Wnt-independent activation of beta-catenin mediated by a Dkk1-Fz5 fusion protein.
An XWnt8-Fz5 fusion protein synergizes with LRP6 to potently activate beta-catenin-dependent signaling. Here, we generated a fusion in which XWnt8 was fused to the N-terminus of LRP6 and show it synergizes with both Fz4 and Fz5 to potently transactivate beta-catenin-dependent Wnt signaling. Based on this, we hypothesized that the main function of Wnt is to nucleate the formation of a physical complex between LRP6 and a Frizzled. Dkk1, but not the related Dkk3, binds LRP6 and inhibits canonical Wnt signaling by blocking the interaction of Wnt and LRP6. Therefore, we reasoned that a covalent fusion of Dkk1 to Fz5 (Dkk1-Fz5) would mimic Wnt ligand by nucleating the formation of a complex containing Fz5 and LRP6, while Dkk3 (Dkk3-Fz5) would not. We found that Dkk1-Fz5, but not Dkk3-Fz5, potently synergized with LRP6 to activate signaling in a dishevelled-dependent manner.
Holmen
Sheri L
SL
Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Robertson
Scott A
SA
Zylstra
Cassandra R
CR
Williams
Bart O
BO
D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D051157:Frizzled Receptors; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D011973:Receptors, LDL / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D051153:Wnt Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C501126:DKK1 protein, human; C501127:Dkk1 protein, mouse; C498589:FZD5 protein, human; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D011973:Receptors, LDL; D017981:Receptors, Neurotransmitter; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin