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Dickkopf-Related Protein 1 (Dkk-1, DKKL1)

Dickkopf-1 (Dkk-1) is encoded by the gene dickkopf together with other members of dickkopf protein family in vertebrates, Dkk-2, –3, –4 and a distant family member soggy, sometimes also called Dickkopf-like protein 1 (DKKL1). Dickkopf name is derived from german dick=thick and kopf=head and this protein was independently found and characterised and named as „Sk“. Dkk-1/Sk is composed from 266 amino acids and has predicted molecular weight 25.8kDa. The protein has one N-glycosylation site at the N-terminus. Dkk proteins possess the signal sequence and have two typical cysteine rich domains. The second cysteine-rich domain is required for binding to Lrp6 and Kremen-2. Up to now known receptors are from the family Lrp (Lrp5/6) and Kremen 1 and 2. Dkks are modulating Wnt signalling. Their effect is mostly inhibitory with exception of the Dkk-2 which is activating Wnt-signalling. Wnt signalling pathways are shifting the cell proliferation, cell identity and cell polarity from embryonic to adult homeostasis. Wnt is forming the complex composed of seven-transmembrane receptor Frizzled (Fz) receptor and a lipoprotein-receptor related protein Lrp5 or Lrp6. This triple complex formation is stabilizing the beta-catenin and activating the pathway. Dkk-1 is inhibiting this process by its interaction with Lrp6 that is blocking the Wnt-Fz-Lrp complex formation. The Lrp6-Dkk-1 is entering the cell by endocytosis allowed by the coreceptor Kremen. Dkk-1 in mouse was found to be exprimed in bone, specifically in osteoblasts and osteocytes. The overexpression of the Dkk-1 in Xenopus is causing the ectopic head formation and blocation by anti-Dkk-1 antibodies lead to microcephaly. In mouse models, when missing the Dkk-1, there was found incomplete development of structures anterior to the midbrain and consequently this lead to the perinatal death. In limb development of Dkk-1 null mice there has been found syndactyly and polydactyly. Dkk-1 ELISA is estimating the Dkk-1 in serum or plasma thus can be used in the cancer research, especially bone and lung cancer, as well as in the Paget’s disease or in the problems with bone calcification.

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