Open AccessRegulation of Wnt/LRP Signaling by Distinct Domains of Dickkopf Proteins
Author(s) -
Barbara K. Brott,
Sergei Y. Sokol
Publication year - 2002
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.22.17.6100-6110.2002
Subject(s) - wnt signaling pathway , biology , xenopus , lrp6 , dkk1 , activator (genetics) , context (archaeology) , microbiology and biotechnology , cysteine , signal transduction , genetics , biochemistry , receptor , gene , paleontology , enzyme
Dickkopfs (Dkks) are secreted developmental regulators composed of two cysteine-rich domains. We report that the effects of Dkks depend on molecular context. Although Wnt8 signaling is inhibited by both Dkk1 and Dkk2 in Xenopus embryos, the same pathway is activated upon interaction of Dkk2 with the Wnt coreceptor LRP6. Analysis of individual Dkk domains and chimeric Dkks shows that the carboxy-terminal domains of both Dkks associate with LRP6 and are necessary and sufficient for Wnt8 inhibition, whereas the amino-terminal domain of Dkk1 plays an inhibitory role in Dkk-LRP interactions. Our study illustrates how an inhibitor of a pathway may be converted into an activator and is the first study to suggest a molecular mechanism for how a ligand other than Wnt can positively regulate beta-catenin signaling.