LRP6

LRP6, or low-density lipoprotein receptor-related protein 6, is a single-pass transmembrane protein in the LDL receptor family. It has an extensive extracellular domain, a single transmembrane region, and a cytoplasmic tail involved in signaling. The protein is expressed in many tissues, with notable roles in development and bone biology.

LRP6 functions as a co-receptor in the canonical Wnt/beta-catenin signaling pathway. When a Wnt ligand binds to Frizzled, LRP6 is recruited to the receptor complex. CK1 and GSK3-mediated phosphorylation of motifs in the cytoplasmic tail creates docking sites for the Axin destruction complex, leading to inhibition of beta-catenin degradation. Stabilized beta-catenin accumulates in the cytoplasm and translocates to the nucleus, where it partners with TCF/LEF transcription factors to regulate Wnt target genes. LRP6 activity is modulated by Dishevelled and endocytic trafficking, linking extracellular signals to intracellular transcriptional responses.

Genetically, LRP6 is essential for normal development. In mice, loss of LRP6 function causes profound developmental defects and embryonic lethality due to disrupted Wnt signaling, while partial loss can affect bone density and adipogenesis. In humans, several rare LRP6 variants have been associated with increased risk of metabolic and cardiovascular diseases, including mutations linked to early coronary artery disease and features of metabolic syndrome. Ongoing research continues to investigate LRP6’s roles in bone biology, metabolism, and cancer, as well as its potential as a therapeutic target for modulating Wnt signaling.