Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow.
Wnt signalling has an important role in cell fate determination, tissue patterning and tumorigenesis. Secreted antagonists of Wnt include Frizzled (Fz)-related proteins (FRPs), Cerberus, Wnt inhibitory factor (WIF) and Dickkopf (Dkk). 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 (K(D) = 0.39 nM). Its receptor was detectable in a complex with a relative molecular mass of 240,000 (M(r) 240K) with [(125)I] Dkk-1 by covalent affinity cross-linking. Wnt signalling through beta-catenin is mediated by the Fz receptor and a recently identified low-density-lipoprotein-receptor-related co-receptor, LRP6/Arrow. 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 Fz or Wnt sequestration through other mechanisms, Dkk-1 specifically inhibits canonical Wnt signalling by binding to the LRP6 component of the receptor complex.
Bafico
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Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, Box 1130, One Gustave L. Levy Place, New York, New York 10029, USA.
Liu
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Yaniv
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Gazit
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Aaronson
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D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D011973:Receptors, LDL / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators; D014162:Transfection; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C501128:dkk1b protein, zebrafish