LRP5

LRP5
Identifiers
Aliases	LRP5, BMND1, EVR1, EVR4, HBM, LR3, LRP-5, LRP7, OPPG, OPS, OPTA1, VBCH2, LDL receptor related protein 5
External IDs	MGI: 1278315 HomoloGene: 1746 GeneCards: LRP5
Gene ontology Molecular function • toxin transporter activity • protein binding • coreceptor activity involved in Wnt signaling pathway • Wnt-activated receptor activity • coreceptor activity involved in canonical Wnt signaling pathway • Wnt-protein binding Cellular component • integral component of membrane • Wnt signalosome • Wnt-Frizzled-LRP5/6 complex • membrane • receptor complex • plasma membrane • endoplasmic reticulum • mitochondrion Biological process • regulation of apoptotic process • positive regulation of osteoblast proliferation • regulation of insulin secretion involved in cellular response to glucose stimulus • endocytosis • limb morphogenesis • extracellular matrix-cell signaling • branching involved in mammary gland duct morphogenesis • somatic stem cell population maintenance • bone marrow development • regulation of canonical Wnt signaling pathway • bone morphogenesis • gastrulation with mouth forming second • embryonic digit morphogenesis • positive regulation of sequence-specific DNA binding transcription factor activity • cell-cell signaling involved in mammary gland development • cholesterol metabolic process • Wnt signaling pathway • negative regulation of osteoblast differentiation • anatomical structure regression • mammary gland duct morphogenesis • regulation of blood pressure • positive regulation of transcription, DNA-templated • multicellular organism development • retina morphogenesis in camera-type eye • vasculature development • apoptotic process involved in blood vessel morphogenesis • positive regulation of mesenchymal cell proliferation • bone remodeling • Wnt signaling pathway involved in dorsal/ventral axis specification • glucose catabolic process • positive regulation of cell proliferation • retinal blood vessel morphogenesis • canonical Wnt signaling pathway • osteoblast development • negative regulation of protein serine/threonine kinase activity • adipose tissue development • cell migration involved in gastrulation • cholesterol homeostasis • bone development • positive regulation of fat cell differentiation • positive regulation of mitotic nuclear division • retina vasculature morphogenesis in camera-type eye • anterior/posterior pattern specification • positive regulation of transcription from RNA polymerase II promoter • regulation of bone remodeling • beta-catenin destruction complex disassembly • response to peptide hormone Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4041	16973
Ensembl	ENSG00000162337	ENSMUSG00000024913
UniProt	O75197	Q91VN0
RefSeq (mRNA)	NM_001291902 NM_002335	NM_008513
RefSeq (protein)	NP_001278831.1 NP_002326.2	NP_032539.2
Location (UCSC)	Chr 11: 68.31 – 68.45 Mb	Chr 19: 3.58 – 3.69 Mb
PubMed search	[1]	[2]
Wikidata

Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene.^[3][4][5] 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 (decrease in bone mass), while a gain-of-function mutation causes drastic increases in bone mass.

Structure

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.^[6]

Function

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.^[6] This protein plays a key role in skeletal homeostasis.^[5]

Transcription

The LRP5 promoter contains binding sites for KLF15 and SP1.^[7] In addition, 5' region region of the LRP5 gene contains four RUNX2 binding sites.^[8] 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^{[9][10][11][12][13][14]} 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.^[15]

Interactions

LRP5 has been shown to interact with AXIN1.^[16][17]

Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.^[18] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.^[19]

Clinical Significance

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.^[20] Shortly thereafter, two studies reported that gain-of-function mutations in LRP5 caused high bone mass.^[21][22] 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.^[23] The majority of the current data supports the concept that bone mass is controlled by LRP5 through the osteocytes.^[24] Mice with the same Lrp5 gain-of-function mutations as also have high bone mass.^[25] The high bone mass is maintained when the mutation only occurs in limbs or in cells of the osteoblastic lineage.^[15] Bone mechanotransduction occurs through Lrp5^[26] and is suppressed if Lrp5 is removed in only osteocytes.^[27] There are promising osteoporosis clinical trials targeting sclerostin, an osteocyte-specific protein which inhibits Wnt signaling by binding to Lrp5.^[24][28] 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^{[9][10][11][12][13][14]} 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.^[15]

LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation.^[29] Mutations in this gene also cause familial exudative vitreoretinopathy.^[5]

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.^[30]

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.^[31]

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.^[32]

The polyphenol curcumin increases the mRNA expression of LRP5.^[33]

Mutations in LRP5 cause polycystic liver disease .^[34]

References

Further reading

External links

• GeneReviews/NCBI/NIH/UW entry on Familial Exudative Vitreoretinopathy, Autosomal Dominant

This article incorporates text from the United States National Library of Medicine, which is in the public domain.