Comparative genomics on DKK2 and DKK4 orthologs

Abstract

WNT family proteins activate the beta-catenin - TCF pathway to induce carcinogenesis through cell fate determination, and also activate the planar cell polarity (PCP) pathway to induce cell motility and metastasis. DKK1, DKK2, DKK3 and DKK4 are secreted-type WNT signaling modulators belonging to the Dickkopf family. Here, we identified and characterized rat Dkk2 and Dkk4 genes by using bioinformatics. Rat Dkk2 and Dkk4 genes, consisting of four exons, were located within AC120263.4 and AC109661.6 genome sequences, respectively. Rat Dkk2 gene encoded a 259-aa protein, showing 95.8% total-amino-acid identity with human DKK2. Rat Dkk4 gene encoded a 221-aa protein, showing 75.4% total-amino-acid identity with human DKK4. Mammalian Dkk family members were secreted proteins with two Cys-rich regions, each containing ten conserved Cys residues. Asn-linked glycosylation site at codon 52 was conserved among mammalian Dkk2 orthologs; however, Asn-linked glycosylation site was not identified among mammalian Dkk4 orthologs. Dkk2 proteins were more conserved than Dkk4 proteins, while Dkk4 promoters were more conserved than Dkk2 promoters. TATA-box was identified within Dkk2 and Dkk4 promoters. MYOD and triple TCF/LEF binding sites were conserved between human DKK4 promoter and rodent Dkk4 promoter. DKK2 mRNA was expressed in Ewing's sarcoma, and fetal heart. DKK4 mRNA was expressed in human embryonic stem (ES) cells differentiated to an early endodermal cell type, breast cancer, and diffuse type gastric cancer. DKK4 orthologs are implicated in the negative feed back mechanism of the WNT/beta-catenin signaling pathway (the canonical WNT signaling pathway).