Developmental Regulation of Wnt Signaling by Nagk and the UDP-GlcNAc Salvage Pathway

Overview

Journal Mech Dev

Publisher Elsevier

Specialties Biology
Cell Biology
Reproductive Medicine

Date 2019 Mar 25

PMID 30904594

Citations 10

Authors

Leif R Neitzel

Zachary T Spencer

Anmada Nayak

Christopher S Cselenyi

Hassina Benchabane

CheyAnne Q Youngblood

Alya Zouaoui

Victoria Ng

Leah Stephens

Trevor Hann

James G Patton

David Robbins

Yashi Ahmed

Ethan Lee

Affiliations

Soon will be listed here.

Abstract

In a screen for human kinases that regulate Xenopus laevis embryogenesis, we identified Nagk and other components of the UDP-GlcNAc glycosylation salvage pathway as regulators of anteroposterior patterning and Wnt signaling. We find that the salvage pathway does not affect other major embryonic signaling pathways (Fgf, TGFβ, Notch, or Shh), thereby demonstrating specificity for Wnt signaling. We show that the role of the salvage pathway in Wnt signaling is evolutionarily conserved in zebrafish and Drosophila. Finally, we show that GlcNAc is essential for the growth of intestinal enteroids, which are highly dependent on Wnt signaling for growth and maintenance. We propose that the Wnt pathway is sensitive to alterations in the glycosylation state of a cell and acts as a nutritional sensor in order to couple growth/proliferation with its metabolic status. We also propose that the clinical manifestations observed in congenital disorders of glycosylation (CDG) in humans may be due, in part, to their effects on Wnt signaling during development.

Citing Articles

Model-based dynamic engineering of for N-acetylglucosamine overproduction.

Lu J, Wu Y, Deng C, Liu Y, Lv X, Li J Biotechnol Notes. 2024; 3:15-24.

PMID: 39416442 PMC: 11446382. DOI: 10.1016/j.biotno.2022.02.001.

The Immunometabolic Gene N-Acetylglucosamine Kinase Is Uniquely Involved in the Heritability of Multiple Sclerosis Severity.

Nataf S, Guillen M, Pays L Int J Mol Sci. 2024; 25(7).

PMID: 38612613 PMC: 11011344. DOI: 10.3390/ijms25073803.

The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling.

Ng V, Spencer Z, Neitzel L, Nayak A, Loberg M, Shen C Nat Commun. 2023; 14(1):6173.

PMID: 37798301 PMC: 10556042. DOI: 10.1038/s41467-023-41836-z.

The Hexosamine Biosynthesis Pathway: Regulation and Function.

Paneque A, Fortus H, Zheng J, Werlen G, Jacinto E Genes (Basel). 2023; 14(4).

PMID: 37107691 PMC: 10138107. DOI: 10.3390/genes14040933.

Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG).

Brasil S, Allocca M, Magrinho S, Santos I, Raposo M, Francisco R Int J Mol Sci. 2022; 23(15).

PMID: 35955863 PMC: 9369176. DOI: 10.3390/ijms23158725.

References

Mahalingam B, Davis E, Matschinsky F, Harrison R, Weber I . Structural model of human glucokinase in complex with glucose and ATP: implications for the mutants that cause hypo- and hyperglycemia. Diabetes. 1999; 48(9):1698-705. DOI: 10.2337/diabetes.48.9.1698. View

Peters J, McKay R, McKay J, Graff J . Casein kinase I transduces Wnt signals. Nature. 1999; 401(6751):345-50. DOI: 10.1038/43830. View

Sakanaka C, Leong P, Xu L, Harrison S, Williams L . Casein kinase iepsilon in the wnt pathway: regulation of beta-catenin function. Proc Natl Acad Sci U S A. 1999; 96(22):12548-52. PMC: 22983. DOI: 10.1073/pnas.96.22.12548. View

Tanimoto H, Itoh S, Ten Dijke P, Tabata T . Hedgehog creates a gradient of DPP activity in Drosophila wing imaginal discs. Mol Cell. 2000; 5(1):59-71. DOI: 10.1016/s1097-2765(00)80403-7. View

Heisenberg C, Tada M, Rauch G, Saude L, Concha M, Geisler R . Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature. 2000; 405(6782):76-81. DOI: 10.1038/35011068. View

