Abstract
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.
Highlights
Wnt/Wg-signalling is critical signalling in all metazoans
We demonstrate that the combined Kinesin-2/Intraflagellar Transport (IFT)-A complex interacts directly with β-catenin/Arm through IFT140 and that this interaction is critical for normal nuclear translocation of β-catenin/Arm
The IFT-A complex is best known for its function in ciliary transport[46,47], and it has been suggested to promote canonical Wnt/Wg-signaling independently of its ciliary role in Drosophila[20]
Summary
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. 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. 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, identifying a mechanism for Kinesin-2/IFT-A in Wnt-signalling that is independent of their ciliary role. IFT particles are composed of about 20 proteins, organized into the IFT-A and IFT-B complexes[24,25] Despite their essential role in ciliogenesis and cilia-associated signaling pathways in vertebrates, such as Hedgehog signaling[26], IFT-A proteins were found to modulate canonical Wnt/Wg-signaling in non-ciliated cells in Drosophila imaginal discs[20], suggesting that IFT-A must function in the Wnt-pathway in a non-ciliary context. It remains unclear how this complex functions mechanistically in Wg/Wnt-signaling; whether IFT-A proteins associate with microtubular structures outside the cilium; and whether the non-ciliary Wnt-signaling-specific function of IFT-A is conserved in vertebrates
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