LRP5

Low density lipoprotein receptor-related protein 5
Identifiers
SymbolsLRP5 ; BMND1; EVR1; EVR4; HBM; LR3; LRP-5; LRP7; OPPG; OPS; OPTA1; VBCH2
External IDsOMIM: 603506 MGI: 1278315 HomoloGene: 1746 GeneCards: LRP5 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez404116973
EnsemblENSG00000162337ENSMUSG00000024913
UniProtO75197Q91VN0
RefSeq (mRNA)NM_001291902NM_008513
RefSeq (protein)NP_001278831NP_032539
Location (UCSC)Chr 11:
68.08 – 68.22 Mb		Chr 19:
3.58 – 3.69 Mb
PubMed search

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

Function

LRP5 is a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins and was originally cloned on the basis of its association with diabetes mellitus type 1 in humans. This protein plays a key role in skeletal homeostasis.[3]

Transcription

The LRP5 promoter contains binding sites for KLF15 and SP1.[4] In addition, 5' region region of the LRP5 gene contains four RUNX2 binding sites.[5] 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[6][7][8][9][10][11] 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.[12]

Interactions

LRP5 has been shown to interact with AXIN1.[13][14]

Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.[15] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.[16]

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.[17] Shortly thereafter, two studies reported that gain-of-function mutations in LRP5 caused high bone mass.[18][19] 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.[20] Few studies support the concept that bone mass is controlled by LRP5 through the osteoblasts or osteocytes.[21] Mice with the same Lrp5 gain-of-function mutations as also have high bone mass.[22] The high bone mass is maintained when the mutation only occurs in limbs or in cells of the osteoblastic lineage.[23] Bone mechanotransduction occurs through Lrp5[24] and is suppressed if Lrp5 is removed in only osteocytes.[25] An alternative model is that Lrp5 controls bone formation by suppressing serotonin synthesis in the duodenum by regulating TPH1 independent of Wnt signaling.[26] There are promising osteoporosis clinical trials targeting an osteocyte-specific Wnt antagonist, sclerostin.[21][27] It must be pointed out that activation of Wnts in mice and humans leads to cancer and we therefore need to view therapies targeting Wnt signaling with utmost care.

LRP5 in humans and mice regulats bone formation while Wnt signaling regulats bone resorption. Lrp6 is therefore a more bonafide Wnt coreceptor in bone than Lrp5 as Lrp6 mutation in mice and humans regulates bone resorption like the Wnt signaling does. Clarification of this issue needs further investigation. An alternative model to Wnt signaling where in LRP5 inhibits expression of TPH1, the rate-limiting biosynthetic enzyme for serotonin, a molecule that regulates bone formation, in enterochromaffin cells of the duodenum in mice and humans [6][7][8][9][10][11] and that excess plasma serotonin leads to inhibition in bone.

LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation.[28] Mutations in this gene also cause familial exudative vitreoretinopathy.[3]

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.[29]

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.[30]

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.[31]

The polyphenol curcumin increases the mRNA expression of LRP5.[32]

Mutations in LRP5 cause polycystic liver disease .[33]

