The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 10 2023
05 10 2023
Historique:
received:
19
12
2021
accepted:
20
09
2023
medline:
9
10
2023
pubmed:
6
10
2023
entrez:
5
10
2023
Statut:
epublish
Résumé
The control of Wnt receptor abundance is critical for animal development and to prevent tumorigenesis, but the mechanisms that mediate receptor stabilization remain uncertain. We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila. By reducing Arrow ubiquitylation and turnover, the Usp46 complex increases cell surface levels of Arrow and enhances the sensitivity of target cells to stimulation by the Wingless morphogen, thereby increasing the amplitude and spatial range of signaling responses. Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/β-catenin, and attenuates or abolishes Wingless target gene activation, which prevents the concentration-dependent regulation of signaling strength. Consequently, Wingless-dependent developmental patterning and tissue homeostasis are disrupted. These results reveal an evolutionarily conserved mechanism that mediates Wnt/Wingless receptor stabilization and underlies the precise activation of signaling throughout the spatial range of the morphogen gradient.
Identifiants
pubmed: 37798281
doi: 10.1038/s41467-023-41843-0
pii: 10.1038/s41467-023-41843-0
pmc: PMC10556106
doi:
Substances chimiques
Drosophila Proteins
0
Wnt1 Protein
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
6174Subventions
Organisme : NIH HHS
ID : P40 OD010949
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023108
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA219189
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM136233
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM113132
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122516
Pays : United States
Organisme : NIH HHS
ID : P40 OD018537
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244188
Pays : United States
Organisme : NIH HHS
ID : S10 OD032310
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM137793
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008554
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM145596
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA281002
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118082
Pays : United States
Organisme : NHGRI NIH HHS
ID : U41 HG000739
Pays : United States
Informations de copyright
© 2023. Springer Nature Limited.
Références
G3 (Bethesda). 2017 Jan 5;7(1):87-93
pubmed: 27793971
Structure. 2015 Nov 3;23(11):2043-54
pubmed: 26388029
Development. 1995 Dec;121(12):4215-25
pubmed: 8575321
Nat Cell Biol. 2012 Oct;14(10):1036-45
pubmed: 22983114
Nature. 2012 Aug 30;488(7413):665-9
pubmed: 22895187
Nature. 2013 Jun 27;498(7455):456-62
pubmed: 23783517
Science. 1996 Oct 11;274(5285):252-5
pubmed: 8824191
Development. 2002 Jun;129(11):2565-76
pubmed: 12015286
Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):E2967-76
pubmed: 25002478
Oncotarget. 2014 Aug 30;5(16):7081-92
pubmed: 25216524
Gene Expr Patterns. 2006 Jun;6(5):504-18
pubmed: 16423565
Development. 2006 Jan;133(2):307-17
pubmed: 16354714
Development. 2002 Apr;129(7):1751-62
pubmed: 11923210
Oncogene. 2013 Jan 24;32(4):471-8
pubmed: 22391563
Nat Commun. 2023 Oct 5;14(1):6173
pubmed: 37798301
J Biol Chem. 2011 Mar 4;286(9):7190-201
pubmed: 21183687
Development. 2005 Dec;132(24):5479-89
pubmed: 16291792
J Cell Biol. 2013 Jun 10;201(6):945-61
pubmed: 23733344
Sci Signal. 2023 Feb 7;16(771):eabn8372
pubmed: 36749823
Development. 2019 Aug 9;146(15):
pubmed: 31399474
