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Contents
LRP5 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | LRP5, BMND1, EVR1, EVR4, HBM, LR3, LRP-5, LRP7, OPPG, OPS, OPTA1, VBCH2, LDL receptor related protein 5, PCLD4, LRP-7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 603506; MGI: 1278315; HomoloGene: 1746; GeneCards: LRP5; OMA:LRP5 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
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.[8]
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.[8] This protein plays a key role in skeletal homeostasis.[7]
Transcription
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]
Interactions
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]
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.[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 cause polycystic liver disease.[36]
References
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Further reading
- He X, Semenov M, Tamai K, Zeng X (Apr 2004). "LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way". Development. 131 (8): 1663–77. doi:10.1242/dev.01117. PMID 15084453. S2CID 2297859.
- Godyna S, Liau G, Popa I, Stefansson S, Argraves WS (Jun 1995). "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. doi:10.1083/jcb.129.5.1403. PMC 2120467. PMID 7775583.
- 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 (Jul 1996). "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. PMC 1915094. PMID 8659519.
- Johnson ML, Gong G, Kimberling W, Reckér SM, Kimmel DB, Recker RB (Jun 1997). "Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13)". American Journal of Human Genetics. 60 (6): 1326–32. doi:10.1086/515470. PMC 1716125. PMID 9199553.
- Dong Y, Lathrop W, Weaver D, Qiu Q, Cini J, Bertolini D, Chen D (Oct 1998). "Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity". Biochemical and Biophysical Research Communications. 251 (3): 784–90. doi:10.1006/bbrc.1998.9545. PMID 9790987.
- 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 (Oct 1998). "Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity". Clinical Genetics. 54 (4): 315–20. doi:10.1034/j.1399-0004.1998.5440409.x. PMID 9831343. S2CID 37420287.
- Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D (Apr 2001). "Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway". Molecular Cell. 7 (4): 801–9. doi:10.1016/S1097-2765(01)00224-6. PMID 11336703.
- Twells RC, Metzker ML, Brown SD, Cox R, Garey C, Hammond H, Hey PJ, Levy E, Nakagawa Y, Philips MS, Todd JA, Hess JF (Mar 2001). "The sequence and gene characterization of a 400-kb candidate region for IDDM4 on chromosome 11q13". Genomics. 72 (3): 231–42. doi:10.1006/geno.2000.6492. PMID 11401438.
- Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X (Jun 2001). "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6". Current Biology. 11 (12): 951–61. Bibcode:2001CBio...11..951S. doi:10.1016/S0960-9822(01)00290-1. PMID 11448771. S2CID 15702819.
- Zorn AM (Aug 2001). "Wnt signalling: antagonistic Dickkopfs". Current Biology. 11 (15): R592–5. Bibcode:2001CBio...11.R592Z. doi:10.1016/S0960-9822(01)00360-8. PMID 11516963. S2CID 14970864.
- Okubo M, Horinishi A, Kim DH, Yamamoto TT, Murase T (Feb 2002). "Seven novel sequence variants in the human low density lipoprotein receptor related protein 5 (LRP5) gene". Human Mutation. 19 (2): 186. doi:10.1002/humu.9012. PMID 11793484. S2CID 41880501.
- Van Hul E, Gram J, Bollerslev J, Van Wesenbeeck L, Mathysen D, Andersen PE, Vanhoenacker F, Van Hul W (Jun 2002). "Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13". Journal of Bone and Mineral Research. 17 (6): 1111–7. doi:10.1359/jbmr.2002.17.6.1111. PMID 12054167. S2CID 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 (Mar 2003). "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. doi:10.1086/368277. PMC 1180253. PMID 12579474.
External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.