Reactome | SMO translocates to the cilium

SMO translocates to the cilium

Stable Identifier

R-HSA-5632668

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

endocytic vesicle membrane, ciliary membrane

ReviewStatus

5/5

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Binding of ligand to the PTCH receptor activates the Hh signaling pathway and results in the accumulation of SMO in the primary cilium (Denef et al, 2000; Corbit et al, 2005; Rohatgi et al, 2007; Milenkovic et al, 2009; Wang et al, 2009; Wilson et al, 2009; reviewed in Briscoe and Therond, 2013). Neither the mechanism for how PTCH represses SMO in the absence of ligand nor how this relief is lifted upon pathway activation are fully understood, however SMO translocation to the cilium appears to depend upon complex formation with beta-arrestin proteins and the anterograde motor protein KIF3A (Chen et al, 2004; Kovacs et al, 2008). GAS8, a SMO- and microtubule-binding protein, is also required for the ciliary localization of SMO, although the mechanism is not clear (Evron et al, 2011; reviewed in Evron et al, 2012). In response to pathway activation, SMO is phosphorylated in a CKI- and ADRBK1/GRK2-dependent fashion and undergoes a conformational change, both of which are required for downstream pathway activation; accumulation of SMO in the cilium is in itself not sufficient (Chen et al, 2011; Zhao et al, 2007; Chen et al, 2010; Rohatgi et al, 2009). In the primary cilium, SMO interacts with the Ellis-van Creveld syndrome proteins 1 and 2 (EVC1 and 2) in a SMO phosphorylation-dependent manner, and the interaction with EVC1 and 2 is required for downstream signal propagation (Yang et al, 2012; Dorn et al, 2012; Capparos-Martin et al, 2013; Pusapati et al, 2014; Yang et al, 2012). SMO activation results in the concentration of SUFU and the GLI proteins in the cilium, the dissociation of the SUFU:GLI complex and the nuclear accumulation of the full length activator form of the GLI proteins (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
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
22277298	GRK2: multiple roles beyond G protein-coupled receptor desensitization Evron, T, Daigle, TL, Caron, MG	Trends Pharmacol. Sci.	2012
22981989	A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia Rohatgi, R, Hughes, CE, Dorn, KV	Dev. Cell	2012
23719536	The mechanisms of Hedgehog signalling and its roles in development and disease Thérond, PP, Briscoe, J	Nat. Rev. Mol. Cell Biol.	2013
10966113	Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened Cohen, SM, Denef, N, Neubüser, D, Perez, L	Cell	2000
19365551	Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium Chuang, PT, Wilson, CW, Chen, MH	PLoS ONE	2009
15618519	Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2 Chen, W, Beachy, PA, Barak, LS, Nelson, CD, Lefkowitz, RJ, de Sauvage, F, Chen, JK, Ren, XR	Science	2004
21659505	Growth Arrest Specific 8 (Gas8) and G protein-coupled receptor kinase 2 (GRK2) cooperate in the control of Smoothened signaling Chen, W, Evron, T, Caron, MG, Meloni, AR, Lu, J, Burkhalter, M, Philipp, M	J. Biol. Chem.	2011
16136078	Vertebrate Smoothened functions at the primary cilium Stainier, DY, Singla, V, Norman, AR, Reiter, JF, Aanstad, P, Corbit, KC	Nature	2005
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
19196978	Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation Walsh, CT, McMahon, AP, Wang, Y, Zhou, Z	Proc. Natl. Acad. Sci. U.S.A.	2009
19948480	Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium Milenkovic, L, Rohatgi, R, Scott, MP	J. Cell Biol.	2009
18497258	Beta-arrestin-mediated localization of smoothened to the primary cilium Chen, W, Liu, R, Kim, J, Wang, J, Chen, M, Whalen, EJ, Kovacs, JJ, Lefkowitz, RJ, Xiao, K	Science	2008
19218434	Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process Milenkovic, L, Rohatgi, R, Scott, MP, Corcoran, RB	Proc. Natl. Acad. Sci. U.S.A.	2009
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
23026747	The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia Ruiz-Perez, VL, Gean, E, Fernandez, M, Goodship, JA, Valencia, M, Pacheco, M, Lapunzina, P, Perez-Aytes, A, Reytor, E, Caparrós-Martín, JA, Peters, H	Hum. Mol. Genet.	2013
17641202	Patched1 regulates hedgehog signaling at the primary cilium Milenkovic, L, Rohatgi, R, Scott, MP	Science	2007