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Wnt/Wg-signalling is critical signalling in all metazoans. Recent studies suggest that IFT-A proteins and Kinesin-2 modulate canonical Wnt/Wg-signalling independently of their ciliary role. Whether they function together in Wnt-signalling and their mechanistic role in the pathway remained unresolved. Here we demonstrate that Kinesin-2 and IFT-A proteins act as a complex during Drosophila Wg-signalling, affecting pathway activity in the same manner, interacting genetically and physically, and co-localizing with β-catenin, the mediator of Wnt/Wg-signalling on microtubules. Following pathway activation, Kinesin-2/IFT-A mutant cells exhibit high cytoplasmic β-catenin levels, yet fail to activate Wg-targets. In mutant tissues in both, Drosophila and mouse/MEFs, nuclear localization of β-catenin is markedly reduced. We demonstrate a conserved, motor-domain dependent function of the Kinesin-2/IFT-A complex in promoting nuclear translocation of β-catenin. We show that this is mediated by protecting β-catenin from a conserved cytoplasmic retention process, thus identifying a mechanism for Kinesin-2/IFT-A in Wnt-signalling that is independent of their ciliary role.

Titel:	Kinesin-2 and IFT-A act as a complex promoting nuclear localization of β-catenin during Wnt signalling.
Autor/in / Beteiligte Person:	Vuong, LT ; Iomini, C ; Balmer, S ; Esposito, D ; Aaronson, SA ; Mlodzik, M
Link:	Zum Volltext
Zeitschrift:	Nature communications, Jg. 9 (2018-12-13), Heft 1, S. 5304
Veröffentlichung:	[London] : Nature Pub. Group, 2018
Medientyp:	academicJournal
ISSN:	2041-1723 (electronic)
DOI:	10.1038/s41467-018-07605-z
Schlagwort:	Active Transport, Cell Nucleus genetics Active Transport, Cell Nucleus physiology Animals Carrier Proteins genetics Cell Nucleus metabolism Drosophila Proteins genetics Kinesins genetics Protein Transport physiology RNA Interference RNA, Small Interfering genetics Signal Transduction physiology Wnt Signaling Pathway physiology Armadillo Domain Proteins metabolism Carrier Proteins metabolism Drosophila embryology Drosophila Proteins metabolism Kinesins metabolism Wings, Animal embryology Wnt Proteins metabolism beta Catenin metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Nat Commun] 2018 Dec 13; Vol. 9 (1), pp. 5304. <i>Date of Electronic Publication: </i>2018 Dec 13. MeSH Terms: Armadillo Domain Proteins / metabolism ; Carrier Proteins / metabolism ; Drosophila / embryology ; Drosophila Proteins / metabolism ; Kinesins / metabolism ; Wings, Animal / embryology ; Wnt Proteins / metabolism ; beta Catenin / metabolism ; Active Transport, Cell Nucleus / genetics ; Active Transport, Cell Nucleus / physiology ; Animals ; Carrier Proteins / genetics ; Cell Nucleus / metabolism ; Drosophila Proteins / genetics ; Kinesins / genetics ; Protein Transport / physiology ; RNA Interference ; RNA, Small Interfering / genetics ; Signal Transduction / physiology ; Wnt Signaling Pathway / physiology References: J Cell Biol. 1999 Nov 1;147(3):507-18. (PMID: 10545496) ; Curr Biol. 2007 Sep 18;17(18):1586-94. (PMID: 17825558) ; Dev Cell. 2009 Jul;17(1):9-26. (PMID: 19619488) ; Nature. 2003 May 22;423(6938):448-52. (PMID: 12717451) ; J Am Soc Nephrol. 2013 Jan;24(1):10-8. (PMID: 23123400) ; Dev Biol. 2002 Apr 15;244(2):305-18. (PMID: 11944939) ; Development. 1997 Jun;124(11):2255-66. (PMID: 9187151) ; Development. 1997 Feb;124(4):871-80. (PMID: 9043068) ; Genetics. 2009 Nov;183(3):885-96. (PMID: 19720863) ; Nat Rev Genet. 2010 May;11(5):331-44. (PMID: 20395968) ; EMBO J. 2012 Jun 13;31(12):2714-36. (PMID: 22617422) ; Development. 