Nuclear translocation of β-catenin in Wg/Wnt signaling via the IFT-A microtubule-associated complex requires Pasovec/Gid8 proteins.

Abstract

Wg/Wnt signaling is critical throughout development and homeostasis and associated with many diseases, including cancer. Wg/Wnt signaling is mediated by β-catenin (Armadillo/Arm in <i>Drosophila</i>) with the IFT-A/Kinesin2 complex promoting nuclear translocation of β-catenin/Arm. Existing information suggests that additional proteins are involved. Here, we demonstrate that a conserved protein, Pasovec (Psv; Gid8 in mammals), with loss-of-function mutants resembling <i>wg</i> and <i>arm</i>/β-catenin mutant phenotypes, is required for nuclear β-catenin/Arm localization. Psv interacts with the IFT-A/Kinesin2 complex, physically binding IFT140, a core component of IFT-A. The Psv/Gid8-IFT140 association is independent of Wg/Wnt-signaling activation. Psv/Gid8 contains a CRA domain, identified as interacting with RanBPM, which mediates its nuclear localization. Mutations in CRA affect Psv/Gid8's own nuclear localization and that of β-catenin/Arm upon Wg/Wnt-signaling activation. Psv with a mutated CRA can act as an inhibitor of Wg/Wnt signaling. Together, this study describes a previously unidentified factor, required for Wg/Wnt signaling, that functions during the nuclear translocation process of β-catenin/Arm.