Ubiquitylation at the Crossroads of Development and Disease

Overview

Journal Nat Rev Mol Cell Biol

Specialties Cell Biology
Molecular Biology

Date 2017 Sep 21

PMID 28928488

Citations 297

Authors

Michael Rape

Affiliations

Soon will be listed here.

Abstract

Human development requires intricate cell specification and communication pathways that allow an embryo to generate and appropriately connect more than 200 different cell types. Key to the successful completion of this differentiation programme is the quantitative and reversible regulation of core signalling networks, and post-translational modification with ubiquitin provides embryos with an essential tool to accomplish this task. Instigated by E3 ligases and reversed by deubiquitylases, ubiquitylation controls many processes that are fundamental for development, such as cell division, fate specification and migration. As aberrant function or regulation of ubiquitylation enzymes is at the roots of developmental disorders, cancer, and neurodegeneration, modulating the activity of ubiquitylation enzymes is likely to provide strategies for therapeutic intervention.

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References

Lasorella A, Stegmuller J, Guardavaccaro D, Liu G, Carro M, Rothschild G . Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature. 2006; 442(7101):471-4. DOI: 10.1038/nature04895. View

Voncken J, Roelen B, Roefs M, de Vries S, Verhoeven E, Marino S . Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc Natl Acad Sci U S A. 2003; 100(5):2468-73. PMC: 151364. DOI: 10.1073/pnas.0434312100. View

Shao S, Brown A, Santhanam B, Hegde R . Structure and assembly pathway of the ribosome quality control complex. Mol Cell. 2015; 57(3):433-44. PMC: 4321881. DOI: 10.1016/j.molcel.2014.12.015. View

Yau R, Rape M . The increasing complexity of the ubiquitin code. Nat Cell Biol. 2016; 18(6):579-86. DOI: 10.1038/ncb3358. View

Sahtoe D, Sixma T . Layers of DUB regulation. Trends Biochem Sci. 2015; 40(8):456-67. DOI: 10.1016/j.tibs.2015.05.002. View

Hernandez A, Klein A, Kirschner M . Kinetic responses of β-catenin specify the sites of Wnt control. Science. 2012; 338(6112):1337-40. DOI: 10.1126/science.1228734. View

Cang Y, Zhang J, Nicholas S, Bastien J, Li B, Zhou P . Deletion of DDB1 in mouse brain and lens leads to p53-dependent elimination of proliferating cells. Cell. 2006; 127(5):929-40. DOI: 10.1016/j.cell.2006.09.045. View

McGourty C, Akopian D, Walsh C, Gorur A, Werner A, Schekman R . Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor. Cell. 2016; 167(2):525-538.e14. DOI: 10.1016/j.cell.2016.09.026. View

Zhu P, Zhou W, Wang J, Puc J, Ohgi K, Erdjument-Bromage H . A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation. Mol Cell. 2007; 27(4):609-21. PMC: 2709280. DOI: 10.1016/j.molcel.2007.07.024. View

10.

Hames R, Wattam S, Yamano H, Bacchieri R, Fry A . APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box. EMBO J. 2001; 20(24):7117-27. PMC: 125337. DOI: 10.1093/emboj/20.24.7117. View

11.

Hao H, Xie Y, Zhang Y, Charlat O, Oster E, Avello M . ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature. 2012; 485(7397):195-200. DOI: 10.1038/nature11019. View

12.

Finley D, Bartel B, Varshavsky A . The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis. Nature. 1989; 338(6214):394-401. DOI: 10.1038/338394a0. View

13.

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

14.

Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S . The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014; 507(7493):508-12. PMC: 6258903. DOI: 10.1038/nature12998. View

15.

Jaakkola P, Mole D, Tian Y, Wilson M, Gielbert J, Gaskell S . Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001; 292(5516):468-72. DOI: 10.1126/science.1059796. View

16.

Winkle C, Olsen R, Kim H, Moy S, Song J, Gupton S . Trim9 Deletion Alters the Morphogenesis of Developing and Adult-Born Hippocampal Neurons and Impairs Spatial Learning and Memory. J Neurosci. 2016; 36(18):4940-58. PMC: 4854964. DOI: 10.1523/JNEUROSCI.3876-15.2016. View

17.

Konishi Y, Stegmuller J, Matsuda T, Bonni S, Bonni A . Cdh1-APC controls axonal growth and patterning in the mammalian brain. Science. 2004; 303(5660):1026-30. DOI: 10.1126/science.1093712. View

18.

Jiang X, Charlat O, Zamponi R, Yang Y, Cong F . Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Mol Cell. 2015; 58(3):522-33. DOI: 10.1016/j.molcel.2015.03.015. View

19.

McMillan B, Schnute B, Ohlenhard N, Zimmerman B, Miles L, Beglova N . A tail of two sites: a bipartite mechanism for recognition of notch ligands by mind bomb E3 ligases. Mol Cell. 2015; 57(5):912-924. PMC: 4355479. DOI: 10.1016/j.molcel.2015.01.019. View

20.

Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M . Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014; 510(7503):162-6. DOI: 10.1038/nature13392. View