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second cysteine-rich (Cys-2) domain of Dickkopf-related protein 3 Dickkopf 3 (Dkk3) is a secreted protein which, in contrast to Dkk1, Dkk2, and Dkk4, does not interact with LRP5/6 (low-density lipoprotein receptor related protein 5 and 6), and thus is a divergent family member that is not considered a true Wnt signaling antagonist. The role of Dkk proteins in cancer is considered mainly tumor suppressive since they are usually down-regulated in cancer cells. Dkk3 links heat shock factor 1 (HSF1) and YAP/TAZ signaling to control aggressive behaviors in cancer-associated fibroblasts; it does so via canonical Wnt signaling. It belongs to the Dickkopf (Dkk) family that comprises a discrete class of secreted Wnt inhibitors. The Wnt gene family is a large class of secreted proteins that are expressed in a variety of tissues and organs, and are required for many developmental processes, including segmentation, endoderm development, limb polarity, neural crest differentiation, kidney morphogenesis, sex determination and brain development. Dkks 1-4 each possesses an N-terminal signal peptide and contains two conserved cysteine-rich domains (Cys-1 and Cys-2) separated by a linker region. Each domain possesses 10 conserved cysteine residues. The Cys-2 domain is closely similar to those in the colipase family; it has been suggested that the Cys-2 domain of Dkks may enable interaction with lipids in order to regulate Wnt function. This model corresponds to the Cys-2 domain of Dkk3. |
Jiyao W et al.(2023). "The conserved domain database in 2023.",