Recombinant Human Dkk-2 Protein

Dickkopf related protein 2 (Dkk-2) is a member of the Dickkopf family of secreted Wnt modulators (1-3). Dkk proteins contain a signal peptide and two conserved cysteine-rich domains that are separated by a linker region. The second cysteine-rich domain mediates Dkk-2 binding activities, and its interaction with  beta -propeller domains of LRP‑5/6 has been mapped (2-4, 7). The 226 amino acid (aa), ~35 kDa mature human Dkk-2 shares 96%, 97%, 97%, 97%, 97% and 98% aa identity with mouse, rat, canine, equine, bovine and porcine Dkk-2, respectively. Mouse Dkk-2 can activate the canonical Wnt signaling pathway in Xenopus embryos, showing evolutionary conservation of function (5). Dkk proteins modify Wnt engagement of a receptor complex composed of a Frizzled protein and a low-density lipoprotein receptor-related protein, either LRP‑5 or LRP‑6 (3). Also, Kremen-1 and Kremen-2 are high affinity receptors for Dkk-1 and Dkk-2 (9). When LRP‑6 is over-expressed, direct high‑affinity binding of Dkk-2 to LRP can enhance canonical Wnt signaling (6-8). However, when Dkk‑2 and LRP‑6 form a ternary complex with Kremen‑2, Wnt signaling is inhibited due to internalization of Dkk‑2/LRP6/Krm2 complexes (9, 10). Thus, depending on the cellular context, Dkk‑2 can either activate or inhibit canonical Wnt signaling (3). In contrast, binding of Dkk-1 or Dkk-4 to LRP is consistently antagonistic (3). Dkk proteins are expressed in mesenchymal tissues and control epithelial transformations. Dkk-2 expression has been studied most in bone and eye, although it is expressed as early as periimplantation in mice (11). Mouse Dkk-1 or Dkk-2 deficiencies have opposite effects on bone homeostasis, despite down‑regulating Wnt antagonism in both cases (12, 13). Dkk-2 expression is induced by Wnts in bone, and is thought to enhance bone density by promoting terminal differentiation of osteoblasts and mineral deposition (12). In contrast, Dkk-1 negatively regulates late osteoblast proliferation, which limits bone density (13). Dkk-2-deficient mice are blind, exhibiting faulty differentiation of corneal epithelium and ectopic blood vessels in the periocular mesenchyme (14, 15).