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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.
- Glass II DA, Karsenty G. Minireview: In vivo analysis of Wnt signaling in bone. Endocrinology 148; 2630-2634.
- Voorzanger-Rousselot N, Goehrig D, Facon F, Clezardin P, Garnero P. Platelet is a major contributor to circulating levels of Dickkopf-1: clinical implications in patients with multiple myeloma. British J. Haemotol. 2009: 145, 264-266.
- Daoussis D, Liossis SN, Solomou EE, Tsanaktsi A, Bounia K, Karampetsou M, Yiannopoulos G, Andonopoulos AP. Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum. 2010; 62:150-158.
- Liu YY, Long L, Wang SY, Guo JP, Ye H, Cui LF, Yuan GH, Li ZG. Circulating Dickkopf-1 and osteoprotegerin in patients with early and longstanding rheumatoid arthritis. Chin Med J. 2010;123:1407-1412.