Nature. 2017 Oct 26;550(7677):481-486
pubmed: 29045389
J Struct Biol. 2016 Dec;196(3):437-447
pubmed: 27650958
Cell. 1996 Nov 29;87(5):833-44
pubmed: 8945511
Nature. 2007 Jul 12;448(7150):151-6
pubmed: 17625558
Nat Methods. 2011 Sep;8(9):737-43
pubmed: 21985007
J Neurochem. 2015 Sep;134(6):1067-80
pubmed: 26077708
PLoS Biol. 2021 Mar 3;19(3):e3001111
pubmed: 33657096
Elife. 2018 Aug 10;7:
pubmed: 30095068
Nat Commun. 2018 Jun 12;9(1):2295
pubmed: 29895891
J Biol Chem. 2012 Aug 24;287(35):29429-41
pubmed: 22778262
J Biol Chem. 2010 Apr 9;285(15):11252-7
pubmed: 20147737
PLoS Genet. 2019 Jun 13;15(6):e1008111
pubmed: 31194729
Nature. 2012 Apr 29;485(7397):195-200
pubmed: 22575959
J Biol Chem. 2013 Nov 29;288(48):34545-54
pubmed: 24145035
Nature. 2008 Oct 23;455(7216):1119-23
pubmed: 18806781
Nature. 2017 Oct 26;550(7677):534-538
pubmed: 29045385
Development. 2014 Jun;141(12):2483-93
pubmed: 24917503
Cell. 2009 Jul 23;138(2):389-403
pubmed: 19615732
PLoS Genet. 2017 Jul 14;13(7):e1006870
pubmed: 28708826
Mol Cell. 2016 Jul 21;63(2):249-260
pubmed: 27373336
Nature. 2014 Jan 9;505(7482):180-5
pubmed: 24390349
J Biol Chem. 2014 Feb 7;289(6):3444-56
pubmed: 24356955
Cell. 2009 Jun 26;137(7):1343-55
pubmed: 19563763
Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):370-7
pubmed: 22203956
Nature. 2000 Sep 28;407(6803):527-30
pubmed: 11029006
Mol Pharmacol. 2020 Feb;97(2):72-89
pubmed: 31787618
Cell. 1998 May 29;93(5):767-77
pubmed: 9630221
PLoS Genet. 2019 Jun 13;15(6):e1008154
pubmed: 31194739
Development. 1997 Feb;124(4):871-80
pubmed: 9043068
Nat Protoc. 2006;1(6):2583-9
pubmed: 17406512
Genes Dev. 2016 Jun 15;30(12):1389-94
pubmed: 27313319
Cell. 2003 Feb 7;112(3):343-54
pubmed: 12581524
Nat Commun. 2016 Sep 14;7:12751
pubmed: 27624192
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15050-5
pubmed: 11742088
Development. 2016 May 15;143(10):1710-20
pubmed: 27190037
Nat Methods. 2016 Oct;13(10):852-4
pubmed: 27595403
Dev Biol. 2006 May 1;293(1):268-83
pubmed: 16530179
Cancers (Basel). 2019 Aug 13;11(8):
pubmed: 31412666
Nature. 2005 May 5;435(7038):58-65
pubmed: 15875013
Cell Syst. 2018 Jan 24;6(1):52-64.e4
pubmed: 29199019
Oncotarget. 2016 Aug 30;7(35):56147-56152
pubmed: 27528229
J Neurosci. 2011 Jan 26;31(4):1341-54
pubmed: 21273419
Trends Neurosci. 2001 May;24(5):251-4
pubmed: 11311363
Cell. 2003 Feb 7;112(3):355-67
pubmed: 12581525
Mol Cell. 2000 Jan;5(1):59-71
pubmed: 10678169
Nat Rev Cancer. 2021 Jan;21(1):5-21
pubmed: 33097916
EMBO J. 2012 Oct 3;31(19):3901-17
pubmed: 22948071
Genetics. 2014 Apr;196(4):961-71
pubmed: 24478335
PLoS Genet. 2021 Apr 2;17(4):e1009469
pubmed: 33798197
Development. 2009 Jul;136(13):2255-64
pubmed: 19502486
J Dev Biol. 2018 Mar 28;6(2):
pubmed: 29615557
J Biol Chem. 2013 Nov 8;288(45):32641-32650
pubmed: 24056413
Cell. 2000 Aug 4;102(3):349-62
pubmed: 10975525
Genes Dev. 2019 Feb 1;33(3-4):209-220
pubmed: 30692207
Development. 1993 Jun;118(2):401-15
pubmed: 8223268
PLoS Genet. 2016 Feb 04;12(2):e1005822
pubmed: 26845150
Elife. 2020 Feb 13;9:
pubmed: 32053108
Nature. 2006 Jan 26;439(7075):475-9
pubmed: 16340959
Elife. 2016 Oct 18;5:
pubmed: 27751231
Genetics. 2016 May;203(1):269-81
pubmed: 26975665
J Biol Chem. 2009 Feb 20;284(8):5343-51
pubmed: 19075014
Nature. 2000 Feb 17;403(6771):789-95
pubmed: 10693810
Genome. 1996 Feb;39(1):174-82
pubmed: 8851804
Elife. 2016 Dec 20;5:
pubmed: 27996937
Science. 1999 Mar 12;283(5408):1739-42
pubmed: 10073940
J Virol. 2014 Aug;88(15):8545-55
pubmed: 24850727
Nature. 2020 Sep;585(7823):85-90
pubmed: 32699409