LRP5: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Robot: Automated text replacement (-{{WikiDoc Cardiology Network Infobox}} +, -<references /> +{{reflist|2}}, -{{reflist}} +{{reflist|2}}))
 
imported>David Eppstein
 
(One intermediate revision by one other user not shown)
Line 1: Line 1:
<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''Low-density lipoprotein receptor-related protein 5''' is a [[protein]] that in humans is encoded by the ''LRP5'' [[gene]].<ref name="pmid9714764">{{cite journal | vauthors = Hey PJ, Twells RC, Phillips MS, Brown SD, Kawaguchi Y, Cox R, Dugan V, Hammond H, Metzker ML, Todd JA, Hess JF | title = Cloning of a novel member of the low-density lipoprotein receptor family | journal = Gene | volume = 216 | issue = 1 | pages = 103–11 | date = Aug 1998 | pmid = 9714764 | pmc =  | doi = 10.1016/S0378-1119(98)00311-4 }}</ref><ref name="pmid10049586">{{cite journal | vauthors = Chen D, Lathrop W, Dong Y | title = Molecular cloning of mouse Lrp7(Lr3) cDNA and chromosomal mapping of orthologous genes in mouse and human | journal = Genomics | volume = 55 | issue = 3 | pages = 314–21 | date = Feb 1999 | pmid = 10049586 | pmc = | doi = 10.1006/geno.1998.5688 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: LRP5 low density lipoprotein receptor-related protein 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4041| accessdate = }}</ref> LRP5 is a key component of the LRP5/[[LRP6]]/[[Frizzled]] co-receptor group that is involved in [[Wnt signaling pathway#The canonical Wnt pathway|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.
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
==Structure==
{{GNF_Protein_box
LRP5 is a transmembrane low-density [[lipoprotein]] [[receptor (biochemistry)|receptor]] that shares a similar structure with [[LRP6]]. In each protein, about 85% of its 1600-[[amino acid|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.<ref name="Williams">{{cite journal | vauthors = Williams BO, Insogna KL | title = Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone | journal = Journal of Bone and Mineral Research | volume = 24 | issue = 2 | pages = 171–8 | date = Feb 2009 | pmid = 19072724 | pmc = 3276354 | doi = 10.1359/jbmr.081235 }}</ref>
| image =
| image_source =
| PDB =  
| Name = Low density lipoprotein receptor-related protein 5
| HGNCid = 6697
| Symbol = LRP5
| AltSymbols =; HBM; BMND1; EVR1; EVR4; LR3; LRP7; OPPG; OPS; OPTA1; VBCH2
| OMIM = 603506
| ECnumber = 
| Homologene = 1746
| MGIid = 1278315
| GeneAtlas_image1 = PBB_GE_LRP5_209468_at_tn.png
| Function = {{GNF_GO|id=GO:0004872 |text = receptor activity}}
| Component = {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006629 |text = lipid metabolic process}} {{GNF_GO|id=GO:0006897 |text = endocytosis}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0008284 |text = positive regulation of cell proliferation}} {{GNF_GO|id=GO:0016055 |text = Wnt receptor signaling pathway}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4041
    | Hs_Ensembl = ENSG00000162337
    | Hs_RefseqProtein = NP_002326
    | Hs_RefseqmRNA = NM_002335
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 11
    | Hs_GenLoc_start = 67836674
    | Hs_GenLoc_end = 67973301
    | Hs_Uniprot = O75197
    | Mm_EntrezGene = 16973
    | Mm_Ensembl = ENSMUSG00000024913
    | Mm_RefseqmRNA = NM_008513
    | Mm_RefseqProtein = NP_032539
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 19
    | Mm_GenLoc_start = 3584836
    | Mm_GenLoc_end = 3686546
    | Mm_Uniprot = Q3UI55
  }}
}}
'''Low density lipoprotein receptor-related protein 5''', also known as '''LRP5''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: LRP5 low density lipoprotein receptor-related protein 5| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4041| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
LRP5 acts as a co-receptor with LRP6 and the [[Frizzled]] protein family members for transducing signals by [[Wnt signaling pathway|Wnt]] proteins through the [[Wnt signaling pathway#The canonical Wnt pathway|canonical Wnt pathway]].<ref name="Williams"/> This protein plays a key role in skeletal homeostasis.<ref name="entrez"/>
| section_title =
| summary_text =
}}


