Functional and structural diversity of the human Dickkopf gene family

被引:454
作者
Krupnik, VE
Sharp, JD
Jiang, C
Robison, K
Chickering, TW
Amaravadi, L
Brown, DE
Guyot, D
Mays, G
Leiby, K
Chang, B
Duong, T
Goodearl, ADJ
Gearing, DP
Sokol, SY
McCarthy, SA
机构
[1] Millennium BioTherapeut Inc, Cambridge, MA 02139 USA
[2] Eli Lilly & Co, Lilly Res Lab, Div Res Technol & Prot, Indianapolis, IN 46285 USA
[3] Beth Deaconess Med Ctr, Div Mol Med, Boston, MA 02215 USA
[4] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02215 USA
基金
美国国家卫生研究院;
关键词
antagonist; frizzled related protein; in situ hybridization; secreted protein; soggy; wingless; Xenopus;
D O I
10.1016/S0378-1119(99)00365-0
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 hDkk4, but not hDkk-2, hDkk-3 or Sgy, suppress Wnt-induced secondary axis induction in Xenopus embryos. hDkk-1 and hDkk4 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.
引用
收藏
页码:301 / 313
页数:13
相关论文
共 39 条
[31]  
Sawada K, 1996, INT J DEV BIOL, V40, P531
[32]   WNT FAMILY PROTEINS ARE SECRETED AND ASSOCIATED WITH THE CELL-SURFACE [J].
SMOLICH, BD ;
MCMAHON, JA ;
MCMAHON, AP ;
PAPKOFF, J .
MOLECULAR BIOLOGY OF THE CELL, 1993, 4 (12) :1267-1275
[33]  
SOKOL SY, 1995, DEVELOPMENT, V121, P1637
[34]   Analysis of dishevelled signalling pathways during Xenopus development [J].
Sokol, SY .
CURRENT BIOLOGY, 1996, 6 (11) :1456-1467
[35]   Frzb, a secreted protein expressed in the Spemann organizer, binds and inhibits Wnt-8 [J].
Wang, SW ;
Krinks, M ;
Lin, KM ;
Luyten, FP ;
Moos, M .
CELL, 1997, 88 (06) :757-766
[36]   Mechanisms of Wnt signaling in development [J].
Wodarz, A ;
Nusse, R .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1998, 14 :59-88
[37]   OVERLAPPING EXPRESSION OF XWNT-3A AND XWNT-1 IN NEURAL TISSUE OF XENOPUS-LAEVIS EMBRYOS [J].
WOLDA, SL ;
MOODY, CJ ;
MOON, RT .
DEVELOPMENTAL BIOLOGY, 1993, 155 (01) :46-57
[38]   The mouse fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation [J].
Zeng, L ;
Fagotto, F ;
Zhang, T ;
Hsu, W ;
Vasicek, TJ ;
Perry, WL ;
Lee, JJ ;
Tilghman, SM ;
Gumbiner, BM ;
Costantini, F .
CELL, 1997, 90 (01) :181-192
[39]   Cell-cell signalling: Frog frizbees [J].
Zorn, AM .
CURRENT BIOLOGY, 1997, 7 (08) :R501-R504