DKK-1 (Dickkopf related protein 1) is a member of the Dickkopf family of proteins that include DKK-1, -2, -3,-4, and Soggy. DKK-1 was discovered by its ability to block Wnt signaling during early Xenopus embryogenesis. DKK-1 antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt proteins. DKK-1 forms ternary complex with LRP5/6 and the transmembane protein Kremen1/2, promoting internalization of LRP5/6 and down regulation of Wnt signaling. DKK-1 contains two conserved cysteine-rich domains separated by a linker region. N-terminal cysteine-rich domain is unique to DKKs while C-terminal cysteine-rich domain has a pattern of 10 cysteines similar to colipase fold. DKK-1 binds with LRP6 with high affinity and this interaction is enhanced by Kremens. The interactions between DKK-1 and both LRP6 and Kremens are mediated via C-terminal cysteine-rich domain. DKKs are expressed throughout development and play important role by locally inhibiting Wnt regulated processes such as limb development, somitogenesis, antero-posterior axial patterning, and eye formation.? In the adult, DKKs are implicated in bone formation and bone disease, cancer and Alzheimer disease. The balance between Wnt signaling and DKK-1 inhibition is important for bone homeostasis. Increased expressions of DKK-1 are found in lung cancers, esophageal squamous cell carcinomas, and hormone-resistant breast cancers. DKK-1 expression is decreased in malignant melanoma and colorectal cancers. DKK-1 has been shown to partially abrogate Wnt3a dependent inhibtion of alkaline phosphase production in BMP2 stimulated osteoprogenitors.