Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize beta-catenin independently of Frizzled proteins.
Secreted signaling proteins of the Wnt family are known to regulate a diverse range of developmental processes, and their signaling pathway through beta-catenin is frequently activated in cancer. The identification of both Frizzled and LRP5/6 (LRP: low-density lipoprotein receptor-related protein) proteins as components of cell-surface receptors for Wnt proteins has raised questions about their individual functions. We have investigated this issue through a structure-function analysis of Frizzled and LRP proteins that have been implicated in Wnt1 signaling. Consistent with other reports, we find that LRP6/Arrow proteins deleted for their extracellular domain are able to activate the Wnt/beta-catenin signaling pathway. Importantly, our results demonstrate that this signaling from LRP6/Arrow derivatives can occur in a Frizzled- and ligand-independent manner. Furthermore, we show that the PPSP motifs within the intracellular domain of LRP6 are required for signaling. In contrast to results with LRP6, overexpression of Frizzled proteins did not activate the pathway. Based on evidence of ligand binding to both Frizzled and LRP6, current models suggest that both proteins are components of a Wnt receptor complex that signals to beta-catenin. In light of these models, our data imply that LRP5/6/Arrow proteins constitute the distal signal-initiating component of these receptors. The results also support the notion that LRP5/6 are candidate oncogenes.
Brennan
Keith
K
Strang Cancer Research Laboratory at The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Gonzalez-Sancho
José M
JM
Castelo-Soccio
Leslie A
LA
Howe
Louise R
LR
Brown
Anthony M C
AM
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000502:physiology*; D017931:DNA Primers; D004331:Drosophila melanogaster; D051157:Frizzled Receptors; D017930:Genes, Reporter; D006801:Humans; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008156:Luciferases / Q000032:analysis; D009857:Oncogenes; D011506:Proteins / Q000502:physiology*; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D051157:Frizzled Receptors; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011506:Proteins; D011973:Receptors, LDL; D015534:Trans-Activators; D051176:beta Catenin; D008156:Luciferases