Functional and structural diversity of the human Dickkopf gene family

Gene. 1999 Oct 1;238(2):301-13. doi: 10.1016/s0378-1119(99)00365-0.


Wnt proteins influence many aspects of embryonic development, and their activity is regulated by several secreted antagonists, including the Xenopus Dickkopf-1 (xDkk-1) protein. xDkk-1 inhibits Wnt activities in Xenopus embryos and may play a role in induction of head structures. Here, we characterize a family of human Dkk-related genes composed of Dkk-1, Dkk-2, Dkk-3, and Dkk-4, together with a unique Dkk-3 related protein termed Soggy (Sgy). hDkks 1-4 contain two distinct cysteine-rich domains in which the positions of 10 cysteine residues are highly conserved between family members. Sgy is a novel secreted protein related to Dkk-3 but which lacks the cysteine-rich domains. Members of the Dkk-related family display unique patterns of mRNA expression in human and mouse tissues, and are secreted when expressed in 293T cells. Furthermore, secreted hDkk-2 and hDkk-4 undergo proteolytic processing which results in cleavage of the second cysteine-rich domain from the full-length protein. Members of the human Dkk-related family differ not only in their structures and expression patterns, but also in their abilities to inhibit Wnt signaling. hDkk-1 and hDkk-4, but not hDkk-2, hDkk-3 or Sgy, suppress Wnt-induced secondary axis induction in Xenopus embryos. hDkk-1 and hDkk-4 do not block axis induction triggered either by Xenopus Dishevelled (Xdsh) or Xenopus Frizzled-8 (Xfz8), both of which function to transduce signals from Wnt ligands. Thus, hDkks 1 and 4 may inhibit Wnt activity by a mechanism upstream of Frizzled. Our findings highlight the structural and functional heterogeneity of human Dkk-related proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line
  • DNA Primers
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Molecular Sequence Data
  • Multigene Family*
  • Protein Processing, Post-Translational
  • Proteins / genetics*
  • Proteins / metabolism
  • RNA, Messenger / genetics
  • Sequence Homology, Amino Acid
  • Xenopus / embryology
  • Xenopus Proteins


  • DKK1 protein, human
  • DNA Primers
  • Dkk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • RNA, Messenger
  • Xenopus Proteins
  • dkk1 protein, Xenopus

Associated data

  • GENBANK/AF177394
  • GENBANK/AF177395
  • GENBANK/AF177396
  • GENBANK/AF177397
  • GENBANK/AF177398
  • GENBANK/AF177399
  • GENBANK/AF177400