1995 Dec;121(12):4215-25. (PMID: 8575321) ; EMBO J. 2008 May 21;27(10):1436-46. (PMID: 18418383) ; Curr Drug Targets. 2008 Jul;9(7):513-31. (PMID: 18673238) ; Cell. 2006 Nov 3;127(3):469-80. (PMID: 17081971) ; Nat Genet. 2011 Jun;43(6):547-53. (PMID: 21552265) ; Nat Cell Biol. 2008 Jan;10(1):70-6. (PMID: 18084282) ; Cell. 1996 Nov 29;87(5):833-44. (PMID: 8945511) ; J Cell Biol. 1996 Dec;135(5):1277-89. (PMID: 8947551) ; Cell. 2008 Apr 18;133(2):340-53. (PMID: 18423204) ; Curr Opin Cell Biol. 2012 Apr;24(2):166-72. (PMID: 22257639) ; Cell. 1997 Jul 25;90(2):225-34. (PMID: 9244297) ; J Cell Biol. 1998 May 18;141(4):993-1008. (PMID: 9585417) ; J Biol Chem. 2012 Apr 6;287(15):11689-703. (PMID: 22170070) ; Semin Cell Dev Biol. 2010 Apr;21(2):163-73. (PMID: 19596460) ; Genesis. 2002 Sep-Oct;34(1-2):51-7. (PMID: 12324947) ; J Cell Sci. 2011 Dec 15;124(Pt 24):4299-308. (PMID: 22193955) ; Curr Opin Cell Biol. 2007 Dec;19(6):612-7. (PMID: 17997088) ; EMBO Rep. 2002 Sep;3(9):834-9. (PMID: 12223464) ; Development. 1997 Apr;124(8):1485-95. (PMID: 9108365) ; Cilia. 2013 Aug 14;2(1):10. (PMID: 23945166) ; Development. 2001 Jun;128(11):2107-17. (PMID: 11493532) ; Nat Cell Biol. 2014 Jul;16(7):663-72. (PMID: 24952464) ; Nat Rev Mol Cell Biol. 2012 Dec;13(12):767-79. (PMID: 23151663) ; Dev Cell. 2015 Sep 28;34(6):705-18. (PMID: 26364750) ; Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4457-62. (PMID: 9114011) ; Curr Biol. 2003 Sep 30;13(19):1687-96. (PMID: 14521834) ; Cell. 2012 Jun 8;149(6):1192-205. (PMID: 22682243) ; Cell. 1998 Jun 26;93(7):1147-58. (PMID: 9657148) ; Curr Biol. 2003 May 27;13(11):960-6. (PMID: 12781135) ; Cell. 2000 Aug 4;102(3):349-62. (PMID: 10975525) ; Annu Rev Cell Dev Biol. 2004;20:781-810. (PMID: 15473860) ; J Cell Sci. 2006 Apr 1;119(Pt 7):1453-63. (PMID: 16554443) ; Development. 1994 Mar;120(3):621-36. (PMID: 8162860) ; Anal Biochem. 1993 Apr;210(1):179-87. (PMID: 8489015) ; Development. 2014 Aug;141(16):3222-32. (PMID: 25063455) ; Development. 1993 Jun;118(2):401-15. (PMID: 8223268) ; Genes Dev. 1999 Apr 15;13(8):935-45. (PMID: 10215621) ; Genome. 1996 Feb;39(1):174-82. (PMID: 8851804) ; Curr Biol. 2000 Aug 24;10(16):979-88. (PMID: 10985385) ; Genesis. 2010 Sep;48(9):522-30. (PMID: 20506262) ; Curr Top Dev Biol. 2008;85:175-95. (PMID: 19147006) ; J Cell Biol. 2001 Apr 2;153(1):13-24. (PMID: 11285270) ; Mol Biol Cell. 2000 Jan;11(1):241-53. (PMID: 10637305) ; J Cell Biol. 1998 Dec 14;143(6):1591-601. (PMID: 9852153) ; Exp Hematol. 2003 Nov;31(11):1007-14. (PMID: 14585362) ; Genes Dev. 1997 Sep 1;11(17):2259-71. (PMID: 9303541) ; Cold Spring Harb Perspect Biol. 2012 Nov 01;4(11):. (PMID: 23024173) ; Curr Biol. 2000 Mar 23;10(6):293-300. (PMID: 10744972) Grant Information: P30 DK074038 United States DK NIDDK NIH HHS; R01 EY013256 United States EY NEI NIH HHS; R35 GM127103 United States GM NIGMS NIH HHS; R01 HD066319 United States HD NICHD NIH HHS; R01 EY022639 United States EY NEI NIH HHS; P30 CA196521 United States CA NCI NIH HHS Substance Nomenclature: 0 (Armadillo Domain Proteins) ; 0 (Carrier Proteins) ; 0 (Drosophila Proteins) ; 0 (RNA, Small Interfering) ; 0 (Wnt Proteins) ; 0 (beta Catenin) ; 0 (rempA protein, Drosophila) ; EC 3.6.1.- (kinesin 2 protein, Drosophila) ; EC 3.6.4.4 (Kinesins) Entry Date(s): Date Created: 20181215 Date Completed: 20190122 Latest Revision: 20211204 Update Code: 20240513 PubMed Central ID: PMC6294004

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Kinesin-2 and IFT-A act as a complex promoting nuclear localization of β-catenin during Wnt signalling.