Recombinant Human Dkk1

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].

Reference

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[3]. Bullock, C.M. et al. (2004) Mol. Pharmacol. 65:582.

[4]. Mao, B. et al. (2001) Nature 411:321.

[5]. Mao, B. et al. (2002) Nature 417:664.

[6]. Kemp, C. et al. (2005) Dev. Dyn. 233:1064.

[7]. Adamska, M. et al. (2004) Dev. Biol. 272:134.

[8]. Li, J. et al. (2006) Bone 36:754.

[9]. Verani, R. et al. (2006) J. Neurochem. 101:242.

[10]. Pinzone, J.J. et al. (2009) Blood 113:517.

[11]. Morvan, F. et al. (2006) J. Bone Miner. Res. 21:934.

[12]. Cappuccio, I. et al. (2005) J. Neurosci. 25:2647.