==References==
== Transcription ==
 
The LRP5 [[promoter (biology)|promoter]] contains binding sites for [[KLF15]] and [[Sp1 transcription factor|SP1]].<ref name="pmid20141633">{{cite journal | vauthors = Li J, Yang Y, Jiang B, Zhang X, Zou Y, Gong Y | title = Sp1 and KLF15 regulate basal transcription of the human LRP5 gene | journal = BMC Genetics | volume = 11 | issue =  | pages = 12 | year = 2010 | pmid = 20141633 | pmc = 2831824 | doi = 10.1186/1471-2156-11-12 }}</ref> In addition, 5' region region of the LRP5 gene contains four [[RUNX2]] binding sites.<ref name="pmid21542013">{{cite journal | vauthors = 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 | title = Functional relevance of the BMD-associated polymorphism rs312009: novel involvement of RUNX2 in LRP5 transcriptional regulation | journal = Journal of Bone and Mineral Research | volume = 26 | issue = 5 | pages = 1133–44 | date = May 2011 | pmid = 21542013 | doi = 10.1002/jbmr.293 }}</ref> 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]]<ref name="pmid19041748">{{cite journal | vauthors = 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 | title = Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum | journal = Cell | volume = 135 | issue = 5 | pages = 825–37 | date = Nov 2008 | pmid = 19041748 | pmc = 2614332 | doi = 10.1016/j.cell.2008.09.059 }}</ref><ref name="pmid22945629">{{cite journal | vauthors = Kode A, Mosialou I, Silva BC, Rached MT, Zhou B, Wang J, Townes TM, Hen R, DePinho RA, Guo XE, Kousteni S | title = FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin | journal = The Journal of Clinical Investigation | volume = 122 | issue = 10 | pages = 3490–503 | date = Oct 2012 | pmid = 22945629 | pmc = 3461930 | doi = 10.1172/JCI64906 }}</ref><ref name="pmid20200960">{{cite journal | vauthors = Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M | title = Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 3 | pages = 673–5 | date = Mar 2010 | pmid = 20200960 | doi = 10.1002/jbmr.44 }}</ref><ref name="pmid19197289">{{cite journal | vauthors = Rosen CJ | title = Breaking into bone biology: serotonin's secrets | journal = Nature Medicine | volume = 15 | issue = 2 | pages = 145–6 | date = Feb 2009 | pmid = 19197289 | doi = 10.1038/nm0209-145 }}</ref><ref name="pmid19594297">{{cite journal | vauthors = Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton LJ, Khosla S | title = Relation of serum serotonin levels to bone density and structural parameters in women | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 2 | pages = 415–22 | date = Feb 2010 | pmid = 19594297 | pmc = 3153390 | doi = 10.1359/jbmr.090721 }}</ref><ref name="pmid21351148">{{cite journal | vauthors = Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, van Hul W, Eastell R, Kassem M, Brixen K | title = 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 = Journal of Bone and Mineral Research | volume = 26 | issue = 8 | pages = 1721–8 | date = Aug 2011 | pmid = 21351148 | doi = 10.1002/jbmr.376 }}</ref> 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.<ref name="pmid21602802">{{cite journal | vauthors = 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 | title = Lrp5 functions in bone to regulate bone mass | journal = Nature Medicine | volume = 17 | issue = 6 | pages = 684–91 | date = Jun 2011 | pmid = 21602802 | pmc = 3113461 | doi = 10.1038/nm.2388 }}</ref>
 
