LRP5 explained

Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene.^{[1] [2] [3]} 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.

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.^[4]

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. This protein plays a key role in skeletal homeostasis.

Transcription

The LRP5 promoter contains binding sites for KLF15 and SP1.^[5] In addition, 5' region of the LRP5 gene contains four RUNX2 binding sites.^[6] 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^{[7] [8] [9] [10] [11] [12]} 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.^[13]

Interactions

LRP5 has been shown to interact with AXIN1.^{[14] [15]}

Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.^[16] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.^[17]

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.^[18] Shortly thereafter, two studies reported that gain-of-function mutations in LRP5 caused high bone mass.^{[19] [20]} 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.^[21] The majority of the current data supports the concept that bone mass is controlled by LRP5 through the osteocytes.^[22] Mice with the same Lrp5 gain-of-function mutations as also have high bone mass.^[23] The high bone mass is maintained when the mutation only occurs in limbs or in cells of the osteoblastic lineage. Bone mechanotransduction occurs through Lrp5^[24] and is suppressed if Lrp5 is removed in only osteocytes.^[25] There are promising osteoporosis clinical trials targeting sclerostin, an osteocyte-specific protein which inhibits Wnt signaling by binding to Lrp5.^[26] 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 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.

LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation.^[27] Mutations in this gene also cause familial exudative vitreoretinopathy.

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.^[28]

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.^[29]

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.^[30]

The polyphenol curcumin increases the mRNA expression of LRP5.^[31]

Mutations in LRP5 cause polycystic liver disease.^[32]

Further reading

• He X, Semenov M, Tamai K, Zeng X . LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way . Development . 131 . 8 . 1663–77 . Apr 2004 . 15084453 . 10.1242/dev.01117 . 2297859 .
• Godyna S, Liau G, Popa I, Stefansson S, Argraves WS . Identification of the low density lipoprotein receptor-related protein (LRP) as an endocytic receptor for thrombospondin-1 . The Journal of Cell Biology . 129 . 5 . 1403–10 . Jun 1995 . 7775583 . 2120467 . 10.1083/jcb.129.5.1403.
• Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R, Peltonen L, Somer H, Hirose T, Dallapiccola B, De Paepe A, Swoboda W, Zabel B, Superti-Furga A, Steinmann B, Brunner HG, Jans A, Boles RG, Adkins W, van den Boogaard MJ, Olsen BR, Warman ML . Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13 . American Journal of Human Genetics . 59 . 1 . 146–51 . Jul 1996 . 8659519 . 1915094.
• Johnson ML, Gong G, Kimberling W, Reckér SM, Kimmel DB, Recker RB . Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13) . American Journal of Human Genetics . 60 . 6 . 1326–32 . Jun 1997 . 9199553 . 1716125 . 10.1086/515470.
• Dong Y, Lathrop W, Weaver D, Qiu Q, Cini J, Bertolini D, Chen D . Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity . Biochemical and Biophysical Research Communications . 251 . 3 . 784–90 . Oct 1998 . 9790987 . 10.1006/bbrc.1998.9545.
• de Crecchio G, Simonelli F, Nunziata G, Mazzeo S, Greco GM, Rinaldi E, Ventruto V, Ciccodicola A, Miano MG, Testa F, Curci A, D'Urso M, Rinaldi MM, Cavaliere ML, Castelluccio P . Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity . Clinical Genetics . 54 . 4 . 315–20 . Oct 1998 . 9831343 . 10.1034/j.1399-0004.1998.5440409.x. 37420287 .
• Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D . Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway . Molecular Cell . 7 . 4 . 801–9 . Apr 2001 . 11336703 . 10.1016/S1097-2765(01)00224-6. free .
• Twells RC, Metzker ML, Brown SD, Cox R, Garey C, Hammond H, Hey PJ, Levy E, Nakagawa Y, Philips MS, Todd JA, Hess JF . The sequence and gene characterization of a 400-kb candidate region for IDDM4 on chromosome 11q13 . Genomics . 72 . 3 . 231–42 . Mar 2001 . 11401438 . 10.1006/geno.2000.6492.
• Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X . Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6 . Current Biology . 11 . 12 . 951–61 . Jun 2001 . 11448771 . 10.1016/S0960-9822(01)00290-1. 15702819 . free . 2001CBio...11..951S .
• Zorn AM . Wnt signalling: antagonistic Dickkopfs . Current Biology . 11 . 15 . R592–5 . Aug 2001 . 11516963 . 10.1016/S0960-9822(01)00360-8. 14970864 . free . 2001CBio...11.R592Z .
• Okubo M, Horinishi A, Kim DH, Yamamoto TT, Murase T . Seven novel sequence variants in the human low density lipoprotein receptor related protein 5 (LRP5) gene . Human Mutation . 19 . 2 . 186 . Feb 2002 . 11793484 . 10.1002/humu.9012. 41880501 .
• Van Hul E, Gram J, Bollerslev J, Van Wesenbeeck L, Mathysen D, Andersen PE, Vanhoenacker F, Van Hul W . Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13 . Journal of Bone and Mineral Research . 17 . 6 . 1111–7 . Jun 2002 . 12054167 . 10.1359/jbmr.2002.17.6.1111. 8308650 .
• Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Bénichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W . Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density . American Journal of Human Genetics . 72 . 3 . 763–71 . Mar 2003 . 12579474 . 1180253 . 10.1086/368277.

External links

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

Notes and References

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2. Chen D, Lathrop W, Dong Y . Molecular cloning of mouse Lrp7(Lr3) cDNA and chromosomal mapping of orthologous genes in mouse and human . Genomics . 55 . 3 . 314–21 . Feb 1999 . 10049586 . 10.1006/geno.1998.5688.
3. Web site: Entrez Gene: LRP5 low density lipoprotein receptor-related protein 5 .
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5. Li J, Yang Y, Jiang B, Zhang X, Zou Y, Gong Y . Sp1 and KLF15 regulate basal transcription of the human LRP5 gene . BMC Genetics . 11 . 12 . 2010 . 20141633 . 2831824 . 10.1186/1471-2156-11-12 . free .
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