TY - JOUR
T1 - Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow
AU - Bafico, Anna
AU - Liu, Guizhong
AU - Yaniv, Abraham
AU - Gazit, Arnona
AU - Aaronson, Stuart A.
N1 - Funding Information:
ACKNOWLEDGEMENTS This work has been supported by an NCI grant (CA71672-04). We thank F. Hess for generously providing LRP5 and LRP6 cDNAs, and R. Kohansky and T. Moran for helpful advice. Correspondence and requests for materials should be addressed to S.A.A.
PY - 2001
Y1 - 2001
N2 - Wnt signalling has an important role in cell fate determination, tissue patterning and tumorigenesis1-4. Secreted antagonists of Wnt include Frizzled (Fz)-related proteins (FRPs)5-7, Cerberus8, Wnt inhibitory factor (WIF)9 and Dickkopf (Dkk)10,11. FRPs, Cerberus and WIF have all been shown to act by binding and sequestering Wnt. We report a novel mechanism of Wnt-signalling inhibition by human Dkk-1. Dkk-1 demonstrated no interaction with Wnt but bound a single cell surface site with high affinity (KD = 0.39 nM). Its receptor was detectable in a complex with a relative molecular mass of 240,000 (Mr 240K) with [125I] Dkk-1 by covalent affinity cross-linking. Wnt signalling through β-catenin is mediated by the Fz receptor12 and a recently identified low-density-lipoprotein-receptor-related co-receptor, LRP6/Arrow13-15. Overproduction of the 200K LRP6 protein, but not of Fz, strikingly increased Dkk-1 binding as well as the amount of the 240K cross-linked complex, which was shown to be composed of Dkk-1 and LRP6. Moreover, Dkk-1 function was completely independent of Fz but LRP6 dramatically interfered with the Dkk-1 inhibition of Wnt signalling. Thus, unlike Wnt antagonists, which exert their effects by molecular mimicry of Fz5-7 or Wnt sequestration through other mechanisms8,9, Dkk-1 specifically inhibits canonical Wnt signalling by binding to the LRP6 component of the receptor complex.
AB - Wnt signalling has an important role in cell fate determination, tissue patterning and tumorigenesis1-4. Secreted antagonists of Wnt include Frizzled (Fz)-related proteins (FRPs)5-7, Cerberus8, Wnt inhibitory factor (WIF)9 and Dickkopf (Dkk)10,11. FRPs, Cerberus and WIF have all been shown to act by binding and sequestering Wnt. We report a novel mechanism of Wnt-signalling inhibition by human Dkk-1. Dkk-1 demonstrated no interaction with Wnt but bound a single cell surface site with high affinity (KD = 0.39 nM). Its receptor was detectable in a complex with a relative molecular mass of 240,000 (Mr 240K) with [125I] Dkk-1 by covalent affinity cross-linking. Wnt signalling through β-catenin is mediated by the Fz receptor12 and a recently identified low-density-lipoprotein-receptor-related co-receptor, LRP6/Arrow13-15. Overproduction of the 200K LRP6 protein, but not of Fz, strikingly increased Dkk-1 binding as well as the amount of the 240K cross-linked complex, which was shown to be composed of Dkk-1 and LRP6. Moreover, Dkk-1 function was completely independent of Fz but LRP6 dramatically interfered with the Dkk-1 inhibition of Wnt signalling. Thus, unlike Wnt antagonists, which exert their effects by molecular mimicry of Fz5-7 or Wnt sequestration through other mechanisms8,9, Dkk-1 specifically inhibits canonical Wnt signalling by binding to the LRP6 component of the receptor complex.
UR - http://www.scopus.com/inward/record.url?scp=0034933057&partnerID=8YFLogxK
U2 - 10.1038/35083081
DO - 10.1038/35083081
M3 - Article
C2 - 11433302
AN - SCOPUS:0034933057
SN - 1465-7392
VL - 3
SP - 683
EP - 686
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 7
ER -