== Interactions ==
 
LRP5 has been shown to [[Protein-protein interaction|interact]] with [[AXIN1]].<ref name="pmid11336703">{{cite journal | vauthors = Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D | title = Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway | journal = Molecular Cell | volume = 7 | issue = 4 | pages = 801–9 | date = Apr 2001 | pmid = 11336703 | doi = 10.1016/S1097-2765(01)00224-6 }}</ref><ref name="pmid18632848">{{cite journal | vauthors = Kim MJ, Chia IV, Costantini F | title = SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability | journal = FASEB Journal | volume = 22 | issue = 11 | pages = 3785–94 | date = Nov 2008 | pmid = 18632848 | pmc = 2574027 | doi = 10.1096/fj.08-113910 }}</ref>
 
Canonical [[Wnt signaling pathway|WNT signals]] are transduced through [[Frizzled]] receptor and LRP5/[[LRP6]] coreceptor to downregulate GSK3beta ([[GSK3B]]) activity not depending on Ser-9 [[phosphorylation]].<ref name="pmid16940750">{{cite journal | vauthors = Katoh M, Katoh M | title = Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades | journal = Cancer Biology & Therapy | volume = 5 | issue = 9 | pages = 1059–64 | date = Sep 2006 | pmid = 16940750 | doi = 10.4161/cbt.5.9.3151 }}</ref> Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-[[catenin]] degradation.<ref name="pmid21098636">{{cite journal | vauthors = Hong JY, Park JI, Cho K, Gu D, Ji H, Artandi SE, McCrea PD | title = Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members | journal = Journal of Cell Science | volume = 123 | issue = Pt 24 | pages = 4351–65 | date = Dec 2010 | pmid = 21098636 | pmc = 2995616 | doi = 10.1242/jcs.067199 }}</ref>
 
==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.<ref>{{cite journal | vauthors = Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Jüppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML | display-authors = 6 | title = LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development | journal = Cell | volume = 107 | issue = 4 | pages = 513–23 | date = Nov 2001 | pmid = 11719191 | doi = 10.1016/S0092-8674(01)00571-2 }}</ref> Shortly thereafter, two studies reported that [[gain-of-function]] mutations in LRP5 caused high bone mass.<ref>{{cite journal | vauthors = Little RD, Carulli JP, Del Mastro RG, [[Josée Dupuis|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 | title = A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait | journal = American Journal of Human Genetics | volume = 70 | issue = 1 | pages = 11–9 | date = Jan 2002 | pmid = 11741193 | pmc = 419982 | doi = 10.1086/338450 }}</ref><ref>{{cite journal | vauthors = Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP | title = High bone density due to a mutation in LDL-receptor-related protein 5 | journal = The New England Journal of Medicine | volume = 346 | issue = 20 | pages = 1513–21 | date = May 2002 | pmid = 12015390 | doi = 10.1056/NEJMoa013444 }}</ref> 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.<ref name="Zhang">{{cite journal | vauthors = Zhang W, Drake MT | title = Potential role for therapies targeting DKK1, LRP5, and serotonin in the treatment of osteoporosis | journal = Current Osteoporosis Reports | volume = 10 | issue = 1 | pages = 93–100 | date = Mar 2012 | pmid = 22210558 | doi = 10.1007/s11914-011-0086-8 }}</ref> The majority of the current data supports the concept that bone mass is controlled by LRP5 through the osteocytes.<ref name="Baron">{{cite journal | vauthors = Baron R, Kneissel M | title = WNT signaling in bone homeostasis and disease: from human mutations to treatments | journal = Nature Medicine | volume = 19 | issue = 2 | pages = 179–92 | date = Feb 2013 | pmid = 23389618 | doi = 10.1038/nm.3074 }}</ref> Mice with the same Lrp5 gain-of-function mutations as also have high bone mass.<ref name="Babij">{{cite journal | vauthors = 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 | title = High bone mass in mice expressing a mutant LRP5 gene | journal = Journal of Bone and Mineral Research | volume = 18 | issue = 6 | pages = 960–74 | date = Jun 2003 | pmid = 12817748 | doi = 10.1359/jbmr.2003.18.6.960 }}</ref> The high bone mass is maintained when the mutation only occurs in limbs or in cells of the osteoblastic lineage.<ref name="pmid21602802"/> Bone [[mechanotransduction]] occurs through Lrp5<ref>{{cite journal | vauthors = Sawakami K, Robling AG, Ai M, Pitner ND, Liu D, Warden SJ, Li J, Maye P, Rowe DW, Duncan RL, Warman ML, Turner CH | title = The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment | journal = The Journal of Biological Chemistry | volume = 281 | issue = 33 | pages = 23698–711 | date = Aug 2006 | pmid = 16790443 | doi = 10.1074/jbc.M601000200 }}</ref> and is suppressed if Lrp5 is removed in only [[osteocytes]].<ref>{{cite journal | vauthors = Zhao L, Shim JW, Dodge TR, Robling AG, Yokota H | title = Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading | journal = Bone | volume = 54 | issue = 1 | pages = 35–43 | date = May 2013 | pmid = 23356985 | pmc = 3602226 | doi = 10.1016/j.bone.2013.01.033 }}</ref> There are promising osteoporosis clinical trials targeting [[sclerostin]], an osteocyte-specific protein which inhibits Wnt signaling by binding to Lrp5.<ref name="Baron"/><ref>{{cite journal | vauthors = Burgers TA, Williams BO | title = Regulation of Wnt/β-catenin signaling within and from osteocytes | journal = Bone | volume = 54 | issue = 2 | pages = 244–9 | date = Jun 2013 | pmid = 23470835 | doi = 10.1016/j.bone.2013.02.022 | pmc=3652284}}</ref> 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]]<ref name="pmid19041748"/><ref name="pmid22945629"/><ref name="pmid20200960"/><ref name="pmid19197289"/><ref name="pmid19594297"/><ref name="pmid21351148"/> 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.<ref name="pmid21602802"/>
 
LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation.<ref name="pmid18263894">{{cite journal | vauthors = Xia CH, Liu H, Cheung D, Wang M, Cheng C, Du X, Chang B, Beutler B, Gong X | title = A model for familial exudative vitreoretinopathy caused by LPR5 mutations | journal = Human Molecular Genetics | volume = 17 | issue = 11 | pages = 1605–12 | date = Jun 2008 | pmid = 18263894 | pmc = 2902293 | doi = 10.1093/hmg/ddn047 }}</ref> Mutations in this gene also cause [[familial exudative vitreoretinopathy]].<ref name="entrez"/>
 
A glial-derived extracellular ligand, Norrin, acts on a transmembrane receptor, [[FZD4|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.<ref name="pmid20688566">{{cite journal | vauthors = Ye X, Wang Y, Nathans J | title = The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease | journal = Trends in Molecular Medicine | volume = 16 | issue = 9 | pages = 417–25 | date = Sep 2010 | pmid = 20688566 | pmc = 2963063 | doi = 10.1016/j.molmed.2010.07.003 }}</ref>
 
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 [[adenosine triphosphate|ATP]] and [[calcium in biology|Ca<sup>2+</sup>]] in response to glucose, and impairment in glucose-induced insulin secretion. [[Inositol trisphosphate|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 [[WNT3A|Wnt-3a]]-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.<ref name="pmid12509515">{{cite journal | vauthors = 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 | title = Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 1 | pages = 229–34 | date = Jan 2003 | pmid = 12509515 | pmc = 140935 | doi = 10.1073/pnas.0133792100 }}</ref>
 
In [[osteoarthritis|osteoarthritic]] [[chondrocyte]]s 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 [[small interfering RNA|siRNA]] against LRP5 resulted in a significant decrease in [[Matrix metallopeptidase 13|MMP13]] mRNA and protein expressions. The [[catabolism|catabolic]] role of LRP5 appears to be mediated by the Wnt/beta-catenin pathway in human osteoarthritis.<ref name="pmid19810105">{{cite journal | vauthors = Papathanasiou I, Malizos KN, Tsezou A | title = Low-density lipoprotein receptor-related protein 5 (LRP5) expression in human osteoarthritic chondrocytes | journal = Journal of Orthopaedic Research | volume = 28 | issue = 3 | pages = 348–53 | date = Mar 2010 | pmid = 19810105 | doi = 10.1002/jor.20993 }}</ref>
 
