TY - JOUR
T1 - Functional and structural diversity of the human Dickkopf gene family
AU - Krupnik, Valery E.
AU - Sharp, John D.
AU - Jiang, Chian
AU - Robison, Keith
AU - Chickering, Troy W.
AU - Amaravadi, Lakshmi
AU - Brown, Diane E.
AU - Guyot, Deborah
AU - Mays, Gail
AU - Leiby, Kevin
AU - Chang, Belle
AU - Duong, Thao
AU - Goodearl, Andrew D.J.
AU - Gearing, David P.
AU - Sokol, Sergei Y.
AU - McCarthy, Sean A.
N1 - Funding Information:
We thank R. Moon for plasmids. We also thank Rick Clark, John Keilty, Betty Woolf, Pam Brauer, Donna Michnick, Kevin McDonald and members of the Millennium DNA sequencing, cDNA library and Full Length cDNA Cloning Groups for skilled assistance and advice. We are grateful to Joe Weber and Bill Holmes for critical comments on the manuscript and Chuck Gray for assistance with collaborations. This work was supported in part by grants from the March of Dimes Birth Defect Foundation and the National Institutes of Health to S.S.
PY - 1999/10/1
Y1 - 1999/10/1
N2 - 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.
AB - 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.
KW - Antagonist
KW - Frizzled related protein
KW - In situ hybridization
KW - Secreted protein
KW - Soggy
KW - Wingless
KW - Xenopus
UR - http://www.scopus.com/inward/record.url?scp=0032850032&partnerID=8YFLogxK
U2 - 10.1016/S0378-1119(99)00365-0
DO - 10.1016/S0378-1119(99)00365-0
M3 - Article
C2 - 10570958
AN - SCOPUS:0032850032
SN - 0378-1119
VL - 238
SP - 301
EP - 313
JO - Gene
JF - Gene
IS - 2
ER -