Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins.
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.
Brott
Barbara K
BK
Department of Microbiology and Molecular Genetics, Harvard Medical School. Molecular Medicine Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Sokol
Sergei Y
SY
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000502:physiology; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006257:Head / Q000196:embryology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008845:Microinjections; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000494:pharmacology; D011973:Receptors, LDL / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000502:physiology; D014162:Transfection; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology; D029961:Zebrafish Proteins; D051176:beta Catenin
C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C501126:DKK1 protein, human; C498622:DKK2 protein, human; C501127:Dkk1 protein, mouse; C498623:Dkk2 protein, Xenopus; D036341:Intercellular Signaling Peptides and Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; 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