Wnt Signalling Protein Dishevelled Acts In The Nucleus, Not Just In The Cytoplasm

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.

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This press release is based on the following article:

Nuclear localization is required for Dishevelled function in Wnt/beta-catenin signalingKeiji Itoh, Barbara K Brott, Gyu-Un Bae, Marianne J Ratcliffe and Sergei Y Sokol

Journal of Biology 2005, 4:3 (15 February 2005)