InterPro: IPR003351 Dishevelled protein

Wnt proteins constitute a large family of secreted signalling molecules that are involved in intercellular signalling during development. The name derives from the first 2 members of the family to be discovered: int-1 (mouse) and wingless (Wg) (Drosophila) [1]. It is now recognised that Wnt signalling controls many cell fate decisions in a variety of different organisms, including mammals. Wnt signalling has been implicated in tumourigenesis, early mesodermal patterning of the embryo, morphogenesis of the brain and kidneys, regulation of mammary gland proliferation and Alzheimer's disease [2].

Wnt signal transduction proceeds initially via binding to their cell surface receptors - the so-called frizzled proteins. This activates the signalling functions of B-catenin and regulates the expression of specific genes important in development [3]. More recently, however, several non-canonical Wnt signalling pathways have been elucidated that act independently of B-catenin. In both cases, the transduction mechanism requires dishevelled protein (Dsh), a cytoplasmic phosphoprotein that acts directly downstream of frizzled [4]. In addition to its role in Wnt signalling, Dsh is also involved in generating planar polarity in Drosophila and has been implicated in the Notch signal transduction cascade. Three human and mouse homologues of Dsh have been cloned (DVL-1 to 3); it is believed that these proteins, like their Drosophila counterpart, are involved in signal transduction. Human and murine orthologues share more than 95% sequence identity and are each 40-50% identical to Drosophila Dsh.

Sequence similarity amongst Dsh proteins is concentrated around three conserved domains: at the N terminus lies a DIX domain (mutations mapping to this region reduce or completely disrupt Wg signalling); a PDZ (or DHR) domain, often found in proteins involved in protein-protein interactions, lies within the central portion of the protein (point mutations within this module have been shown to have little effect on Wg-mediated signal transduction); and a DEP domain is located towards the C terminus and is conserved among a set of proteins that regulate various GTPases (whilst genetic and molecular assays have shown this module to be dispensable for Wg signalling, it is thought to be important in planar polarity signalling in flies [4]).

This domain is specific to the signalling protein dishevelled. In Drosophila melanogaster, the dishevelled segment polarity protein is required to establish coherent arrays of polarized cells and segments in embryos. It plays a role in wingless signalling, possibly through the reception of the wingless signal by target cells and subsequent redistribution of arm protein in response to that signal in embryos.The domain is found adjacent to the PDZ domain (IPR001478), often in conjunction with DEP (IPR000591) and DIX (IPR001158).