DKK-1 (Dickkopf-Related Protein-1)

Dickkopf related protein 1 (Dkk-1) was the first identified member of the Dickkopf family of secreted proteins that includes Dkk-1, -2, -3, -4, and a related protein, Soggy.  Dickkopf (meaning “stubborn” or “thick headed”) was discovered as an inducer of head formation in Xenopus.  Dkk proteins contain two conserved cysteine-rich domains separated by a linker region.  The C-terminal domain, which contains a colipase fold with a conserved pattern of ten cysteine residues, is necessary and sufficient for Wnt inhibition.  Mature human Dkk-1 is a 40 kDa glycosylated protein that shows 86%, 87%, 91%, and 90% amino acid sequence identity with mouse, rat, bovine and rabbit Dkk-1, respectively.  It also shows 42% and 36% a.a. identity with human Dkk-2 and Dkk-4 respectively, with similarity mainly within the cysteine-rich domains.

Dkk-1 and Dkk-4 are well documented antagonists of the canonical Wnt signaling pathway.  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, LPR5 or LPR6.  Dkk-1 antagonizes Wnt by forming ternary complexes of LRP5/6 with Kremen1 or Kremen2.  Internalization of the Dkk-1/LRP6/Krm2 complex down-regulates Wnt signaling.  Dkk-1 has also been proposed to have Wnt-independent activity in some human cancer cell lines.  Dkk-1 is expressed throughout embryogenesis and antagonizes Wnt-7a during limb development, in developing neurons, keratinocytes, hair follicles, and the retina of the eye.

Another of the Wnt signaling pathways is the Wnt/beta-catenin (canonical) pathway that plays an important role in regulating osteoblast proliferation and differentiation (see reference 1).  Post-natally, Dkk-1 is expressed mainly by osteoblasts and osteocytes.  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.  High Dkk-1 expression has been shown, and may be pathogenic in, conditions where bone is eroded, such as rheumatoid arthritis, multiple myeloma, Paget’s disease, and glucocorticoid-induced osteoporosis.  Although the main phenotypes of experimental Dkk-1 deficiency are bone related, it is important for regulating Wnt activity in other areas as well.

Dkk-1 is also vigorously expressed in platelets (see reference 2).  Activation of platelets, such as during the clotting process when collecting serum samples, leads to the release of Dkk-1. Thus, caution is recommended when interpreting serum Dkk-1 values.  Patients with atherosclerosis appear to release more Dkk-1 as a result of platelet activation than normal controls.  Dkk-1 has been hypothesized to play a role in platelet-mediated endothelial cell activation leading to plaque formation.

The DKK-1 immunoassay is a solid phase ELISA designed to measure human DKK-1 in cell culture supernates, serum, and plasma.  The assay employs the quantitative sandwich enzyme immunoassay technique.  *Note: Due to instability of specimen it is recommended that two aliquots be submitted in the event that repeat anlysis is needed.