GLI proteins are phosphorylated

Stable Identifier
Reaction [omitted]
Homo sapiens
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Hh signaling induces phosphorylation of full-length GLI that coincides with its nuclear localization and transcription factor activity (Humke et al, 2010; reviewed in Hui and Angers, 2011). Although this is depicted as occuring in the nucleus, the identity and location of the kinase(s) is not definitively known, nor is the ordering of the phosphorylation and translocation events (Wen et al, 2010; Humke et al, 2010; reviewed in Hui and Angers, 2011). Both cytoplasmic/ciliary and nuclear full-length GLI proteins are likely subject to phosphorylation, and the interaction between the numerous regulatory events is not clear. CDC2L1 was identified as a kinase that positively regulates Hh pathway activity, and it was shown to bind SUFU and promote the dissociation of the GLI1:SUFU complex in a kinase-dependent manner in mouse, but it has not been implicated in the phosphorylation of the GLI transcription factors themselves (Evangelista et al, 2008). ULK3 is another kinase that positively regulates Hh signaling and has been proposed to phosphorylate GLI proteins to promote their transcriptional activity (Maloverjan et al, 2010a; Maloverjan et al, 2010b; reviewed in Maloverjan and Piirsoo, 2012). DYRK family kinases are also implicated in the post-transcriptional regulation of the GLI proteins in both a positive and a negative manner (Mao et al, 2002; Lauth et al, 2010; Varjosalo et al, 2008).
Once in the nucleus, phosphorylated GLI transcription factors bind to promoters of Hh-responsive genes such as PTCH1, PTCH2, GLI1 and HHIP to activate transcription (Vokes et al, 2007; Vokes et al 2007; Lee et al, 2010; reviewed in Briscoe and Therond, 2013). The full-length transcriptionally active GLI proteins are labile and subject to SPOP-dependent proteolysis (Chen et al, 2009; Zhang et al, 2009; Wen et al, 2010).
Literature References
PubMed ID Title Journal Year
18827223 Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction

Davis, DP, Ye, W, Ashique, A, Parker, L, Lee, J, Evangelista, M, Peterson, AS, Lim, TY, de Sauvage, FJ

Sci Signal 2008
21801010 Gli proteins in development and disease

Hui, CC, Angers, S

Annu. Rev. Cell Dev. Biol. 2011
20154143 Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation

Scales, SJ, Hongo, JA, Wen, X, Evangelista, M, Lai, CK, de Sauvage, FJ

Mol. Cell. Biol. 2010
22391301 Mammalian homologues of Drosophila fused kinase

Piirsoo, M, Maloverjan, A

Vitam. Horm. 2012
19878745 Identification of a novel serine/threonine kinase ULK3 as a positive regulator of Hedgehog pathway

Kogerman, P, Osterlund, T, Piirsoo, M, Maloverjan, A, Michelson, P

Exp. Cell Res. 2010
20460306 Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis

Wong, WH, McMahon, AP, Ji, H, Scott, MP, Lee, EY, Vokes, SA, Ma, W, Ouyang, Z, Zhou, B

Proc. Natl. Acad. Sci. U.S.A. 2010
19955409 Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase

Yue, T, Li, S, Zhang, Q, Wang, B, Shi, Q, Jiang, J, Chen, Y

Proc. Natl. Acad. Sci. U.S.A. 2009
12138125 Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1

Wu, G, Kogerman, P, Maye, P, Tejedor, FJ, Xie, W, Mao, J, Toftgard, R, Wu, D

J. Biol. Chem. 2002
19684112 Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved

Li, YJ, Zhang, X, Hui, CC, Chuang, PT, Gacayan, R, Law, KK, Wilson, CW, Lu, CS, Chen, MH

Genes Dev. 2009
20512148 DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS

Barbacid, M, Guerra, C, Jin, Q, Fendrich, V, Shimokawa, T, Toftgård, R, Bergström, A, Lauth, M, Tostar, U

Nat. Struct. Mol. Biol. 2010
17442700 Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning

Davidson, EH, Giles, S, Wong, WH, Longabaugh, WJ, McCuine, S, McMahon, AP, Ji, H, Tenzen, T, Vokes, SA, Zhong, S

Development 2007
20643644 Dual function of UNC-51-like kinase 3 (Ulk3) in the Sonic hedgehog signaling pathway

Kogerman, P, Kasak, L, Piirsoo, M, Maloverjan, A, Østerlund, T, Peil, L

J. Biol. Chem. 2010
18832070 A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb

Wong, WH, McMahon, AP, Ji, H, Vokes, SA

Genes Dev. 2008
20360384 The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins

Milenkovic, L, Rohatgi, R, Scott, MP, Humke, EW, Dorn, KV

Genes Dev. 2010
18455992 Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling

Björklund, M, Varjosalo, M, Kivioja, T, Syvänen, H, Kilpinen, S, Kallioniemi, O, Taipale, J, Sun, Z, Stunnenberg, HG, He, WW, Cheng, F, Ojala, P

Cell 2008
Catalyst Activity

protein serine/threonine kinase activity of unknown kinase [nucleoplasm]

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