References

  1. ↑ Hey PJ, Twells RC, Phillips MS, Yusuke Nakagawa, Brown SD, Kawaguchi Y, Cox R, Guochun Xie, Dugan V, Hammond H, Metzker ML, Todd JA, Hess JF (Oct 1998). "Cloning of a novel member of the low-density lipoprotein receptor family". Gene 216 (1): 103–11. doi:10.1016/S0378-1119(98)00311-4. PMID 9714764.
  2. ↑ Chen D, Lathrop W, Dong Y (May 1999). "Molecular cloning of mouse Lrp7(Lr3) cDNA and chromosomal mapping of orthologous genes in mouse and human". Genomics 55 (3): 314–21. doi:10.1006/geno.1998.5688. PMID 10049586.
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: LRP5 low density lipoprotein receptor-related protein 5".
  4. ↑ Li J, Yang Y, Jiang B, Zhang X, Zou Y, Gong Y (2010). "Sp1 and KLF15 regulate basal transcription of the human LRP5 gene". BMC Genet. 11: 12. doi:10.1186/1471-2156-11-12. PMC 2831824. PMID 20141633.
  5. ↑ Agueda L, Velázquez-Cruz R, Urreizti R, Yoskovitz G, Sarrión P, Jurado S, Güerri R, Garcia-Giralt N, Nogués X, Mellibovsky L, Díez-Pérez A, Marie PJ, Balcells S, Grinberg D (May 2011). "Functional relevance of the BMD-associated polymorphism rs312009: novel involvement of RUNX2 in LRP5 transcriptional regulation". J. Bone Miner. Res. 26 (5): 1133–44. doi:10.1002/jbmr.293. PMID 21542013.
  6. ↑ 6.0 6.1 Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G (November 2008). "Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum". Cell 135 (5): 825–37. doi:10.1016/j.cell.2008.09.059. PMC 2614332. PMID 19041748.
  7. ↑ 7.0 7.1 Kode A, Mosialou I, Silva BC, Rached MT, Zhou B, Wang J, Townes TM, Hen R, Depinho RA, Guo XE, Kousteni S. (2012). "FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin.". J Clin Invest. 122 (10): 3490–503. doi:10.1172/JCI64906. PMC 3461930. PMID 22945629.
  8. ↑ 8.0 8.1 Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M (2010). "Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin". J Bone Miner Res. 25 (3): 673–5. doi:10.1002/jbmr.44. PMID 20200960.
  9. ↑ 9.0 9.1 Rosen CJ (2009). "Breaking into bone biology: serotonin's secrets". Nat Med. 15 (2): 145–6. doi:10.1038/nm0209-145. PMID 19197289.
  10. ↑ 10.0 10.1 Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton LJ 3rd, Khosla S (2010). "Relation of serum serotonin levels to bone density and structural parameters in women". J Bone Miner Res. 25 (2): 415–22. doi:10.1359/jbmr.090721. PMC 3153390. PMID 19594297.
  11. ↑ 11.0 11.1 Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, Van Hul W, Eastell R, Kassem M, Brixen K. (2011). "Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high bone mass phenotype due to a mutation in Lrp5". J Bone Miner Res. 26 (8): 1721–8. doi:10.1002/jbmr.376. PMID 21351148.
  12. ↑ Cui Y, Niziolek PJ, MacDonald BT, Zylstra CR, Alenina N, Robinson DR, Zhong Z, Matthes S, Jacobsen CM, Conlon RA, Brommage R, Liu Q, Mseeh F, Powell DR, Yang QM, Zambrowicz B, Gerrits H, Gossen JA, He X, Bader M, Williams BO, Warman ML, Robling AG (June 2011). "Lrp5 functions in bone to regulate bone mass". Nat. Med. 17 (6): 684–91. doi:10.1038/nm.2388. PMC 3113461. PMID 21602802.
  13. ↑ Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D (April 2001). "Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway". Mol. Cell 7 (4): 801–9. doi:10.1016/S1097-2765(01)00224-6. PMID 11336703.
  14. ↑ Kim MJ, Chia IV, Costantini F (November 2008). "SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability". FASEB J. 22 (11): 3785–94. doi:10.1096/fj.08-113910. PMC 2574027. PMID 18632848.
  15. ↑ Katoh M, Katoh M (September 2006). "Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades". Cancer Biol. Ther. 5 (9): 1059–64. doi:10.4161/cbt.5.9.3151. PMID 16940750.
  16. ↑ Hong JY, Park JI, Cho K, Gu D, Ji H, Artandi SE, McCrea PD (December 2010). "Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members". J. Cell. Sci. 123 (Pt 24): 4351–65. doi:10.1242/jcs.067199. PMC 2995616. PMID 21098636.
  17. ↑ Gong Y et al. (November 2001). "LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development". Cell 107 (4): 513–523. doi:10.1016/S0092-8674(01)00571-2. PMID 11719191.
  18. ↑ Little RD et al. (January 2002). "A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait". American Journal of Human Genetics 70 (1): 11–19. doi:10.1086/338450. PMC 419982. PMID 11741193.
