title: Functional and structural diversity of the human Dickkopf gene family.
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.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School and Division of Molecular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: V E
authors.initials: VE
authors.lastname: Krupnik
authors.forename: J D
authors.initials: JD
authors.lastname: Sharp
authors.forename: C
authors.initials: C
authors.lastname: Jiang
authors.forename: K
authors.initials: K
authors.lastname: Robison
authors.forename: T W
authors.initials: TW
authors.lastname: Chickering
authors.forename: L
authors.initials: L
authors.lastname: Amaravadi
authors.forename: D E
authors.initials: DE
authors.lastname: Brown
authors.forename: D
authors.initials: D
authors.lastname: Guyot
authors.forename: G
authors.initials: G
authors.lastname: Mays
authors.forename: K
authors.initials: K
authors.lastname: Leiby
authors.forename: B
authors.initials: B
authors.lastname: Chang
authors.forename: T
authors.initials: T
authors.lastname: Duong
authors.forename: A D
authors.initials: AD
authors.lastname: Goodearl
authors.forename: D P
authors.initials: DP
authors.lastname: Gearing
authors.forename: S Y
authors.initials: SY
authors.lastname: Sokol
authors.forename: S A
authors.initials: SA
authors.lastname: McCarthy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014981:Xenopus / Q000196:embryology; D029867:Xenopus Proteins
chemical_list: C501126:DKK1 protein, human; D017931:DNA Primers; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D029867:Xenopus Proteins; C110182:dkk1 protein, Xenopus