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 human Dkk-1 is a 40 kDa glycosylated protein that shares 86%, 87%, 90% and 91% aa sequence identity with mouse, rat, rabbit and bovine Dkk-1, respectively. It also shares 42% and 36% aa identity with human 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 down-regulate 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 [10]. Insufficient or excess Dkk-1 activity in bone results in increased or decreased bone density, respectively [8, 11]. In adults, Dkk-1 is expressed in osteoblasts and osteocytes, and neurons. Cerebral ischemia induces Dkk-1 expression, which contributes to neuronal cell death [12].
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