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{{Infobox_gene}}
{{PBB_Controls
'''Low-density lipoprotein receptor-related protein 6''' is a [[protein]] that in humans is encoded by the ''LRP6'' [[gene]].<ref name="pmid9704021">{{cite journal |vauthors=Brown SD, Twells RC, Hey PJ, Cox RD, Levy ER, Soderman AR, Metzker ML, Caskey CT, Todd JA, Hess JF |title=Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family |journal=Biochem. Biophys. Res. Commun. |volume=248 |issue=3 |pages=879–88 |year=1998 |pmid=9704021 |doi=10.1006/bbrc.1998.9061}}</ref><ref name="entrez">{{cite web | title = Entrez Gene: LRP6 low density lipoprotein receptor-related protein 6| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4040}}</ref> LRP6 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]].
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| update_protein_box = yes
| update_summary = yes
| update_citations = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
==Structure==
{{GNF_Protein_box
LRP6 is a transmembrane low-density [[lipoprotein]] [[receptor (biochemistry)|receptor]] that shares a similar structure with [[LRP5]]. 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=J. Bone Miner. Res. |volume=24 |issue=2 |pages=171–8 |year=2009 |pmid=19072724 |pmc=3276354 |doi=10.1359/jbmr.081235 |url=}}</ref>
| image =
| image_source =
| PDB =  
| Name = Low density lipoprotein receptor-related protein 6
| HGNCid = 6698
| Symbol = LRP6
| AltSymbols =; FLJ90062; FLJ90421
| OMIM = 603507
| ECnumber = 
| Homologene = 1747
| MGIid = 1298218
| GeneAtlas_image1 = PBB_GE_LRP6_34697_at_tn.png
| GeneAtlas_image2 = PBB_GE_LRP6_205606_at_tn.png
| Function = {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0005041 |text = low-density lipoprotein receptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}}
| Component = {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006897 |text = endocytosis}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0009952 |text = anterior/posterior pattern formation}} {{GNF_GO|id=GO:0010003 |text = gastrulation (sensu Mammalia)}} {{GNF_GO|id=GO:0016055 |text = Wnt receptor signaling pathway}} {{GNF_GO|id=GO:0030178 |text = negative regulation of Wnt receptor signaling pathway}} {{GNF_GO|id=GO:0035115 |text = embryonic forelimb morphogenesis}} {{GNF_GO|id=GO:0035116 |text = embryonic hindlimb morphogenesis}} {{GNF_GO|id=GO:0042074 |text = cell migration involved in gastrulation}} {{GNF_GO|id=GO:0042733 |text = embryonic digit morphogenesis}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4040
    | Hs_Ensembl = ENSG00000070018
    | Hs_RefseqProtein = NP_002327
    | Hs_RefseqmRNA = NM_002336
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 12164958
    | Hs_GenLoc_end = 12311013
    | Hs_Uniprot = O75581
    | Mm_EntrezGene = 16974
    | Mm_Ensembl = ENSMUSG00000030201
    | Mm_RefseqmRNA = NM_008514
    | Mm_RefseqProtein = NP_032540
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 134416479
    | Mm_GenLoc_end = 134507739
    | Mm_Uniprot = Q3TS86
  }}
}}
'''Low density lipoprotein receptor-related protein 6''', also known as '''LRP6''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: LRP6 low density lipoprotein receptor-related protein 6| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4040| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
==Function==
{{PBB_Summary
LRP6 acts as a co-receptor with LRP5 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"/>
| section_title =  
 
| summary_text =  
==Interactions==
}}
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 Biol. Ther. |volume=5 |issue=9 |pages=1059–64 |year=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="Hong">{{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=J. Cell Sci. |volume=123 |issue=Pt 24 |pages=4351–65 |year=2010 |pmid=21098636 |pmc=2995616 |doi=10.1242/jcs.067199 |url=}}</ref>
 
LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like [[DKK1]]<ref name="Semenov">{{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=Curr. Biol. |volume=11 |issue=12 |pages=951–61 |year=2001 |pmid=11448771 |doi= 10.1016/s0960-9822(01)00290-1|url=}}</ref>), [[sclerostin]], R-spondins and members of the cysteine-knot-type protein family.<ref name="Williams"/>
 
