Briscoe and Therond, 2013).

Literature References
PubMed ID Title Journal Year
22986504 Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

Yang, C, Chen, W, Jiang, J, Chen, Y

Cell Res. 2012
12192414 Patched acts catalytically to suppress the activity of Smoothened

Cooper, MK, Maiti, T, Beachy, PA, Taipale, J

Nature 2002
21695114 Sonic Hedgehog dependent phosphorylation by CK1? and GRK2 is required for ciliary accumulation and activation of smoothened

Yue, T, Jia, J, Ma, G, Sasai, N, Briscoe, J, Jiang, J, Chen, Y

PLoS Biol. 2011
15691767 Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus

Tong, C, Wang, G, Zhang, W, Zhao, Y, Wang, B, Jiang, J, Jia, J

Dev Cell 2005
21801010 Gli proteins in development and disease

Hui, CC, Angers, S

Annu. Rev. Cell Dev. Biol. 2011
14636583 Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2

Beachy, PA, Weis-Garcia, F, Oh, S, Wang, B, Lum, L, Zhang, C, Taipale, J, von Kessler, DP, Gong, R, Mann, RK

Mol Cell 2003
16459297 Divergence of hedgehog signal transduction mechanism between Drosophila and mammals

Li, SP, Varjosalo, M, Taipale, J

Dev. Cell 2006
22981989 A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia

Rohatgi, R, Hughes, CE, Dorn, KV

Dev. Cell 2012
10966113 Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened

Cohen, SM, Denef, N, Neubüser, D, Perez, L

Cell 2000
23719536 The mechanisms of Hedgehog signalling and its roles in development and disease

Thérond, PP, Briscoe, J

Nat. Rev. Mol. Cell Biol. 2013
24845016 G-protein-coupled receptors, Hedgehog signaling and primary cilia

Rohatgi, R, Mukhopadhyay, S

Semin. Cell Dev. Biol. 2014
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

Zhao, Y, Jia, J, Li, S, Tong, C, Liu, Y, Wang, B, Jiang, J, Chen, Y

Genes Dev. 2010
14614827 Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2

Robbins, DJ, Hooper, JE, Ascano M, Jr, Suber, LM, Ogden, SK, Stegman, MA

Curr Biol 2003
23079593 Hedgehog signaling and the cilium: in the zone

Eggenschwiler, J

Dev. Cell 2012
19906846 Patched regulates Smoothened trafficking using lipoprotein-derived lipids

Eugster, C, Khaliullina, H, Carvalho, M, Riedel, F, Eaton, S, Panáková, D

Development 2009
16339192 Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates

Huangfu, D, Anderson, KV

Development 2006
20395968 The primary cilium: a signalling centre during vertebrate development

Anderson, KV, Goetz, SC

Nat. Rev. Genet. 2010
17762891 Patching the gaps in Hedgehog signalling

Rohatgi, R, Scott, MP

Nat. Cell Biol. 2007
20412775 The long-range activity of Hedgehog is regulated in the apical extracellular space by the glypican Dally and the hydrolase Notum

Gallet, A, Ayers, KL, Thérond, PP, Staccini-Lavenant, L

Dev. Cell 2010
24582806 EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia

Aravind, L, Rohatgi, R, Sugianto, P, Zhang, D, Hughes, CE, Dorn, KV, Pusapati, GV

Dev. Cell 2014
17960137 Hedgehog regulates smoothened activity by inducing a conformational switch

Tong, C, Jiang, J, Zhao, Y

Nature 2007
21356043 Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus

Campbell, J, Blair, HJ, Ruiz-Perez, VL, Goodship, JA, MacArthur, K, Tompson, S, Liu, YN, Ponting, CP

BMC Biol. 2011
17641202 Patched1 regulates hedgehog signaling at the primary cilium

Milenkovic, L, Rohatgi, R, Scott, MP

Science 2007
19081070 Hedgehog signaling in development and cancer

Hui, CC, Jiang, J

Dev. Cell 2008
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