DKK3 gene is 46367 bp long, containing nine exons that span over 50 kbp of genomic DNA (Kobayashi et al., 2002). There are two exons in exon 1, which are alternatively used in two different transcripts. Totally, three transcript variants are known.

DKK3 gene is transcribed into three different isoforms (NM_015881, 2650 bp, NM_013253, 2635 bp, and NM_001018057, 2587 bp). Two of them result from alternative use of first exon (i.e. exon 1a and exon 1b, although they are both non-coding). One more variant lacks exon 1. All the variants share exons 2 to 8, and code for a 350 aa functioning protein.

None sited.

DKK3 protein possesses several defined regions, which may confer multiple functions to the protein. Amino acid (aa) 1-21 is a signal peptide (SP) that characterizes this protein as a secreted protein. Four putative N-glycosylated sites and O-glycosylated at one site region (aa 26-46) suggest that the protein may undergo posttranslational modification before its secretion.
Two cysteine-rich domains are conserved over species. N-terminal one is DKK_N (formerly called Cys-1) and C-terminal one is called Colipase fold (formerly called Cys-2). Both two domains contain 10 cysteine residues and are separated by a 12 aa linker region. Colipase fold features lipid hydrolysis and may contribute to lipid binding (interact with cell surface LRP5/LRP6, for instance.) Colipase fold is solved to form interactive surface with finger-like structure. The presence of coiled-coil domain suggests possible protein-protein interaction. All these structural features facilitate Wnt/DKK interactions (as will be apparent below). Moreover, DKK3 possesses potential proteolytic cleavage sites by furin-type proteases, suggesting that the protein is subject to posttranslational processing.

Human DKK3 DNA/RNA expression is widely observed in human normal tissues. Northern blotting analyses reveal that DKK3 mRNA is expressed in brain, heart, lung, liver, pancreas, spleen, kidney, small intestine, colon, skeletal muscle and placenta. Amongst them, DKK3 expression is particularly high in heart and brain.
Reflecting the alias of this gene, RIG (Regulated in glioma) or REIC (Reduced expression in cancer), DKK3 mRNA and protein expression is deregulated in a wide range of tumors, including glioma, gastric carcinoma, colorectal carcinoma, hepatocellular carcinoma, pancreatic cancer, leukemia, renal cell carcinoma, bladder carcinoma, prostate cancer, testicular carcinoma, ovarian carcinoma, cervical cancer, breast cancers, non-small cell lung cancer, mesothelioma and skin cancers. This downregulation in mRNA expression is caused by promoter hypermethylation. Thus, DKK3 is thought to be a potential tumor suppressor, and is focussed as a therapeutic target. However, in DKK3 protein expression level, some reports show that DKK3 protein expression is up-regulated, suggesting cancer specific expression pattern and potential alternative role in cancer invasion.

DKK3 protein is an extracellular secreted protein. Its intracellular localization is observed in cytoplasm, organelle and endoplasmic reticulum.

DKK is firstly identified in Xenopus embryogenesis (Glinka et al., 1998), and named after its role as head inducer, Dickkopf (dick=thick, kopf=head). DKK binds to the Wnt co-receptor, lipoprotein receptor-related protein5/6 class (LRP5/6), and exert antagonistic function for Wnt induced beta-catenin stabilization (Fedi et al., 1999; He et al., 2004). DKKs play an important role in vertebrate antero-posterior axial patterning, limb formation, eye formation and bone formation (Niehrs, 2006).
The Wnt signaling inhibitory ability differs between the DKK members; DKK1 and DKK4 can inhibit Wnt/beta-catenin pathway, and DKK2 can both inhibit and activate beta-catenin signaling (Wu et al., 2000), and co-receptor class of Kremen protein facilitates DKK1, 2, and 4 binding to block Wnt signaling (Bafico et al., 2001). However, DKK3 neither bind to LRP5/6 nor does Kremen (Mao et al., 2003; Brott et al., 2001).
The receptor for DKK3 is yet to be investigated and its Wnt/beta-catenin inhibitory function is still elusive (Veeck et al., 2012). However, Wnt modulating function of DKK3 are reported in several kinds of malignancies including glioma (Mizobuchi et al., 2008), breast cancer (Wang et al., 2008), prostate cancer (Abarzua et al., 2005 and Kawano et al., 2006) and lung cancer (Yue et al., 2008). And because of its obvious tumor suppressor function, DKK3 is regarded as tumor suppressor.
Recently, intracellular function of DKK3 was noted. Cytoplasmic DKK3 may bind to beta TrCP, and facilitate beta-catenin degradation (Lee et al., 2009).
In cancers, DKK3 mRNA expression is down-regulated by promoter methylation (see below), but there is a discrepancy between mRNA expression and protein expression in tissue samples, which may reflect tumor heterogeneity.

DKK3 homolog is conserved over species, in vertebrates including zebrafish, murine, rat, chicken, dog, cow, Rhesus monkey and chimpanzee and invertebrate, such as Dictyostelium, cnidarian, tunicate and ascidian.
In vertebrates, DKK proteins consist from 4 members (i.e. DKK1, 2, 3 and 4). Although all these proteins possess two cysteine-rich domains, the homology among DKK1, 2 and 4 is 41-50%, whereas that between DKK3 and other members it is 37-40%.

Neither germinal nor somatic mutation is reported. 5 single nucleotide polymorphisms (SNP) are known (rs3206824, rs11022095, rs1472189, rs7396187, and rs2291599). Please refer to the link below.