Notum Deacylates Wnt Proteins to Suppress Signalling Activity

Overview

Journal Nature

Specialty Science

Date 2015 Mar 4

PMID 25731175

Citations 220

Authors

Satoshi Kakugawa

Paul F Langton

Matthias Zebisch

Steve Howell

Tao-Hsin Chang

Yan Liu

Ten Feizi

Ganka Bineva

Nicola OReilly

Ambrosius P Snijders

E Yvonne Jones

Jean-Paul Vincent

Affiliations

Soon will be listed here.

Abstract

Signalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase.

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References

Teleman A, Cohen S . Dpp gradient formation in the Drosophila wing imaginal disc. Cell. 2001; 103(6):971-80. DOI: 10.1016/s0092-8674(00)00199-9. View

Freeman M . Feedback control of intercellular signalling in development. Nature. 2000; 408(6810):313-9. DOI: 10.1038/35042500. View

Giraldez A, Copley R, Cohen S . HSPG modification by the secreted enzyme Notum shapes the Wingless morphogen gradient. Dev Cell. 2002; 2(5):667-76. DOI: 10.1016/s1534-5807(02)00180-6. View

Fukui S, Feizi T, Galustian C, Lawson A, Chai W . Oligosaccharide microarrays for high-throughput detection and specificity assignments of carbohydrate-protein interactions. Nat Biotechnol. 2002; 20(10):1011-7. DOI: 10.1038/nbt735. View

Lum L, Yao S, Mozer B, Rovescalli A, Von Kessler D, Nirenberg M . Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science. 2003; 299(5615):2039-45. DOI: 10.1126/science.1081403. View

Willert K, Brown J, Danenberg E, Duncan A, Weissman I, Reya T . Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003; 423(6938):448-52. DOI: 10.1038/nature01611. View

Xu Q, Wang Y, Dabdoub A, Smallwood P, Williams J, Woods C . Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004; 116(6):883-95. DOI: 10.1016/s0092-8674(04)00216-8. View

Bornemann D, Duncan J, Staatz W, Selleck S, Warrior R . Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways. Development. 2004; 131(9):1927-38. DOI: 10.1242/dev.01061. View

Xu H, Morishima M, Wylie J, Schwartz R, Bruneau B, Lindsay E . Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development. 2004; 131(13):3217-27. DOI: 10.1242/dev.01174. View

10.

Kreuger J, Perez L, Giraldez A, Cohen S . Opposing activities of Dally-like glypican at high and low levels of Wingless morphogen activity. Dev Cell. 2004; 7(4):503-12. DOI: 10.1016/j.devcel.2004.08.005. View

11.

Kirkpatrick C, Dimitroff B, Rawson J, Selleck S . Spatial regulation of Wingless morphogen distribution and signaling by Dally-like protein. Dev Cell. 2004; 7(4):513-23. DOI: 10.1016/j.devcel.2004.08.004. View

12.

Belenkaya T, Han C, Yan D, Opoka R, Khodoun M, Liu H . Drosophila Dpp morphogen movement is independent of dynamin-mediated endocytosis but regulated by the glypican members of heparan sulfate proteoglycans. Cell. 2004; 119(2):231-44. DOI: 10.1016/j.cell.2004.09.031. View

13.

Basler K, Struhl G . Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature. 1994; 368(6468):208-14. DOI: 10.1038/368208a0. View

14.

Alexandre C, Jacinto A, Ingham P . Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins. Genes Dev. 1996; 10(16):2003-13. DOI: 10.1101/gad.10.16.2003. View

15.

REICHSMAN F, Smith L, Cumberledge S . Glycosaminoglycans can modulate extracellular localization of the wingless protein and promote signal transduction. J Cell Biol. 1996; 135(3):819-27. PMC: 2121077. DOI: 10.1083/jcb.135.3.819. View

16.

Duncan J, GILMAN A . A cytoplasmic acyl-protein thioesterase that removes palmitate from G protein alpha subunits and p21(RAS). J Biol Chem. 1998; 273(25):15830-7. DOI: 10.1074/jbc.273.25.15830. View

17.

Krissinel E, Henrick K . Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 1):2256-68. DOI: 10.1107/S0907444904026460. View

18.

Glise B, Miller C, Crozatier M, Halbisen M, Wise S, Olson D . Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog. Dev Cell. 2005; 8(2):255-66. DOI: 10.1016/j.devcel.2005.01.003. View

19.

Laskowski R, Watson J, Thornton J . ProFunc: a server for predicting protein function from 3D structure. Nucleic Acids Res. 2005; 33(Web Server issue):W89-93. PMC: 1160175. DOI: 10.1093/nar/gki414. View

20.

Hacker U, Nybakken K, Perrimon N . Heparan sulphate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol. 2005; 6(7):530-41. DOI: 10.1038/nrm1681. View