  19. ↑ Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (May 2002). "High bone density due to a mutation in LDL-receptor-related protein 5". The New England Journal of Medicine 346 (20): 1513–1521. doi:10.1056/NEJMoa013444. PMID 12015390.
  20. ↑ Zhang W, Drake MT (March 2012). "Potential role for therapies targeting DKK1, LRP5, and serotonin in the treatment of osteoporosis". Current osteoporosis reports 10 (1): 93–100. doi:10.1007/s11914-011-0086-8. PMID 22210558.
  21. ↑ 21.0 21.1 Baron R and Kneissel M (February 2013). "WNT signaling in bone homeostasis and disease: from human mutations to treatments". Nature Medicine 19 (2): 179–192. doi:10.1038/nm.3074. PMID 23389618.
  22. ↑ Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML, Reddy PS, Bodine PVN, Robinson JA, Bhat B, Marzolf J, Moran RA, Bex F (June 2003). "High bone mass in mice expressing a mutant LRP5 gene". Journal of bone and mineral research 18 (6): 960–974. doi:10.1359/jbmr.2003.18.6.960. PMID 12817748.
  23. ↑ Cui Y, Niziolek PJ, MacDonald BT, Zylstra CR, Alenina N, Robinson DR, Zhong Z, Matthes S, Jacobsen CM, Conlon RA, Brommage R, Liu Q, Mseeh F, Powell DR, Yang QM, Zambrowicz B, Gerrits H, Gossen JA, He X, Bader M, Williams BO, Warman ML, Robling AG. (June 2011). "Lrp5 functions in bone to regulate bone mass". Nature Medicine 17 (6): 684–691. doi:10.1038/nm.2388. PMC 3113461. PMID 21602802.
  24. ↑ Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, Li J, Maye P, Rowe DW, Duncan RL, Warman ML, Turner CH (August 2006). "The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment". The Journal of Biological Chemistry 281 (33): 23698–23711. doi:10.1074/jbc.M601000200. PMID 16790443.
  25. ↑ Zhao L, Shim JW, Dodge TR, Robling AG, Yokota H (May 2013). "Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading". Bone 54 (1): 35–43. doi:10.1016/j.bone.2013.01.033. PMC 3602226. PMID 23356985.
  26. ↑ Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G (November 2008). "Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum". Cell 135 (5): 825–837. doi:10.1016/j.cell.2008.09.059. PMC 2614332. PMID 19041748.
  27. ↑ Burgers TA, Williams BO (June 2013). "Regulation of Wnt/beta-catenin signaling within and from osteocytes". Bone 54 (2): 244–249. doi:10.1016/j.bone.2013.02.022. PMID 23470835.
  28. ↑ Xia CH, Liu H, Cheung D, Wang M, Cheng C, Du X, Chang B, Beutler B, Gong X (June 2008). "A model for familial exudative vitreoretinopathy caused by LPR5 mutations". Hum. Mol. Genet. 17 (11): 1605–12. doi:10.1093/hmg/ddn047. PMC 2902293. PMID 18263894.
  29. ↑ Ye X, Wang Y, Nathans J (September 2010). "The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease". Trends Mol Med 16 (9): 417–25. doi:10.1016/j.molmed.2010.07.003. PMC 2963063. PMID 20688566.
  30. ↑ Fujino T, Asaba H, Kang MJ, Ikeda Y, Sone H, Takada S, Kim DH, Ioka RX, Ono M, Tomoyori H, Okubo M, Murase T, Kamataki A, Yamamoto J, Magoori K, Takahashi S, Miyamoto Y, Oishi H, Nose M, Okazaki M, Usui S, Imaizumi K, Yanagisawa M, Sakai J, Yamamoto TT (January 2003). "Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion". Proc. Natl. Acad. Sci. U.S.A. 100 (1): 229–34. doi:10.1073/pnas.0133792100. PMC 140935. PMID 12509515.
  31. ↑ Papathanasiou I, Malizos KN, Tsezou A (March 2010). "Low-density lipoprotein receptor-related protein 5 (LRP5) expression in human osteoarthritic chondrocytes". J. Orthop. Res. 28 (3): 348–53. doi:10.1002/jor.20993. PMID 19810105.
  32. ↑ Ahn J, Lee H, Kim S, Ha T (June 2010). "Curcumin-induced suppression of adipogenic differentiation is accompanied by activation of Wnt/beta-catenin signaling". Am. J. Physiol., Cell Physiol. 298 (6): C1510–6. doi:10.1152/ajpcell.00369.2009. PMID 20357182.
  33. ↑ Cnossen, W. R.; Te Morsche, R. H.; Hoischen, A; Gilissen, C; Chrispijn, M; Venselaar, H; Mehdi, S; Bergmann, C; Veltman, J. A.; Drenth, J. P. (2014). "Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis". Proceedings of the National Academy of Sciences 111 (14): 5343–8. doi:10.1073/pnas.1309438111. PMC 3986119. PMID 24706814.

Further reading

External links

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