Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation.
Multiple signaling pathways, including Wnt signaling, participate in animal development, stem cell biology, and human cancer. Although many components of the Wnt pathway have been identified, unresolved questions remain as to the mechanism by which Wnt binding to its receptors Frizzled and Low-density lipoprotein receptor-related protein 6 (LRP6) triggers downstream signaling events. With live imaging of vertebrate cells, we show that Wnt treatment quickly induces plasma membrane-associated LRP6 aggregates. LRP6 aggregates are phosphorylated and can be detergent-solubilized as ribosome-sized multiprotein complexes. Phospho-LRP6 aggregates contain Wnt-pathway components but no common vesicular traffic markers except caveolin. The scaffold protein Dishevelled (Dvl) is required for LRP6 phosphorylation and aggregation. We propose that Wnts induce coclustering of receptors and Dvl in LRP6-signalosomes, which in turn triggers LRP6 phosphorylation to promote Axin recruitment and beta-catenin stabilization.
Bilic
Josipa
J
Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Huang
Ya-Lin
YL
Davidson
Gary
G
Zimmermann
Timo
T
Cruciat
Cristina-Maria
CM
Bienz
Mariann
M
Niehrs
Christof
C
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002499:Centrifugation, Density Gradient; D003593:Cytoplasm / Q000378:metabolism; D000072261:Dishevelled Proteins; D004330:Drosophila; D029721:Drosophila Proteins; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D010750:Phosphoproteins; D012097:Repressor Proteins; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; C000606588:dsh protein, Drosophila; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3