CSNK1A1 binds SMO dimer

Stable Identifier
R-HSA-5632671
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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Activation of SMO in vertebrate cells depends upon its sequential phosphorylation by CSNK1A1/CK1alpha and ADRBK1/GRK2 kinases. Phosphorylation is thought to promote a conformational change in the SMO C-terminal tails, destabilizing an intramolecular interaction within the tail and promoting a more open conformation that brings the two tails of the SMO dimer into closer proximity (Chen et al, 2010; Chen et al, 2011; Wilson et al, 2009). This mechanism parallels the activation of Smo in Drosophila, where phosphorylation of consensus PKA and CK1 sites in the C-terminus promotes conformational change (Zhao et al, 2007). In both Drosophila and vertebrates, the kinases interact with SMO as assessed by co-precipitation (Zhao et al, 2007; Chen et al, 2010; Chen et al, 2011). In vertebrate cells, SHH stimulation appears to promote a 2-step activation of SMO. In the first step, CSNK1A1 binds to the C-terminal tails in the closed conformation. Initial CSNK1A1-mediated phosphorylation promotes the open conformation and increases the binding affinity of both CSNK1A1 and ADRBK1/GRK2 for the SMO tail, establishing a positive feedback loop to enhance SMO phosphorylation (Chen et al, 2010; Chen et al, 2011; Meloni et al 2006; Philipp et al, 2008). CSNK1A1 accumulates in the primary cilium in an SHH-dependent manner, and the kinetics of SMO phosphorylation are faster there than in the whole cell. Phosphorylation also depends on the kinesin II ciliary motor KIF3A, and promotes the ciliary accumulation of SMO, possibly in a ARRB-dependent manner (Chen et al, 2011; Meloni et al, 2006).

Literature References
PubMed ID Title Journal Year
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

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

Genes Dev. 2010
21695114 Sonic Hedgehog dependent phosphorylation by CK1? and GRK2 is required for ciliary accumulation and activation of smoothened

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

PLoS Biol. 2011
16908539 Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2

Meloni, AR, Fralish, GB, Kelly, P, Salahpour, A, Chen, JK, Wechsler-Reya, RJ, Lefkowitz, RJ, Caron, MG

Mol. Cell. Biol. 2006
18815277 Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinase

Philipp, M, Fralish, GB, Meloni, AR, Chen, W, MacInnes, AW, Barak, LS, Caron, MG

Mol. Biol. Cell 2008
17960137 Hedgehog regulates smoothened activity by inducing a conformational switch

Zhao, Y, Tong, C, Jiang, J

Nature 2007
19365551 Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium

Wilson, CW, Chen, MH, Chuang, PT

PLoS ONE 2009
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