The polyphenol curcumin increases the mRNA expression of LRP5.<ref name="pmid20357182">{{cite journal | vauthors = Ahn J, Lee H, Kim S, Ha T | title = Curcumin-induced suppression of adipogenic differentiation is accompanied by activation of Wnt/beta-catenin signaling | journal = American Journal of Physiology. Cell Physiology | volume = 298 | issue = 6 | pages = C1510-6 | date = Jun 2010 | pmid = 20357182 | doi = 10.1152/ajpcell.00369.2009 }}</ref>
{{Clear}}
 
Mutations in LRP5 cause {{SWL|type=mutation_results_in|target=polycystic liver disease|label=polycystic liver disease}}.<ref>{{cite journal | vauthors = Cnossen WR, te Morsche RH, Hoischen A, Gilissen C, Chrispijn M, Venselaar H, Mehdi S, Bergmann C, Veltman JA, Drenth JP | title = Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 14 | pages = 5343–8 | date = Apr 2014 | pmid = 24706814 | pmc = 3986119 | doi = 10.1073/pnas.1309438111 }}</ref>
 
== References ==
{{reflist|2}}
{{reflist|2}}
==Further reading==
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = He X, Semenov M, Tamai K, Zeng X | title = LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way | journal = Development | volume = 131 | issue = 8 | pages = 1663–77 | date = Apr 2004 | pmid = 15084453 | doi = 10.1242/dev.01117 }}
| citations =
* {{cite journal | vauthors = Godyna S, Liau G, Popa I, Stefansson S, Argraves WS | title = Identification of the low density lipoprotein receptor-related protein (LRP) as an endocytic receptor for thrombospondin-1 | journal = The Journal of Cell Biology | volume = 129 | issue = 5 | pages = 1403–10 | date = Jun 1995 | pmid = 7775583 | pmc = 2120467 | doi = 10.1083/jcb.129.5.1403 }}
*{{cite journal | author=He X, Semenov M, Tamai K, Zeng X |title=LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. |journal=Development |volume=131 |issue= 8 |pages= 1663-77 |year= 2004 |pmid= 15084453 |doi= 10.1242/dev.01117 }}
* {{cite journal | vauthors = 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 | title = Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13 | journal = American Journal of Human Genetics | volume = 59 | issue = 1 | pages = 146–51 | date = Jul 1996 | pmid = 8659519 | pmc = 1915094 | doi =  }}
*{{cite journal | author=Godyna S, Liau G, Popa I, ''et al.'' |title=Identification of the low density lipoprotein receptor-related protein (LRP) as an endocytic receptor for thrombospondin-1. |journal=J. Cell Biol. |volume=129 |issue= 5 |pages= 1403-10 |year= 1995 |pmid= 7775583 |doi= }}
* {{cite journal | vauthors = Johnson ML, Gong G, Kimberling W, Reckér SM, Kimmel DB, Recker RB | title = Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13) | journal = American Journal of Human Genetics | volume = 60 | issue = 6 | pages = 1326–32 | date = Jun 1997 | pmid = 9199553 | pmc = 1716125 | doi = 10.1086/515470 }}
*{{cite journal | author=Gong Y, Vikkula M, Boon L, ''et al.'' |title=Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. |journal=Am. J. Hum. Genet. |volume=59 |issue= 1 |pages= 146-51 |year= 1996 |pmid= 8659519 |doi=  }}
* {{cite journal | vauthors = Dong Y, Lathrop W, Weaver D, Qiu Q, Cini J, Bertolini D, Chen D | title = Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity | journal = Biochemical and Biophysical Research Communications | volume = 251 | issue = 3 | pages = 784–90 | date = Oct 1998 | pmid = 9790987 | doi = 10.1006/bbrc.1998.9545 }}
*{{cite journal | author=Johnson ML, Gong G, Kimberling W, ''et al.'' |title=Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13) |journal=Am. J. Hum. Genet. |volume=60 |issue= 6 |pages= 1326-32 |year= 1997 |pmid= 9199553 |doi= }}
* {{cite journal | vauthors = 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 | title = Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity | journal = Clinical Genetics | volume = 54 | issue = 4 | pages = 315–20 | date = Oct 1998 | pmid = 9831343 | doi = 10.1034/j.1399-0004.1998.5440409.x }}
*{{cite journal  | author=Hey PJ, Twells RC, Phillips MS, ''et al.'' |title=Cloning of a novel member of the low-density lipoprotein receptor family. |journal=Gene |volume=216 |issue= 1 |pages= 103-11 |year= 1998 |pmid= 9714764 |doi=  }}
* {{cite journal | vauthors = Mao J, Wang J, Liu B, Pan W, Farr GH, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D | title = Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway | journal = Molecular Cell | volume = 7 | issue = 4 | pages = 801–9 | date = Apr 2001 | pmid = 11336703 | doi = 10.1016/S1097-2765(01)00224-6 }}
*{{cite journal | author=Dong Y, Lathrop W, Weaver D, ''et al.'' |title=Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity. |journal=Biochem. Biophys. Res. Commun. |volume=251 |issue= 3 |pages= 784-90 |year= 1998 |pmid= 9790987 |doi= 10.1006/bbrc.1998.9545 }}
* {{cite journal | vauthors = Twells RC, Metzker ML, Brown SD, Cox R, Garey C, Hammond H, Hey PJ, Levy E, Nakagawa Y, Philips MS, Todd JA, Hess JF | title = The sequence and gene characterization of a 400-kb candidate region for IDDM4 on chromosome 11q13 | journal = Genomics | volume = 72 | issue = 3 | pages = 231–42 | date = Mar 2001 | pmid = 11401438 | doi = 10.1006/geno.2000.6492 }}
*{{cite journal | author=de Crecchio G, Simonelli F, Nunziata G, ''et al.'' |title=Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity. |journal=Clin. Genet. |volume=54 |issue= 4 |pages= 315-20 |year= 1999 |pmid= 9831343 |doi=  }}
* {{cite journal | vauthors = Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X | title = Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6 | journal = Current Biology | volume = 11 | issue = 12 | pages = 951–61 | date = Jun 2001 | pmid = 11448771 | doi = 10.1016/S0960-9822(01)00290-1 }}
*{{cite journal  | author=Chen D, Lathrop W, Dong Y |title=Molecular cloning of mouse Lrp7(Lr3) cDNA and chromosomal mapping of orthologous genes in mouse and human. |journal=Genomics |volume=55 |issue= 3 |pages= 314-21 |year= 1999 |pmid= 10049586 |doi= 10.1006/geno.1998.5688 }}
* {{cite journal | vauthors = Zorn AM | title = Wnt signalling: antagonistic Dickkopfs | journal = Current Biology | volume = 11 | issue = 15 | pages = R592-5 | date = Aug 2001 | pmid = 11516963 | doi = 10.1016/S0960-9822(01)00360-8 }}
*{{cite journal | author=Mao J, Wang J, Liu B, ''et al.'' |title=Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. |journal=Mol. Cell |volume=7 |issue= 4 |pages= 801-9 |year= 2001 |pmid= 11336703 |doi= }}
* {{cite journal | vauthors = Okubo M, Horinishi A, Kim DH, Yamamoto TT, Murase T | title = Seven novel sequence variants in the human low density lipoprotein receptor related protein 5 (LRP5) gene | journal = Human Mutation | volume = 19 | issue = 2 | pages = 186 | date = Feb 2002 | pmid = 11793484 | doi = 10.1002/humu.9012 }}
*{{cite journal | author=Twells RC, Metzker ML, Brown SD, ''et al.'' |title=The sequence and gene characterization of a 400-kb candidate region for IDDM4 on chromosome 11q13. |journal=Genomics |volume=72 |issue= 3 |pages= 231-42 |year= 2001 |pmid= 11401438 |doi= 10.1006/geno.2000.6492 }}
