Recombinant Rat Dkk-1 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 separated by a linker region. Each domain contains ten cysteine residues (1-3). Mature rat Dkk-1 is a 40 kDa glycosylated protein that shows 96%, 86% and 82% aa sequence identity with mouse, human and cow Dkk-1, respectively. It also shows 41% and 34% aa identity with rat Dkk-2 and Dkk-4, respectively. Dkk-1 and Dkk-4 are well documented antagonists of the canonical Wnt signaling pathway (1, 2). 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, LRP5 or LRP6 (4). Dkk-1 antagonizes Wnt by forming ternary complexes of LRP5/6 with Kremen1 or Kremen2 (4, 5). Dkk-1/LRP6/Krm2 complex internalization has been shown to downregulate Wnt signaling (4, 5). Dkk-1 is expressed throughout development and antagonizes Wnt-7a during limb development (6, 7). Other sites of expression include developing neurons, hair follicles and the retina of the eye (8, 9). The balance between Wnt signaling and Dkk-1 inhibition is critical for bone formation and homeostasis. Insufficient or excess Dkk-1 activity in bone results in increased or decreased bone density, respectively (8, 10). In adults, Dkk-1 is expressed in osteoblasts and osteocytes, and neurons. Neuronal expression appears to be required for ischemic neuronal death (11).