The Output of Hedgehog Signaling is Controlled by the Dynamic Association Between Suppressor of Fused and the Gli Proteins

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2010 Apr 3

PMID 20360384

Citations 270

Authors

Eric W Humke

Karolin V Dorn

Ljiljana Milenkovic

Matthew P Scott

Rajat Rohatgi

Affiliations

Soon will be listed here.

Abstract

The transcriptional program orchestrated by Hedgehog signaling depends on the Gli family of transcription factors. Gli proteins can be converted to either transcriptional activators or truncated transcriptional repressors. We show that the interaction between Gli3 and Suppressor of Fused (Sufu) regulates the formation of either repressor or activator forms of Gli3. In the absence of signaling, Sufu restrains Gli3 in the cytoplasm, promoting its processing into a repressor. Initiation of signaling triggers the dissociation of Sufu from Gli3. This event prevents formation of the repressor and instead allows Gli3 to enter the nucleus, where it is converted into a labile, differentially phosphorylated transcriptional activator. This key dissociation event depends on Kif3a, a kinesin motor required for the function of primary cilia. We propose that the Sufu-Gli3 interaction is a major control point in the Hedgehog pathway, a pathway that plays important roles in both development and cancer.

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References

Pearse 2nd R, Collier L, Scott M, Tabin C . Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators. Dev Biol. 1999; 212(2):323-36. PMC: 4530617. DOI: 10.1006/dbio.1999.9335. View

Taipale J, Chen J, Cooper M, Wang B, MANN R, Milenkovic L . Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature. 2000; 406(6799):1005-9. DOI: 10.1038/35023008. View

Jia J, Kolterud A, Zeng H, Hoover A, Teglund S, Toftgard R . Suppressor of Fused inhibits mammalian Hedgehog signaling in the absence of cilia. Dev Biol. 2009; 330(2):452-60. PMC: 2687323. DOI: 10.1016/j.ydbio.2009.04.009. View

Ogden S, Fei D, Schilling N, Ahmed Y, Hwa J, Robbins D . G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling. Nature. 2008; 456(7224):967-70. PMC: 2744466. DOI: 10.1038/nature07459. View

Mao J, Maye P, Kogerman P, Tejedor F, Toftgard R, Xie W . Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J Biol Chem. 2002; 277(38):35156-61. DOI: 10.1074/jbc.M206743200. View

Huangfu D, Anderson K . Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A. 2005; 102(32):11325-30. PMC: 1183606. DOI: 10.1073/pnas.0505328102. View

Kise Y, Morinaka A, Teglund S, Miki H . Sufu recruits GSK3beta for efficient processing of Gli3. Biochem Biophys Res Commun. 2009; 387(3):569-74. DOI: 10.1016/j.bbrc.2009.07.087. View

Chen J, Taipale J, Young K, Maiti T, Beachy P . Small molecule modulation of Smoothened activity. Proc Natl Acad Sci U S A. 2002; 99(22):14071-6. PMC: 137838. DOI: 10.1073/pnas.182542899. View

Ding Q, Fukami S, Meng X, Nishizaki Y, Zhang X, Sasaki H . Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Curr Biol. 1999; 9(19):1119-22. DOI: 10.1016/s0960-9822(99)80482-5. View

10.

Smelkinson M, Zhou Q, Kalderon D . Regulation of Ci-SCFSlimb binding, Ci proteolysis, and hedgehog pathway activity by Ci phosphorylation. Dev Cell. 2007; 13(4):481-95. PMC: 2063588. DOI: 10.1016/j.devcel.2007.09.006. View

11.

Corbit K, Shyer A, Dowdle W, Gaulden J, Singla V, Chen M . Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat Cell Biol. 2007; 10(1):70-6. DOI: 10.1038/ncb1670. View

12.

Chen M, Wilson C, Li Y, Law K, Lu C, Gacayan R . Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev. 2009; 23(16):1910-28. PMC: 2725943. DOI: 10.1101/gad.1794109. View

13.

Wang Q, Holmgren R . The subcellular localization and activity of Drosophila cubitus interruptus are regulated at multiple levels. Development. 1999; 126(22):5097-106. DOI: 10.1242/dev.126.22.5097. View

14.

Wang B, Fallon J, Beachy P . Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 2000; 100(4):423-34. DOI: 10.1016/s0092-8674(00)80678-9. View

15.

Svard J, Heby-Henricson K, Henricson K, Persson-Lek M, Rozell B, Lauth M . Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell. 2006; 10(2):187-97. DOI: 10.1016/j.devcel.2005.12.013. View

16.

Pastorino L, Ghiorzo P, Nasti S, Battistuzzi L, Cusano R, Marzocchi C . Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am J Med Genet A. 2009; 149A(7):1539-43. DOI: 10.1002/ajmg.a.32944. View

17.

Wang B, Li Y . Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci U S A. 2005; 103(1):33-8. PMC: 1325010. DOI: 10.1073/pnas.0509927103. View

18.

Tempe D, Casas M, Karaz S, Blanchet-Tournier M, Concordet J . Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Mol Cell Biol. 2006; 26(11):4316-26. PMC: 1489100. DOI: 10.1128/MCB.02183-05. View

19.

Seifert A, Allan L, Clarke P . DYRK1A phosphorylates caspase 9 at an inhibitory site and is potently inhibited in human cells by harmine. FEBS J. 2008; 275(24):6268-80. DOI: 10.1111/j.1742-4658.2008.06751.x. View

20.

Methot N, Basler K . Suppressor of fused opposes hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development. 2000; 127(18):4001-10. DOI: 10.1242/dev.127.18.4001. View