Functional and structural diversity of the human Dickkopf gene family

Valery E. Krupnik, John D. Sharp, Chian Jiang, Keith Robison, Troy W. Chickering, Lakshmi Amaravadi, Diane E. Brown, Deborah Guyot, Gail Mays, Kevin Leiby, Belle Chang, Thao Duong, Andrew D.J. Goodearl, David P. Gearing, Sergei Y. Sokol, Sean A. McCarthy

Research output: Contribution to journalArticlepeer-review

418 Scopus citations

Abstract

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. (C) 1999 Elsevier Science B.V. All rights reserved.

Original languageEnglish
Pages (from-to)301-313
Number of pages13
JournalGene
Volume238
Issue number2
DOIs
StatePublished - 1 Oct 1999
Externally publishedYes

Keywords

  • Antagonist
  • Frizzled related protein
  • In situ hybridization
  • Secreted protein
  • Soggy
  • Wingless
  • Xenopus

Fingerprint

Dive into the research topics of 'Functional and structural diversity of the human Dickkopf gene family'. Together they form a unique fingerprint.

Cite this