LRP5

LRP5

Low density lipoprotein receptor-related protein 5
Identifiers
Symbols  ; BMND1; EVR1; EVR4; HBM; LR3; LRP-5; LRP7; OPPG; OPS; OPTA1; VBCH2
External IDs GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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

Contents

  • Function 1
  • Transcription 2
  • Interactions 3
  • Clinical Significance 4
  • References 5
  • Further reading 6
  • External links 7

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.  
  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.  
  3. ^ a b c "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.  
  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.  
  6. ^ a b 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.  
  7. ^ a b 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.  
  8. ^ a b 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.  
  9. ^ a b Rosen CJ (2009). "Breaking into bone biology: serotonin's secrets". Nat Med. 15 (2): 145–6.  
  10. ^ a b 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.  
  11. ^ a b 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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  17. ^ Gong Y et al. (November 2001). "LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development". Cell 107 (4): 513–523.  
  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.  
  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.  
  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.  
  21. ^ a b 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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  27. ^ Burgers TA, Williams BO (June 2013). "Regulation of Wnt/beta-catenin signaling within and from osteocytes". Bone 54 (2): 244–249.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  

Further reading

  • He X, Semenov M, Tamai K, Zeng X (2004). "LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way.". Development 131 (8): 1663–77.  
  • Godyna S, Liau G, Popa I, et al. (1995). "Identification of the low density lipoprotein receptor-related protein (LRP) as an endocytic receptor for thrombospondin-1.". J. Cell Biol. 129 (5): 1403–10.  
  • Gong Y, Vikkula M, Boon L, et al. (1996). "Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13.". Am. J. Hum. Genet. 59 (1): 146–51.  
  • Johnson ML, Gong G, Kimberling W, et al. (1997). "Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13)". Am. J. Hum. Genet. 60 (6): 1326–32.  
  • Dong Y, Lathrop W, Weaver D, et al. (1998). "Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity.". Biochem. Biophys. Res. Commun. 251 (3): 784–90.  
  • de Crecchio G, Simonelli F, Nunziata G, et al. (1999). "Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity.". Clin. Genet. 54 (4): 315–20.  
  • Mao J, Wang J, Liu B, et al. (2001). "Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway.". Mol. Cell 7 (4): 801–9.  
  • Twells RC, Metzker ML, Brown SD, et al. (2001). "The sequence and gene characterization of a 400-kb candidate region for IDDM4 on chromosome 11q13.". Genomics 72 (3): 231–42.  
  • Semënov MV, Tamai K, Brott BK, et al. (2001). "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6.". Curr. Biol. 11 (12): 951–61.  
  • Zorn AM (2001). "Wnt signalling: antagonistic Dickkopfs.". Curr. Biol. 11 (15): R592–5.  
  • Gong Y, Slee RB, Fukai N, et al. (2002). "LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.". Cell 107 (4): 513–23.  
  • Little RD, Carulli JP, Del Mastro RG, et al. (2002). "A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.". Am. J. Hum. Genet. 70 (1): 11–9.  
  • Okubo M, Horinishi A, Kim DH, et al. (2002). "Seven novel sequence variants in the human low density lipoprotein receptor related protein 5 (LRP5) gene.". Hum. Mutat. 19 (2): 186.  
  • Boyden LM, Mao J, Belsky J, et al. (2002). "High bone density due to a mutation in LDL-receptor-related protein 5.". N. Engl. J. Med. 346 (20): 1513–21.  
  • Van Hul E, Gram J, Bollerslev J, et al. (2002). "Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13.". J. Bone Miner. Res. 17 (6): 1111–7.  
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903.  
  • Fujino T, Asaba H, Kang MJ, et al. (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.  
  • Van Wesenbeeck L, Cleiren E, Gram J, et al. (2003). "Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density.". Am. J. Hum. Genet. 72 (3): 763–71.  

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.