==Clinical significance==
Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis.<ref name="Williams"/> Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass.<ref name="Kang"/> LRP6 is critical in bone's [[anabolic]] response to [[parathyroid hormone]] (PTH) treatment, whereas LRP5 is not involved.<ref name="Kang">{{cite journal |vauthors=Kang KS, Robling AG |title=New Insights into Wnt-Lrp5/6-β-Catenin Signaling in Mechanotransduction |journal=Front Endocrinol (Lausanne) |volume=5 |issue= |pages=246 |year=2014 |pmid=25653639 |pmc=4299511 |doi=10.3389/fendo.2014.00246 |url=}}</ref> On the other hand, LRP6 does not appear active in [[mechanotransduction]] (bone's response to forces), while LRP5 is critical in that role.<ref name="Kang"/>  
Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.<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 = 179–192 |date=February 2013 | doi = 10.1038/nm.3074 | pmid = 23389618}}</ref><ref>{{Cite journal | vauthors = Burgers TA, Williams BO | title = Regulation of Wnt/beta-catenin signaling within and from osteocytes | journal = Bone | volume = 54 | issue = 2 | pages = 244–249 |date=June 2013 | doi = 10.1016/j.bone.2013.02.022 | pmid = 23470835 | pmc=3652284}}</ref>


==References==
==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 |year= 2004 |pmid= 15084453 |doi= 10.1242/dev.01117 }}
| citations =
*{{cite journal   |vauthors=Hillier LD, Lennon G, Becker M, etal |title=Generation and analysis of 280,000 human expressed sequence tags. |journal=Genome Res. |volume=6 |issue= 9 |pages= 807–28 |year= 1997 |pmid= 8889549 |doi=10.1101/gr.6.9.807 }}
*{{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=Baens M, Wlodarska I, Corveleyn A, etal |title=A physical, transcript, and deletion map of chromosome region 12p12.3 flanked by ETV6 and CDKN1B: hypermethylation of the LRP6 CpG island in two leukemia patients with hemizygous del(12p). |journal=Genomics |volume=56 |issue= 1 |pages= 40–50 |year= 1999 |pmid= 10036184 |doi= 10.1006/geno.1998.5685 }}
*{{cite journal | author=Hillier LD, Lennon G, Becker M, ''et al.'' |title=Generation and analysis of 280,000 human expressed sequence tags. |journal=Genome Res. |volume=6 |issue= 9 |pages= 807-28 |year= 1997 |pmid= 8889549 |doi=  }}
*{{cite journal   |vauthors=Tamai K, Semenov M, Kato Y, etal |title=LDL-receptor-related proteins in Wnt signal transduction. |journal=Nature |volume=407 |issue= 6803 |pages= 530–5 |year= 2000 |pmid= 11029007 |doi= 10.1038/35035117 }}
*{{cite journal | author=Brown SD, Twells RC, Hey PJ, ''et al.'' |title=Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family. |journal=Biochem. Biophys. Res. Commun. |volume=248 |issue= 3 |pages= 879-88 |year= 1998 |pmid= 9704021 |doi= 10.1006/bbrc.1998.9061 }}
*{{cite journal  |vauthors=Mao B, Wu W, Li Y, etal |title=LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. |journal=Nature |volume=411 |issue= 6835 |pages= 321–5 |year= 2001 |pmid= 11357136 |doi= 10.1038/35077108 }}
*{{cite journal | author=Baens M, Wlodarska I, Corveleyn A, ''et al.'' |title=A physical, transcript, and deletion map of chromosome region 12p12.3 flanked by ETV6 and CDKN1B: hypermethylation of the LRP6 CpG island in two leukemia patients with hemizygous del(12p). |journal=Genomics |volume=56 |issue= 1 |pages= 40-50 |year= 1999 |pmid= 10036184 |doi= 10.1006/geno.1998.5685 }}
*{{cite journal   |vauthors=Semënov MV, Tamai K, Brott BK, etal |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=10.1016/S0960-9822(01)00290-1  }}
*{{cite journal | author=Tamai K, Semenov M, Kato Y, ''et al.'' |title=LDL-receptor-related proteins in Wnt signal transduction. |journal=Nature |volume=407 |issue= 6803 |pages= 530-5 |year= 2000 |pmid= 11029007 |doi= 10.1038/35035117 }}
*{{cite journal   |vauthors=Li L, Mao J, Sun L, etal |title=Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. |journal=J. Biol. Chem. |volume=277 |issue= 8 |pages= 5977–81 |year= 2002 |pmid= 11742004 |doi= 10.1074/jbc.M111131200 }}
*{{cite journal | author=Mao B, Wu W, Li Y, ''et al.'' |title=LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. |journal=Nature |volume=411 |issue= 6835 |pages= 321-5 |year= 2001 |pmid= 11357136 |doi= 10.1038/35077108 }}
*{{cite journal   |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |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 | pmc=139241 }}
*{{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=Caricasole A, Ferraro T, Iacovelli L, etal |title=Functional characterization of WNT7A signaling in PC12 cells: interaction with A FZD5 x LRP6 receptor complex and modulation by Dickkopf proteins. |journal=J. Biol. Chem. |volume=278 |issue= 39 |pages= 37024–31 |year= 2003 |pmid= 12857724 |doi= 10.1074/jbc.M300191200 }}
