protein_function: Antagonizes canonical Wnt signaling by inhibiting LRP5,6interaction with Wnt and by forming a ternary complex with thetransmembrane protein KREMEN that promotes internalization ofLRP5,6. DKKs play an important role in vertebrate development,where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis andeye formation. In the adult, Dkks are implicated in bone formationand bone disease, cancer and Alzheimer disease (By similarity)..
DKK4 is a membersof the Dickkopf family which are negative regulators of the growth-promoting Wnt , beta-catenin signaling pathway. By FISH, the DKK4 gene was mapped to chromosome 8p11.2-p11.1. The secreted protein contains two cysteine rich regions and is involved in embryonic development through its interactions with the Wnt signaling pathway. Activity of this protein is modulated by binding to the Wnt co-receptor and the co-factor kremen 2. The expression of DKK4 was significantly reduced in hepatocellular carcinomas (HCCs), particularly in HCCs that showed cytoplasmic beta- catenin accumulation. DKK4 expression was also reduced in HCC cell lines. Ectopic expression of DKK4 in 2 HCC cell lines reduced beta-catenin and cyclin D1 protein levels and attenuated beta-catenin activity in reporter gene assays.