Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene. [5] [6] [7] 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.
LRP5 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP6. 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. [8]
LRP5 acts as a co-receptor with LRP6 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway. [8] This protein plays a key role in skeletal homeostasis. [7]
The LRP5 promoter contains binding sites for KLF15 and SP1. [9] In addition, 5' region of the LRP5 gene contains four RUNX2 binding sites. [10] LRP5 has been shown in mice and humans to inhibit expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum [11] [12] [13] [14] [15] [16] and that excess plasma serotonin leads to inhibition in bone. On the other hand, one study in mouse has shown a direct effect of Lrp5 on bone. [17]
LRP5 has been shown to interact with AXIN1. [18] [19]
Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation. [20] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation. [21]
The Wnt signaling pathway was first linked to bone development when a loss-of-function mutation in LRP5 was found to cause osteoporosis-pseudoglioma syndrome. [22] Shortly thereafter, two studies reported that gain-of-function mutations in LRP5 caused high bone mass. [23] [24] Many bone density related diseases are caused by mutations in the LRP5 gene. There is controversy whether bone grows through Lrp5 through bone or the intestine. [25] The majority of the current data supports the concept that bone mass is controlled by LRP5 through the osteocytes. [26] Mice with the same Lrp5 gain-of-function mutations as also have high bone mass. [27] The high bone mass is maintained when the mutation only occurs in limbs or in cells of the osteoblastic lineage. [17] Bone mechanotransduction occurs through Lrp5 [28] and is suppressed if Lrp5 is removed in only osteocytes. [29] There are promising osteoporosis clinical trials targeting sclerostin, an osteocyte-specific protein which inhibits Wnt signaling by binding to Lrp5. [26] [30] An alternative model that has been verified in mice and in humans is that Lrp5 controls bone formation by inhibiting expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin, a molecule that regulates bone formation, in enterochromaffin cells of the duodenum [11] [12] [13] [14] [15] [16] and that excess plasma serotonin leads to inhibition in bone. Another study found that a different Tph1-inhibitor decreased serotonin levels in the blood and intestine, but did not affect bone mass or markers of bone formation. [17]
LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation. [31] Mutations in this gene also cause familial exudative vitreoretinopathy. [7]
A glial-derived extracellular ligand, Norrin, acts on a transmembrane receptor, Frizzled4, a coreceptor, Lrp5, and an auxiliary membrane protein, TSPAN12, on the surface of developing endothelial cells to control a transcriptional program that regulates endothelial growth and maturation. [32]
LRP5 knockout in mice led to increased plasma cholesterol levels on a high-fat diet because of the decreased hepatic clearance of chylomicron remnants. When fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance with marked reduction in intracellular ATP and Ca2+ in response to glucose, and impairment in glucose-induced insulin secretion. IP3 production in response to glucose was also reduced in LRP5—islets possibly caused by a marked reduction of various transcripts for genes involved in glucose sensing in LRP5—islets. LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets. [33]
In osteoarthritic chondrocytes the Wnt/beta-catenin pathway is activated with a significant up-regulation of beta-catenin mRNA expression. LRP5 mRNA and protein expression are also significantly up-regulated in osteoarthritic cartilage compared to normal cartilage, and LRP5 mRNA expression was further increased by vitamin D. Blocking LRP5 expression using siRNA against LRP5 resulted in a significant decrease in MMP13 mRNA and protein expressions. The catabolic role of LRP5 appears to be mediated by the Wnt/beta-catenin pathway in human osteoarthritis. [34]
The polyphenol curcumin increases the mRNA expression of LRP5. [35]
Mutations in LRP5 can cause polycystic liver disease. [36]
In cellular biology, 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, pronounced "wint", 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.
Sclerostin is a protein that in humans is encoded by the SOST gene. It is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN family of bone morphogenetic protein (BMP) antagonists. Sclerostin is produced primarily by the osteocyte but is also expressed in other tissues, and has anti-anabolic effects on bone formation.
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.
Lymphoid enhancer-binding factor 1 (LEF1) is a protein that in humans is encoded by the LEF1 gene. It is a member of T cell factor/lymphoid enhancer factor (TCF/LEF) family.
Proto-oncogene Wnt-1, or Proto-oncogene Int-1 homolog is a protein that in humans is encoded by the WNT1 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.
Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) also known as G-protein coupled receptor 49 (GPR49) or G-protein coupled receptor 67 (GPR67) is a protein that in humans is encoded by the LGR5 gene. It is a member of GPCR class A receptor proteins. R-spondin proteins are the biological ligands of LGR5. LGR5 is expressed across a diverse range of tissue such as in the muscle, placenta, spinal cord and brain and particularly as a biomarker of adult stem cells in certain tissues.
Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene.
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
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.
Low-density lipoprotein receptor-related protein 4 (LRP-4), also known as multiple epidermal growth factor-like domains 7 (MEGF7), is a protein that in humans is encoded by the LRP4 gene. LRP-4 is a member of the Lipoprotein receptor-related protein family and may be a regulator of Wnt signaling.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
Lipids: lipoprotein particle metabolism | ||
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| Lipoprotein particle classes and subclasses |
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| Apolipoproteins | ||
| Extracellular enzymes | ||
| Lipid transfer proteins | ||
| Cell surface receptors | ||
| ATP-binding cassette transporter | ||
