Dishevelled (Dsh) proteins possess three conserved domains: an amino-terminal DIX domain, a central PDZ and a carboxyl-terminal DEP domain. They acts downstream of Fz receptors in the Wnt signalling pathway, which controls a variety of developmental and homeostatic events []. Dishevelled-2 (DVL-2) participates in Wnt signalling by binding to the cytoplasmic C terminus of frizzled family members and transducing the Wnt signal to down-stream effectors [].
Proteins of the dishevelled family (Dsh and Dvl) play a key role in thetransduction of the Wg/Wnt signal from the cell surface tothe nucleus: in response to Wnt signal, they block the degradation of beta-catenin by interacting with the scaffolding protein axin. The N terminus ofproteins of the dishevelled family and the C terminus of proteins of the axinfamily share a region of homology of about 85 amino acids, which has beencalled DIX for DIshevelled and aXin []. The DIX domain is found associated with PDZ and DEP domains in proteins of the dishevelled family and with an RGS domain in proteins of the axin family. DIX has been shown to be a protein-protein interaction domain that is important for homo- and hetero-oligomerization of proteins of the dishevelled and axin families [, , , ]. The DIX domain has also be shownto be a signalling module that can target proteins to actin stress fibres andcytoplasmic vesicles to control Wnt signalling [].The Dvl2 DIX domain has been shown to form a predominantly helical structure[].A third type of DIX domain-possessing protein, known as Coiled-coil-DIX1 (Ccd1) or Dixin, forms homomeric and heteromeric complexes with Dvl and Axin and is positive regulator of Wnt signaling [].
Proteins of the dishevelled family (Dsh and Dvl) play a key role in thetransduction of the Wg/Wnt signal from the cell surface tothe nucleus: in response to Wnt signal, they block the degradation of beta-catenin by interacting with the scaffolding protein axin. The N terminus ofproteins of the dishevelled family and the C terminus of proteins of the axinfamily share a region of homology of about 85 amino acids, which has beencalled DIX for DIshevelled and aXin []. The DIX domain is found associated with PDZ and DEP domains in proteins of the dishevelled family and with an RGS domain in proteins of the axin family. DIX has been shown to be a protein-protein interaction domain that is important for homo- and hetero-oligomerization of proteins of the dishevelled and axin families [, , , ]. The DIX domain has also be shownto be a signalling module that can target proteins to actinstress fibres andcytoplasmic vesicles to control Wnt signalling [].The Dvl2 DIX domain has been shown to form a predominantly helical structure[].A third type of DIX domain-possessing protein, known as Coiled-coil-DIX1 (Ccd1) or Dixin, forms homomeric and heteromeric complexes with Dvl and Axin and is positive regulator of Wnt signaling [].
This entry includes the dishevelled (Dsh) proteins and dixin (also known as coiled-coil-DIX1, Ccd1).The transduction mechanism requires dishevelled protein (Dsh), a cytoplasmic phosphoprotein that acts directly downstream of frizzled []. 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. Furthermore, Dsh plays a vital molecular role in neural tube closure. Disruption of dishevelled signalling in Xenopus and inactivation of the genes encoding dishevelled 1 and dishevelled 2 (Dvl1 and Dvl2) in the mouse yield similar phenotypes, in which the neural tube fails to close []. 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 [].Ccd1 is another DIX domain-possessing protein that forms complexes with the Dishevelled homologue Dvl and Axin. Ccd1 is a positive regulator of Wnt signalling []. It regulates JNK activation by AXIN1 and DVL2 [].
