In line with these properties, Dact proteins positively as well as negatively regulate the Wnt B Catenin pathway and positively regulate the Wnt PCP pathway. In addition, specifically Dact2 has been implicated in the suppression of TgfB dependent wound healing and Nodal dependent mesoderm induction due to its ability to facilitate lysosomal degradation of Alk5. In addition to these selleck established roles, Dact proteins have been shown to stabilize p120 Catenin which in turn sequesters the transcriptional repressor Kaiso, thus leading to the activation of Kaiso targets. Since the p120 Dact interaction is stimulated by Wnt and is mediated by Dvl, and because many Kaiso targets are also Tcf Lef targets, the p120 Catenin Kaiso pathway is seen as a parallel pathway to the Wnt B Catenin pathway.

Dact proteins have been shown to also modulate Wnt signaling mediators in a ligand independent fashion Dact proteins shuttle between the nucleus and cytoplasm, and can block nuclear B Catenin function by disrupting B Catenin Lef1 complexes and enhancing Lef1 HDAC interaction. However, they can also promote Tcf Lef function when the Dact N terminal domain interacts with these transcription factors. In addition, Dact proteins can interact with Dbf4 which, independent from its role in cell cycle regulation, inhibits B Catenin targets. Finally, Dact function has been shown to depend on its phosphorylation state which is controlled in two ways firstly, in the absence of Wnt, Dact is unphosphorylated, binds to Dvl and blocks its ability to protect B Catenin from phosphorylation, thus promoting B Catenin deg radation.

In the presence of Wnt, CKI �� not only phosphorylates Dvl but also Dact. this decreases their affinity and promotes the Cilengitide resolution of B Catenin destruc tion complex, thereby stabilizing B Catenin. It also allows Dact to promote the function of Tcf Lef molecules, thus further enhancing the Wnt response. Secondly, cyclic AMP activated PKA phosphorylates Dact. this allows the binding of 14 3 3B which also blocks the ability of Dact to promote Dvl degradation, thus enhancing Wnt signal transduction. Taken together, Dact proteins have emerged as nodal points in the simultaneous control of the various Wnt and TgfB signaling pathways. Dact are modular proteins, using different structural domains to interact with their specific partners. The functions of some of these domains have already been characterized.