Wnt signalling protein Dishevelled acts in the nucleus, not just in the cytoplasm

Researchers have identified that Dishevelled doesn’t only function in the cytoplasm and at the cell membrane – it must also pass into the nucleus. A study published today in Journal of Biology reveals that Dishevelled, a key player in the Wnt/beta-catenin signalling pathway, has to be localised in the nucleus to perform a key aspect of its function. This discovery should shed light on both normal embryonic development and the development of cancer.

In the paper, Sergei Sokol and colleagues, from Harvard Medical School, show that Dishevelled (Dsh) is constantly shuttling between the nucleus and the cytoplasm, owing to its nuclear export and import sequences, but that it has to be in the nucleus to respond to certain Wnt signals transmitted through the ‘canonical’ Wnt signalling pathway.

Dsh has always been considered to be a cytoplasmic protein, exerting its function as a stabiliser of beta-catenin in the cell cytoplasm after stimulation by Wnt secreted ligands binding to Frizzled receptors on the cell surface.

Sokol and colleagues show using Xenopus embryos and mammalian cultured cells that a mutated version of Dsh, which accumulates in the nucleus, is functional in the Wnt signalling pathway. Preventing Dsh from getting into the nucleus, however, either by mutating the nuclear localisation signal of the protein or by using a drug that disables the nuclear export machinery, impairs function. In mammalian cells, endogenous Dsh responds to Wnt ligands by mobilising to the nucleus.

“Our findings are consistent with a scenario in which Wnt signaling may cause nuclear translocation of Dsh followed by formation of a stable beta-catenin/Tcf3 complex and transcriptional activation of target genes”, explain the authors. Dsh’s exact role in the nucleus, however, is still unclear.

Dsh is also important in non-canonical Wnt signaling pathways, which involve proteins such as Rho GTPase and JNK. Sokol and colleagues show that nuclear localisation of Dsh is not required for its function in non-canonical signaling.