TY - JOUR
T1 - Kinesin-2 and IFT-A act as a complex promoting nuclear localization of β-catenin during Wnt signalling
AU - Vuong, Linh T.
AU - Iomini, Carlo
AU - Balmer, Sophie
AU - Esposito, Davide
AU - Aaronson, Stuart A.
AU - Mlodzik, Marek
N1 - Funding Information:
We thank the Bloomington Stock Center, Vienna Drosophila RNAi center, Drosophila Genomics Resource Center (DGRC) and Developmental Studies Hybridoma Bank for fly strains and antibodies. We are most grateful to Ken Cadigan for helpful discussions and UAS-Arm* flies; Bradley Yoder and the University of Alabama/Hepatorenal Fibrocystic Disease Core Center (P30 DK074038) for providing the Ift88tm1Bky (here referred to as Ift88fx/fx) and the null Ift88 mouse alleles; and K.W. Choi for anti-Klp64D antibody and UAS-Klp64DΔABD, UAS-Klp64DT114A, and UAS-Klp64D-HA fly strains and Kinesin-2 and Arm constructs for GST pull-down assays. We thank H. Bellen for anti-Sens antibody; L. Gusella for anti-IFT88; G. Pazour for providing Ift140−/−MEFs and anti-IFT140 antibody; R. Nusse for anti-Axin; T. Avidor-Reiss for IFT121-GFP, IFT140-GFP and oseg1179 flies; M. Kernan for rempA21Ci; and Richard Mann for tub-exdV5 flies, respectively. We thank Jong-Sun Kang, Qing Liu, Varun Arvind, and Anna Yang for their help in experiments involving MEFs, and all Mlodzik and Iomini lab members for helpful inputs and discussion, and A. Humphries, U. Weber, and G. Collu for critical comments on the manuscript. Confocal microscopy was performed at the Tisch Cancer Institute Microscopy Core, supported by grant P30 CA196521 from the NCI. This work was supported by National Institutes of Health grants GM127103 to M.M., EY022639 to C.I., HD066319 to M.M. and S.A.A., and a Breast Cancer Research Foundation grant to S.A.A.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-07605-z
DO - 10.1038/s41467-018-07605-z
M3 - Article
C2 - 30546012
AN - SCOPUS:85058436797
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5304
ER -