Katoh Yuriko, Katoh Masaru
M&M Medical BioInformatics, Hongo, Japan.
Int J Mol Med. 2005 Sep;16(3):477-81.
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).
WNT家族蛋白通过决定细胞命运激活β-连环蛋白-TCF途径来诱导致癌作用，还通过激活平面细胞极性（PCP）途径来诱导细胞迁移和转移。DKK1、DKK2、DKK3和DKK4是属于Dickkopf家族的分泌型WNT信号调节剂。在此，我们利用生物信息学鉴定并表征了大鼠Dkk2和Dkk4基因。大鼠Dkk2和Dkk4基因均由四个外显子组成，分别位于AC120263.4和AC109661.6基因组序列内。大鼠Dkk2基因编码一种259个氨基酸的蛋白质，与人类DKK2的总氨基酸同一性为95.8%。大鼠Dkk4基因编码一种221个氨基酸的蛋白质，与人类DKK4的总氨基酸同一性为75.4%。哺乳动物Dkk家族成员是具有两个富含半胱氨酸区域的分泌蛋白，每个区域含有十个保守的半胱氨酸残基。密码子52处的天冬酰胺连接糖基化位点在哺乳动物Dkk2直系同源物中是保守的；然而，在哺乳动物Dkk4直系同源物中未鉴定到天冬酰胺连接糖基化位点。Dkk2蛋白比Dkk4蛋白更保守，而Dkk4启动子比Dkk2启动子更保守。在Dkk2和Dkk4启动子内鉴定到了TATA框。人类DKK4启动子和啮齿动物Dkk4启动子之间的MYOD和三重TCF/LEF结合位点是保守的。DKK2 mRNA在尤因肉瘤和胎儿心脏中表达。DKK4 mRNA在分化为早期内胚层细胞类型的人类胚胎干细胞、乳腺癌和弥漫型胃癌中表达。DKK4直系同源物参与WNT/β-连环蛋白信号通路（经典WNT信号通路）的负反馈机制。
