Dishevelled binding antagonist of beta catenin 1 (Dact1, previously known as Dapper, Dpr1, Frodo) is a
protein that in humans is encoded by the DACT1
gene.[1] Dact1 was originally described in 2002 as a
negative regulator of
Wnt signaling by binding and destabilizing
Dishevelled.[2] More recent investigation into the molecular function of Dact1 has identified its principle role in the cell as a scaffold to generate membrane-less biomolecular condensates through liquid-liquid phase separation.[3] Mutations in the phase-separating regions of Dact1 lead to
Townes-Brock Syndrome 2 while its overexpression is associated with
bone metastasis.[3]
Regulation and function
Dact1 is regulated by the TGF-β pathway through Smad2/3 binding sites in its promoter region.[4] Dact1 is degraded through the proteasome[3] and is described as a Wnt activator,[5] a Wnt suppressor,[2] or alternately a Wnt-independent regulator of the autophagosome.[6] The Dact1 protein is annotated with 10 intrinsically disordered domains, a nuclear localization sequence, a nuclear export sequence, a PDZ binding domain, and a coiled-coiled domain.[3] AI-based protein folding predictions describe a highly disordered exterior calyx surrounding an ordered interior.[7] Dact1 has been reported to interact with numerous proteins including itself, Dishevelled, p120, LEF, 14-3-3 proteins, VPS34, Miz1, Vangl, and Dact2 through immunoprecipitation studies.[8][9][10][11][12] More recent studies into the role of Dact1 in forming "Frodosomes",[13][3] or membrane-less, organelle-like biomolecular condensates, identified a Dact1 protein signature that included many previously identified interactors as well as new proteins such as Casein Kinase 2.[14][3]
Health and disease
Dact1 is an essential regulator of development through its role in regulating Wnt activity and its deletion is embryonically lethal. Heterozygous mutations in Dact1 cause Townes-Brock Syndrome 2 in humans which is inherited in an autosomal dominant pattern.[15] High levels of Dact1 mRNA predicts worse outcome in breast cancer bone metastasis and is an essential protein in the bone metastatic cascade.[3]