LRP5

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External IDsGeneCards: [1]
Orthologs
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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 (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.[4] This protein plays a key role in skeletal homeostasis.[3]

Transcription

The LRP5 promoter contains binding sites for KLF15 and SP1.[5] In addition, 5' region 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.[13] 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.[22][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[7][8][9][10][11][12] 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.[13]

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.[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.[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]

References

  1. ↑ Hey PJ, Twells RC, Phillips MS, Brown SD, Kawaguchi Y, Cox R, Dugan V, Hammond H, Metzker ML, Todd JA, Hess JF (Aug 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 (Feb 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. ↑ 4.0 4.1 Williams BO, Insogna KL (Feb 2009). "Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone". Journal of Bone and Mineral Research. 24 (2): 171–8. doi:10.1359/jbmr.081235. PMC 3276354. PMID 19072724.
  5. ↑ 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 Genetics. 11: 12. doi:10.1186/1471-2156-11-12. PMC 2831824. PMID 20141633.
  6. ↑ 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". Journal of Bone and Mineral Research. 26 (5): 1133–44. doi:10.1002/jbmr.293. PMID 21542013.
  7. ↑ 7.0 7.1 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 (Nov 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.
  8. ↑ 8.0 8.1 Kode A, Mosialou I, Silva BC, Rached MT, Zhou B, Wang J, Townes TM, Hen R, DePinho RA, Guo XE, Kousteni S (Oct 2012). "FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin". The Journal of Clinical Investigation. 122 (10): 3490–503. doi:10.1172/JCI64906. PMC 3461930. PMID 22945629.
  9. ↑ 9.0 9.1 Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M (Mar 2010). "Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin". Journal of Bone and Mineral Research. 25 (3): 673–5. doi:10.1002/jbmr.44. PMID 20200960.
  10. ↑ 10.0 10.1 Rosen CJ (Feb 2009). "Breaking into bone biology: serotonin's secrets". Nature Medicine. 15 (2): 145–6. doi:10.1038/nm0209-145. PMID 19197289.
  11. ↑ 11.0 11.1 Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton LJ, Khosla S (Feb 2010). "Relation of serum serotonin levels to bone density and structural parameters in women". Journal of Bone and Mineral Research. 25 (2): 415–22. doi:10.1359/jbmr.090721. PMC 3153390. PMID 19594297.
  12. ↑ 12.0 12.1 Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, van Hul W, Eastell R, Kassem M, Brixen K (Aug 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". Journal of Bone and Mineral Research. 26 (8): 1721–8. doi:10.1002/jbmr.376. PMID 21351148.
  13. ↑ 13.0 13.1 13.2 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 (Jun 2011). "Lrp5 functions in bone to regulate bone mass". Nature Medicine. 17 (6): 684–91. doi:10.1038/nm.2388. PMC 3113461. PMID 21602802.
  14. ↑ 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.
  15. ↑ Kim MJ, Chia IV, Costantini F (Nov 2008). "SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability". FASEB Journal. 22 (11): 3785–94. doi:10.1096/fj.08-113910. PMC 2574027. PMID 18632848.
  16. ↑ Katoh M, Katoh M (Sep 2006). "Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades". Cancer Biology & Therapy. 5 (9): 1059–64. doi:10.4161/cbt.5.9.3151. PMID 16940750.
  17. ↑ Hong JY, Park JI, Cho K, Gu D, Ji H, Artandi SE, McCrea PD (Dec 2010). "Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members". Journal of Cell Science. 123 (Pt 24): 4351–65. doi:10.1242/jcs.067199. PMC 2995616. PMID 21098636.
  18. ↑ Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, et al. (Nov 2001). "LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development". Cell. 107 (4): 513–23. doi:10.1016/S0092-8674(01)00571-2. PMID 11719191.
  19. ↑ Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML (Jan 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): 11–9. doi:10.1086/338450. PMC 419982. PMID 11741193.
  20. ↑ 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): 1513–21. doi:10.1056/NEJMoa013444. PMID 12015390.
  21. ↑ Zhang W, Drake MT (Mar 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.
  22. ↑ 22.0 22.1 Baron R, Kneissel M (Feb 2013). "WNT signaling in bone homeostasis and disease: from human mutations to treatments". Nature Medicine. 19 (2): 179–92. doi:10.1038/nm.3074. PMID 23389618.
  23. ↑ Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML, Reddy PS, Bodine PV, Robinson JA, Bhat B, Marzolf J, Moran RA, Bex F (Jun 2003). "High bone mass in mice expressing a mutant LRP5 gene". Journal of Bone and Mineral Research. 18 (6): 960–74. doi:10.1359/jbmr.2003.18.6.960. PMID 12817748.
  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 (Aug 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): 23698–711. 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. ↑ Burgers TA, Williams BO (Jun 2013). "Regulation of Wnt/β-catenin signaling within and from osteocytes". Bone. 54 (2): 244–9. doi:10.1016/j.bone.2013.02.022. PMC 3652284. PMID 23470835.
  27. ↑ Xia CH, Liu H, Cheung D, Wang M, Cheng C, Du X, Chang B, Beutler B, Gong X (Jun 2008). "A model for familial exudative vitreoretinopathy caused by LPR5 mutations". Human Molecular Genetics. 17 (11): 1605–12. doi:10.1093/hmg/ddn047. PMC 2902293. PMID 18263894.
  28. ↑ Ye X, Wang Y, Nathans J (Sep 2010). "The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease". Trends in Molecular Medicine. 16 (9): 417–25. doi:10.1016/j.molmed.2010.07.003. PMC 2963063. PMID 20688566.
  29. ↑ 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 (Jan 2003). "Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion". Proceedings of the National Academy of Sciences of the United States of America. 100 (1): 229–34. doi:10.1073/pnas.0133792100. PMC 140935. PMID 12509515.
  30. ↑ Papathanasiou I, Malizos KN, Tsezou A (Mar 2010). "Low-density lipoprotein receptor-related protein 5 (LRP5) expression in human osteoarthritic chondrocytes". Journal of Orthopaedic Research. 28 (3): 348–53. doi:10.1002/jor.20993. PMID 19810105.
  31. ↑ Ahn J, Lee H, Kim S, Ha T (Jun 2010). "Curcumin-induced suppression of adipogenic differentiation is accompanied by activation of Wnt/beta-catenin signaling". American Journal of Physiology. Cell Physiology. 298 (6): C1510–6. doi:10.1152/ajpcell.00369.2009. PMID 20357182.
  32. ↑ Cnossen WR, te Morsche RH, Hoischen A, Gilissen C, Chrispijn M, Venselaar H, Mehdi S, Bergmann C, Veltman JA, Drenth JP (Apr 2014). "Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis". Proceedings of the National Academy of Sciences of the United States of America. 111 (14): 5343–8. doi:10.1073/pnas.1309438111. PMC 3986119. PMID 24706814.

Further reading

External links

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