LDL-receptor-related protein 6 is a receptor for Dickkopf proteins.
Wnt glycoproteins have been implicated in diverse processes during embryonic patterning in metazoa. They signal through frizzled-type seven-transmembrane-domain receptors to stabilize beta-catenin. Wnt signalling is antagonized by the extracellular Wnt inhibitor dickkopf1 (dkk1), which is a member of a multigene family. dkk1 was initially identified as a head inducer in Xenopus embryos but the mechanism by which it blocks Wnt signalling is unknown. LDL-receptor-related protein 6 (LRP6) is required during Wnt/beta-catenin signalling in Drosophila, Xenopus and mouse, possibly acting as a co-receptor for Wnt. Here we show that LRP6 (ref. 7) is a specific, high-affinity receptor for Dkk1 and Dkk2. Dkk1 blocks LRP6-mediated Wnt/beta-catenin signalling by interacting with domains that are distinct from those required for Wnt/Frizzled interaction. dkk1 and LRP6 interact antagonistically during embryonic head induction in Xenopus where LRP6 promotes the posteriorizing role of Wnt/beta-catenin signalling. Thus, DKKs inhibit Wnt co-receptor function, exemplifying the modulation of LRP signalling by antagonists.
Mao
B
B
Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Wu
W
W
Li
Y
Y
Hoppe
D
D
Stannek
P
P
Glinka
A
A
Niehrs
C
C
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D018925:Chemokines; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D004627:Embryonic Induction; D006257:Head / Q000196:embryology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction; D013379:Substrate Specificity; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology; D029961:Zebrafish Proteins; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; D018925:Chemokines; D003598:Cytoskeletal Proteins; C501126:DKK1 protein, human; C498622:DKK2 protein, human; C498624:DKK3 protein, human; C501127:Dkk1 protein, mouse; C498623:Dkk2 protein, Xenopus; C498625:Dkk3 protein, Xenopus; C113865:FZD8 protein, Xenopus; D036341:Intercellular Signaling Peptides and Proteins; C555475:LRP6 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C110182:dkk1 protein, Xenopus; C501128:dkk1b protein, zebrafish; C094521:wnt8a protein, zebrafish