LRP6

Domain

The YWTD-EGF-like domains 1 and 2 are required for the interaction with Wnt-frizzled complex. The YWTD-EGF-like domains 3 and 4 are required for the interaction with DKK1.

The PPPSP motifs play a central role in signal transduction by being phosphorylated, leading to activate the Wnt signaling pathway.

Function

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).

Involvement in disease

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.

None

The disease is caused by variants affecting the gene represented in this entry.

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).

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

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.

Sequence similarities

Belongs to the LDLR family.

Tissue specificity

Widely coexpressed with LRP5 during embryogenesis and in adult tissues.

Cellular localization

• Cell membrane
• Single-pass type I membrane protein
• 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).

Alternative names

• Low-density lipoprotein receptor-related protein 6
• LRP-6
• LRP6

Database links

• entrezGene:4041
• entrezGene:4040
• omim:603507
• omim:603506
• swissprot:O75581
• swissprot:O75197

Target type

Proteins

Primary research area

Oncology

Molecular weight

180429Da