*{{cite journal | author=Li L, Mao J, Sun L, ''et al.'' |title=Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. |journal=J. Biol. Chem. |volume=277 |issue= 8 |pages= 5977-81 |year= 2002 |pmid= 11742004 |doi= 10.1074/jbc.M111131200 }}
*{{cite journal  | vauthors =Liu G, Bafico A, Harris VK, Aaronson SA |title=A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor. |journal=Mol. Cell. Biol. |volume=23 |issue= 16 |pages= 5825–35 |year= 2003 |pmid= 12897152 |doi=10.1128/MCB.23.16.5825-5835.2003  | pmc=166321  }}
*{{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  | vauthors =Zilberberg A, Yaniv A, Gazit A |title=The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway. |journal=J. Biol. Chem. |volume=279 |issue= 17 |pages= 17535–42 |year= 2004 |pmid= 14739301 |doi= 10.1074/jbc.M311292200 }}
*{{cite journal  | author=Caricasole A, Ferraro T, Iacovelli L, ''et al.'' |title=Functional characterization of WNT7A signaling in PC12 cells: interaction with A FZD5 x LRP6 receptor complex and modulation by Dickkopf proteins. |journal=J. Biol. Chem. |volume=278 |issue= 39 |pages= 37024-31 |year= 2003 |pmid= 12857724 |doi= 10.1074/jbc.M300191200 }}
*{{cite journal  | vauthors =Wang X, Adhikari N, Li Q, Hall JL |title=LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells. |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=287 |issue= 6 |pages= H2376–83 |year= 2005 |pmid= 15271658 |doi= 10.1152/ajpheart.01173.2003 }}
*{{cite journal  | author=Liu G, Bafico A, Harris VK, Aaronson SA |title=A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor. |journal=Mol. Cell. Biol. |volume=23 |issue= 16 |pages= 5825-35 |year= 2003 |pmid= 12897152 |doi= }}
*{{cite journal   |vauthors=Suzuki Y, Yamashita R, Shirota M, etal |title=Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. |journal=Genome Res. |volume=14 |issue= 9 |pages= 1711–8 |year= 2004 |pmid= 15342556 |doi= 10.1101/gr.2435604  | pmc=515316 }}
*{{cite journal | author=Zilberberg A, Yaniv A, Gazit A |title=The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway. |journal=J. Biol. Chem. |volume=279 |issue= 17 |pages= 17535-42 |year= 2004 |pmid= 14739301 |doi= 10.1074/jbc.M311292200 }}
*{{cite journal   |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 | pmc=528928 }}
*{{cite journal | author=Wang X, Adhikari N, Li Q, Hall JL |title=LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells. |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=287 |issue= 6 |pages= H2376-83 |year= 2005 |pmid= 15271658 |doi= 10.1152/ajpheart.01173.2003 }}
*{{cite journal   |vauthors=Li Y, Lu W, He X, etal |title=LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution. |journal=Oncogene |volume=23 |issue= 56 |pages= 9129–35 |year= 2005 |pmid= 15516984 |doi= 10.1038/sj.onc.1208123 }}
*{{cite journal | author=Suzuki Y, Yamashita R, Shirota M, ''et al.'' |title=Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. |journal=Genome Res. |volume=14 |issue= 9 |pages= 1711-8 |year= 2004 |pmid= 15342556 |doi= 10.1101/gr.2435604 }}
*{{cite journal  | vauthors =Semënov M, Tamai K, He X |title=SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. |journal=J. Biol. Chem. |volume=280 |issue= 29 |pages= 26770–5 |year= 2005 |pmid= 15908424 |doi= 10.1074/jbc.M504308200 }}
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal   |vauthors=Li Y, Chen J, Lu W, etal |title=Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding. |journal=J. Cell Sci. |volume=118 |issue= Pt 22 |pages= 5305–14 |year= 2006 |pmid= 16263759 |doi= 10.1242/jcs.02651 }}
*{{cite journal | author=Li Y, Lu W, He X, ''et al.'' |title=LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution. |journal=Oncogene |volume=23 |issue= 56 |pages= 9129-35 |year= 2005 |pmid= 15516984 |doi= 10.1038/sj.onc.1208123 }}
*{{cite journal  | vauthors =Mi K, Dolan PJ, Johnson GV |title=The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity. |journal=J. Biol. Chem. |volume=281 |issue= 8 |pages= 4787–94 |year= 2006 |pmid= 16365045 |doi= 10.1074/jbc.M508657200 }}
*{{cite journal  | author=Semënov M, Tamai K, He X |title=SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. |journal=J. Biol. Chem. |volume=280 |issue= 29 |pages= 26770-5 |year= 2005 |pmid= 15908424 |doi= 10.1074/jbc.M504308200 }}
*{{cite journal | author=Li Y, Chen J, Lu W, ''et al.'' |title=Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding. |journal=J. Cell. Sci. |volume=118 |issue= Pt 22 |pages= 5305-14 |year= 2006 |pmid= 16263759 |doi= 10.1242/jcs.02651 }}
*{{cite journal  | author=Mi K, Dolan PJ, Johnson GV |title=The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity. |journal=J. Biol. Chem. |volume=281 |issue= 8 |pages= 4787-94 |year= 2006 |pmid= 16365045 |doi= 10.1074/jbc.M508657200 }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
{{Lipoprotein metabolism}}
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{{gene-12-stub}}

