Description
Dickkopf-Related Protein 4 (DKK4) is a member of the DKK protein family that includes DKK1, DKK2, DKK3, and DKK4. DKK1 and DKK4 are Wnt antagonists. DKK1 and DKK4 antagonize Wnt/β-Catenin signaling by direct high affinity binding to the Wnt coreceptor LRP5/6 and inhibiting interaction of LRP5/6 with the Wnt Frizzled complex. DKK1 and DKK4 also bind the transmembrane proteins Kremen1 (Krm1) and Kremen 2 (Krm2) with high affinity. Krm2 has been shown to form a ternary complex with DKK1or DKK4 and LRP5/LRP6 to trigger internalization of the complex and removal of LRP6 from the cell surface. Thus, DKK1/DKK4 and Kremens function synergistically to antagonize LRP5/LRP6 mediated Wnt activity. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease