Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. [5] [6] LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. [5] [6] LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
LRP6 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP5. In each protein, about 85% of its 1600-amino-acid length is extracellular. Each has four β-propeller motifs at the amino terminal end that alternate with four epidermal growth factor (EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell. [7]
LRP6 acts as a co-receptor with LRP5 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway. [7]
Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation. [8] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation. [9]
LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1 [10] ), sclerostin, R-spondins and members of the cysteine-knot-type protein family. [7]
Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis. [7] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass. [11] LRP6 is critical in bone's anabolic response to parathyroid hormone (PTH) treatment, whereas LRP5 is not involved. [11] On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role. [11] Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials. [12] [13]
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
The low-density lipoprotein receptor gene family codes for a class of structurally related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is cholesterol homeostasis. In humans, excess cholesterol in the blood is captured by low-density lipoprotein (LDL) and removed by the liver via endocytosis of the LDL receptor. Recent evidence indicates that the members of the LDL receptor gene family are active in the cell signalling pathways between specialized cells in many, if not all, multicellular organisms.
Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.
Axin-1 is a protein that in humans is encoded by the AXIN1 gene.
Proto-oncogene Wnt-1, or Proto-oncogene Int-1 homolog is a protein that in humans is encoded by the WNT1 gene.
Frizzled-2(Fz-2) is a protein that in humans is encoded by the FZD2 gene.
Frizzled-5(Fz-5) is a protein that in humans is encoded by the FZD5 gene.
Frizzled-1(Fz-1) is a protein that in humans is encoded by the FZD1 gene.
Frizzled-6(Fz-6) is a protein that in humans is encoded by the FZD6 gene.
Frizzled-8(Fz-8) is a protein that in humans is encoded by the FZD8 gene.
Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A loss-of-function mutation causes osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a gain-of-function mutation causes drastic increases in bone mass.
Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene.
Secreted frizzled-related protein 1, also known as SFRP1, is a protein which in humans is encoded by the SFRP1 gene.
Protein Wnt-5a is a protein that in humans is encoded by the WNT5A gene.
Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.
Protein Wnt-7a is a protein that in humans is encoded by the WNT7A gene.
Dickkopf-related protein 2 is a protein in the Dickkopf family that in humans is encoded by the DKK2 gene.
Kremen protein 1 is a protein that in humans is encoded by the KREMEN1 gene. Kremen1 is conserved in chordates including amphioxus and most vertebrate species. The protein is a type I transmembrane receptor of ligands Dickkopf1, Dickkopf2, Dickkopf3, Dickkopf4, EpCAM and Rspondin1.
Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway.
Dickkopf (DKK) is a family of proteins consisting of five members as of 2020. That is, vertebrates usually contain five genes that are members of the family. The most well-studied is Dickkopf-related protein 1 (DKK1). DKK proteins inhibit the Wnt signaling pathway coreceptors LRP5 and LRP6. They bind with high affinity as ligands to KREMEN1 and KREMEN2, which are transmembrane proteins. DKK proteins have important roles in the development of vertebrates.
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