Recombinant Human Dkk-1 Biotinylated Protein

Dickkopf related protein 1 (Dkk-1) is the founding member of the Dickkopf family of proteins that includes Dkk-1, -2, -3, -4, and a related protein, Soggy (1, 2). Dkk proteins are secreted proteins that contain two conserved cysteine-rich domains (CRDs) separated by a linker region. Each domain contains ten cysteine residues (1-3). Mature human Dkk-1 is a 40 kDa glycosylated protein that shares 83% amino acid sequence identity with mouse and rat Dkk-1. Dkk-1 is a well-characterized antagonist of Wnt/beta-Catenin signaling (1, 2, 4, 5). This pathway is activated by Wnt engagement of a receptor complex composed of the Frizzled proteins and one of two low-density lipoprotein receptor-related proteins, LRP-5 or LRP-6 (4). Crystallographic studies have shown that Dkk-1 interacts with LRP-6 as a bipartite inhibitor, with both CRDs binding the extracellular domain of LRP-6 simultaneously (4, 6-8). Dkk-1/LRP-6/Krm2 complex internalization has been shown to down-regulate Wnt signaling (4, 9). Dkk-1 is expressed throughout development and antagonizes Wnt-7a during limb development (10, 11). Other sites of expression include developing neurons, hair follicles, and the retina (12, 13). The balance between Wnt signaling and Dkk-1 inhibition is critical for bone formation and homeostasis (14). Insufficient or excess Dkk-1 activity in bone results in increased or decreased bone density, respectively (12, 15). In adults, Dkk-1 is expressed in osteoblasts and osteocytes, and neurons. Cerebral ischemia induces Dkk-1 expression, which contributes to neuronal cell death (16). Dkk-1 also likely has a complex role in cancer, as it has been shown to act as a tumor suppressor and also to promote metastasis (17-19).