Open AccessA Novel Mechanism for Wnt Activation of Canonical Signaling through the LRP6 Receptor
Author(s) -
Guizhong Liu,
Anna Bafico,
Violaine Harris,
Stuart A. Aaronson
Publication year - 2003
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.23.16.5825-5835.2003
Subject(s) - lrp6 , wnt signaling pathway , allosteric regulation , biology , microbiology and biotechnology , signal transduction , transmembrane protein , transmembrane domain , receptor , intracellular , biochemistry
LDL receptor-related protein 6 (LRP6) is a Wnt coreceptor in the canonical signaling pathway, which plays essential roles in embryonic development. We demonstrate here that wild-type LRP6 forms an inactive dimer through interactions mediated by epidermal growth factor repeat regions within the extracellular domain. A truncated LRP6 comprising its transmembrane and cytoplasmic domains is expressed as a constitutively active monomer whose signaling ability is inhibited by forced dimerization. Conversely, Wnts are shown to activate canonical signaling through LRP6 by inducing an intracellular conformational switch which relieves allosteric inhibition imposed on the intracellular domains. Thus, Wnt canonical signaling through LRP6 establishes a novel mechanism for receptor activation which is opposite to the general paradigm of ligand-induced receptor oligomerization.