Dishevelled

Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh (Dvl in mammals) is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice (Dvl1, -2, -3) and humans (DVL-1, -2, -3). Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway. Dishevelled plays important roles in both the embryo and the adult, ranging from cellular differentiation and cell polarity to social behavior. There are three human genes that encode for the dishevelled proteins: DVL1 DVL2 DVL3 DVL is an integral part of the Wnt canonical pathway (β-catenin dependent) and non-canonical pathway (β-catenin-independent). In either of these, DVL acts downstream of a Frizzled receptor, although the pathways are distinct. The Wnt canonical pathway, also known as the Wnt/β-catenin pathway, is activated during development, regulation, cell differentiation, and proliferation. The Wnt canonical pathway moves DVL between the cytoplasm and nucleus, via a conserved nuclear export sequence (NES) and a nuclear localization sequence (NLS), both necessary for proper functioning. The binding of Wnt to Frizzled receptors helps recruit DVL to the membrane, providing a site for Axin and GSK3β to bind and phosphorylate LRP5/6 (transmembrane low-density lipoprotein receptor-related protein), preventing constitutive degradation of β-catenin. The prevention of this degradation DVL allows for β-catenin buildup in the nucleus, where it acts as a coactivator for TCF (T cell factor) to activate Wnt responsive genes. Conversely, without Wnt signaling, the destruction complex, made of APC, CKI, GSK3β and Axin, degrades β-catenin buildup, keeping the concentration of β-catenin in the cell low.