Latest revision as of 20:13, 8 November 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene.[1][2] LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

Structure

LRP6 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP5. 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.[3]

Function

LRP6 acts as a co-receptor with LRP5 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway.[3]

Interactions

Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.[4] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.[5]

LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1[6]), sclerostin, R-spondins and members of the cysteine-knot-type protein family.[3]

Clinical significance

Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis.[3] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass.[7] LRP6 is critical in bone's anabolic response to parathyroid hormone (PTH) treatment, whereas LRP5 is not involved.[7] On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role.[7] Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.[8][9]

References

  1. ↑ Brown SD, Twells RC, Hey PJ, Cox RD, Levy ER, Soderman AR, Metzker ML, Caskey CT, Todd JA, Hess JF (1998). "Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family". Biochem. Biophys. Res. Commun. 248 (3): 879–88. doi:10.1006/bbrc.1998.9061. PMID 9704021.
  2. ↑ "Entrez Gene: LRP6 low density lipoprotein receptor-related protein 6".
  3. ↑ 3.0 3.1 3.2 3.3 Williams BO, Insogna KL (2009). "Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone". J. Bone Miner. Res. 24 (2): 171–8. doi:10.1359/jbmr.081235. PMC 3276354. PMID 19072724.
  4. ↑ Katoh M, Katoh M (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.
  5. ↑ Hong JY, Park JI, Cho K, Gu D, Ji H, Artandi SE, McCrea PD (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.
  6. ↑ Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X (2001). "Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6". Curr. Biol. 11 (12): 951–61. doi:10.1016/s0960-9822(01)00290-1. PMID 11448771.
  7. ↑ 7.0 7.1 7.2 Kang KS, Robling AG (2014). "New Insights into Wnt-Lrp5/6-β-Catenin Signaling in Mechanotransduction". Front Endocrinol (Lausanne). 5: 246. doi:10.3389/fendo.2014.00246. PMC 4299511. PMID 25653639.
  8. ↑ Baron R, 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.
  9. ↑ 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. PMC 3652284. PMID 23470835.

Further reading


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