Hinderlich S, Berger M, Schwarzkopf M, Effertz K, REUTTER W . Molecular cloning and characterization of murine and human N-acetylglucosamine kinase. Eur J Biochem. 2000; 267(11):3301-8. DOI: 10.1046/j.1432-1327.2000.01360.x. View

Rossetti L . Perspective: Hexosamines and nutrient sensing. Endocrinology. 2000; 141(6):1922-5. DOI: 10.1210/endo.141.6.7566. View

Nolo R, Abbott L, Bellen H . Senseless, a Zn finger transcription factor, is necessary and sufficient for sensory organ development in Drosophila. Cell. 2000; 102(3):349-62. DOI: 10.1016/s0092-8674(00)00040-4. View

Kim C, Oda T, Itoh M, Jiang D, Artinger K, Chandrasekharappa S . Repressor activity of Headless/Tcf3 is essential for vertebrate head formation. Nature. 2000; 407(6806):913-6. PMC: 4018833. DOI: 10.1038/35038097. View

10.

van de Water S, van de Wetering M, Joore J, Esseling J, Bink R, Clevers H . Ectopic Wnt signal determines the eyeless phenotype of zebrafish masterblind mutant. Development. 2001; 128(20):3877-88. DOI: 10.1242/dev.128.20.3877. View

11.

Holmen S, Salic A, Zylstra C, Kirschner M, Williams B . A novel set of Wnt-Frizzled fusion proteins identifies receptor components that activate beta -catenin-dependent signaling. J Biol Chem. 2002; 277(38):34727-35. DOI: 10.1074/jbc.M204989200. View

12.

Berger M, Chen H, Reutter W, Hinderlich S . Structure and function of N-acetylglucosamine kinase. Identification of two active site cysteines. Eur J Biochem. 2002; 269(17):4212-8. DOI: 10.1046/j.1432-1033.2002.03117.x. View

13.

Zeitler R, Giannis A, Danneschewski S, Henk E, Henk T, Bauer C . Inhibition of N-acetylglucosamine kinase and N-acetylmannosamine kinase by 3-O-methyl-N-acetyl-D-glucosamine in vitro. Eur J Biochem. 1992; 204(3):1165-8. DOI: 10.1111/j.1432-1033.1992.tb16743.x. View

14.

Swiatek W, Tsai I, Klimowski L, Pepler A, Barnette J, Yost H . Regulation of casein kinase I epsilon activity by Wnt signaling. J Biol Chem. 2004; 279(13):13011-7. DOI: 10.1074/jbc.M304682200. View

15.

Cheatham B . Enough is enough: nutrient sensors and insulin resistance. Endocrinology. 2004; 145(5):2115-7. DOI: 10.1210/en.2004-0146. View

16.

Moriishi T, Shibata Y, Tsukazaki T, Yamaguchi A . Expression profile of Xenopus banded hedgehog, a homolog of mouse Indian hedgehog, is related to the late development of endochondral ossification in Xenopus laevis. Biochem Biophys Res Commun. 2005; 328(4):867-73. DOI: 10.1016/j.bbrc.2005.01.032. View

17.

Cavodeassi F, Carreira-Barbosa F, Young R, Concha M, Allende M, Houart C . Early stages of zebrafish eye formation require the coordinated activity of Wnt11, Fz5, and the Wnt/beta-catenin pathway. Neuron. 2005; 47(1):43-56. PMC: 2790414. DOI: 10.1016/j.neuron.2005.05.026. View

18.

Batut J, Vandel L, Leclerc C, Daguzan C, Moreau M, Neant I . The Ca2+-induced methyltransferase xPRMT1b controls neural fate in amphibian embryo. Proc Natl Acad Sci U S A. 2005; 102(42):15128-33. PMC: 1257693. DOI: 10.1073/pnas.0502483102. View

19.

Swain R, Katoh M, Medina A, Steinbeisser H . Xenopus frizzled-4S, a splicing variant of Xfz4 is a context-dependent activator and inhibitor of Wnt/beta-catenin signaling. Cell Commun Signal. 2005; 3:12. PMC: 1291380. DOI: 10.1186/1478-811X-3-12. View

20.

Freeze H . Genetic defects in the human glycome. Nat Rev Genet. 2006; 7(7):537-51. DOI: 10.1038/nrg1894. View