* {{cite journal | vauthors = Van Hul E, Gram J, Bollerslev J, Van Wesenbeeck L, Mathysen D, Andersen PE, Vanhoenacker F, Van Hul W | title = Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13 | journal = Journal of Bone and Mineral Research | volume = 17 | issue = 6 | pages = 1111–7 | date = Jun 2002 | pmid = 12054167 | doi = 10.1359/jbmr.2002.17.6.1111 }}
*{{cite journal | author=Semënov MV, Tamai K, Brott BK, ''et al.'' |title=Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. |journal=Curr. Biol. |volume=11 |issue= 12 |pages= 951-61 |year= 2001 |pmid= 11448771 |doi= }}
* {{cite journal | vauthors = 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 | title = Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density | journal = American Journal of Human Genetics | volume = 72 | issue = 3 | pages = 763–71 | date = Mar 2003 | pmid = 12579474 | pmc = 1180253 | doi = 10.1086/368277 }}
*{{cite journal | author=Zorn AM |title=Wnt signalling: antagonistic Dickkopfs. |journal=Curr. Biol. |volume=11 |issue= 15 |pages= R592-5 |year= 2001 |pmid= 11516963 |doi= }}
*{{cite journal  | author=Gong Y, Slee RB, Fukai N, ''et al.'' |title=LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. |journal=Cell |volume=107 |issue= 4 |pages= 513-23 |year= 2002 |pmid= 11719191 |doi=  }}
*{{cite journal  | author=Little RD, Carulli JP, Del Mastro RG, ''et al.'' |title=A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. |journal=Am. J. Hum. Genet. |volume=70 |issue= 1 |pages= 11-9 |year= 2002 |pmid= 11741193 |doi=  }}
*{{cite journal | author=Okubo M, Horinishi A, Kim DH, ''et al.'' |title=Seven novel sequence variants in the human low density lipoprotein receptor related protein 5 (LRP5) gene. |journal=Hum. Mutat. |volume=19 |issue= 2 |pages= 186 |year= 2002 |pmid= 11793484 |doi= 10.1002/humu.9012 }}
*{{cite journal | author=Boyden LM, Mao J, Belsky J, ''et al.'' |title=High bone density due to a mutation in LDL-receptor-related protein 5. |journal=N. Engl. J. Med. |volume=346 |issue= 20 |pages= 1513-21 |year= 2002 |pmid= 12015390 |doi= 10.1056/NEJMoa013444 }}
*{{cite journal  | author=Van Hul E, Gram J, Bollerslev J, ''et al.'' |title=Localization of the gene causing autosomal dominant osteopetrosis type I to chromosome 11q12-13. |journal=J. Bone Miner. Res. |volume=17 |issue= 6 |pages= 1111-7 |year= 2002 |pmid= 12054167 |doi=  }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  | author=Fujino T, Asaba H, Kang MJ, ''et al.'' |title=Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue= 1 |pages= 229-34 |year= 2003 |pmid= 12509515 |doi= 10.1073/pnas.0133792100 }}
*{{cite journal | author=Van Wesenbeeck L, Cleiren E, Gram J, ''et al.'' |title=Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. |journal=Am. J. Hum. Genet. |volume=72 |issue= 3 |pages= 763-71 |year= 2003 |pmid= 12579474 |doi= }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
== External links ==
{{WikiDoc Sources}}
*[https://www.ncbi.nlm.nih.gov/books/NBK1147/  GeneReviews/NCBI/NIH/UW entry on Familial Exudative Vitreoretinopathy, Autosomal Dominant]
 
{{NLM content}}
{{Lipoprotein metabolism}}

Latest revision as of 01:32, 16 December 2018

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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

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

Retrieved from "https://www.wikidoc.org/index.php?title=LRP5&oldid=1527799"