LRP6

LRP6 is a member of the low density lipoprotein (LDL) receptor gene family. LDL receptors are transmembrane cell surface proteins involved in receptor-mediated endocytosis of lipoprotein and protein ligands. The protein encoded by this gene functions as a receptor or, with Frizzled, a co-receptor for Wnt and thereby transmits the canonical Wnt/beta-catenin signaling cascade. Through its interaction with the Wnt/beta-catenin signaling cascade this gene plays a role in the regulation of cell differentiation, proliferation, and migration and the development of many cancer types.

LRP6

Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in bone formation. The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalsomes and inhibiting AXIN1/GSK3-mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation (By similarity).

Canonical Wnt signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Canonical Wnt signaling pathway involved in neural crest cell differentiation1 PublicationIC:BHF-UCL
Canonical Wnt signaling pathway involved in regulation of cell proliferation1 PublicationIC:BHF-UCL
Cell-cell adhesionIEA:Ensembl
Cellular response to cholesterolManual Assertion Based On ExperimentIMP:BHF-UCL
Chemical synaptic transmissionManual Assertion Based On ExperimentIBA:GO_CentralDopaminergic neuron differentiationISS:ParkinsonsUK-UCL
Midbrain dopaminergic neuron differentiationManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Negative regulation of protein kinase activityManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of protein phosphorylationManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of protein serine/threonine kinase activityManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of smooth muscle cell apoptotic processManual Assertion Based On ExperimentIMP:BHF-UCL
Neural crest cell differentiationManual Assertion Based On ExperimentIDA:BHF-UCL
Neural crest formationManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of cell cycleManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of cytosolic calcium ion concentrationIEA:Ensembl
Positive regulation of DNA-binding transcription factor activityManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIMP:BHF-UCL
Protein localization to plasma membraneManual Assertion Based On ExperimentIPI:ParkinsonsUK-UCL
Receptor-mediated endocytosis involved in cholesterol transportManual Assertion Based On ExperimentIBA:GO_Central
Response to peptide hormoneIEA:Ensembl
Wnt signaling pathwayManual Assertion Based On ExperimentIDA:ParkinsonsUK-UCL
Wnt signaling pathway involved in midbrain dopaminergic neuron differentiationManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Wnt signaling pathway involved in somitogenesisManual Assertion Based On ExperimentIBA:GO_Central

Cell membrane
Endoplasmic reticulum
Membrane raft
On Wnt signaling, undergoes a cycle of caveolin- or clathrin-mediated endocytosis and plasma membrane location. Released from the endoplasmic reticulum on palmitoylation. Mono-ubiquitination retains it in the endoplasmic reticulum in the absence of palmitoylation. On Wnt signaling, phosphorylated, aggregates and colocalizes with AXIN1 and GSK3B at the plasma membrane in LRP6-signalsomes. Chaperoned to the plasma membrane by MESD (By similarity).

Coronary artery disease, autosomal dominant, 2 (ADCAD2):
A common heart disease characterized by reduced or absent blood flow in one or more of the arteries that encircle and supply the heart. Its most important complication is acute myocardial infarction.
Tooth agenesis, selective, 7 (STHAG7):
An autosomal dominant form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth).

Extracellular: 20-1370
Helical: 1371-1393
Cytoplasmic: 1394-1613

Dual phosphorylation of cytoplasmic PPPSP motifs sequentially by GSK3 and CK1 is required for AXIN1-binding, and subsequent stabilization and activation of beta-catenin via preventing GSK3-mediated phosphorylation of beta-catenin. Phosphorylated, in vitro, by GRK5/6 within and outside the PPPSP motifs. Phosphorylation at Ser-1490 by CDK14 during G2/M phase leads to regulation of the Wnt signaling pathway during the cell cycle. Phosphorylation by GSK3B is induced by RPSO1 binding and inhibited by DKK1. Phosphorylated, in vitro, by casein kinase I on Thr-1479.
Undergoes gamma-secretase-dependent regulated intramembrane proteolysis (RIP). The extracellular domain is first released by shedding, and then, through the action of gamma-secretase, the intracellular domain (ICD) is released into the cytoplasm where it is free to bind to GSK3B and to activate canonical Wnt signaling.
Palmitoylation on the two sites near the transmembrane domain leads to release of LRP6 from the endoplasmic reticulum.
Mono-ubiquitinated which retains LRP6 in the endoplasmic reticulum. Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.
N-glycosylation is required for cell surface location.