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LRP6

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LRP6
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLRP6, ADCAD2, STHAG7, LDL receptor related protein 6
External IDsOMIM: 603507; MGI: 1298218; HomoloGene: 1747; GeneCards: LRP6; OMA:LRP6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4040

16974

Ensembl

ENSG00000070018
ENSG00000281324

ENSMUSG00000030201

UniProt

O75581

O88572

RefSeq (mRNA)

NM_002336

NM_008514

RefSeq (protein)

NP_002327

NP_032540

Location (UCSC)Chr 12: 12.12 – 12.27 MbChr 6: 134.42 – 134.54 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene.[5][6] LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

Structure

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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 YWTD β-propeller motifs at the amino terminal end that alternate with four epidermal growth factor (EGF)-like repeats, followed by three LDLR type A repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid transmembrane helix followed by a 207-amino-acid segment that is internal to the cell.[7][8]

Function

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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.[8]

A LRP6 mutant lacking the intracellular domain is defective in Wnt signaling[9] while LRP6 mutant lacking the extracellular domain (but anchored on the membrane) are constitutively active.[10]

Interactions

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Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.[11] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.[12]

LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1[13]), sclerostin, R-spondins and members of the cysteine-knot-type protein family.[8]

Clinical significance

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Common genetic variants of LRP6 have been associated with the risks for hyperlipidemia,[14] atherosclerosis,[15] coronary disease,[16] and late-onset Alzheimer's disease[17] in the general population.

Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis.[8] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass.[18] LRP6 is critical in bone's anabolic response to parathyroid hormone (PTH) treatment, whereas LRP5 is not involved.[18] On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role.[18] Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.[19][20]

References

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  1. ^ a b c ENSG00000281324 GRCh38: Ensembl release 89: ENSG00000070018, ENSG00000281324 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030201 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ "Entrez Gene: LRP6 low density lipoprotein receptor-related protein 6".
  7. ^ Cheng Z, Biechele T, Wei Z, Morrone S, Moon RT, Wang L, Xu W (November 2011). "Crystal structures of the extracellular domain of LRP6 and its complex with DKK1". Nature Structural & Molecular Biology. 18 (11): 1204–1210. doi:10.1038/nsmb.2139. PMC 3249237.
  8. ^ a b c d 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.
  9. ^ Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X (September 2000). "LDL-receptor-related proteins in Wnt signal transduction". Nature. 407 (6803): 530–535. doi:10.1038/35035117.
  10. ^ Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C (17 May 2001). "LDL-receptor-related protein 6 is a receptor for Dickkopf proteins". Nature. 411 (6835): 321–325. doi:10.1038/35077108.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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. Bibcode:2001CBio...11..951S. doi:10.1016/s0960-9822(01)00290-1. PMID 11448771. S2CID 15702819.
  14. ^ Tomaszewski M, Charchar FJ, Barnes T, Gawron-Kiszka M, Sedkowska A, Podolecka E, Kowalczyk J, Rathbone W, Kalarus Z, Grzeszczak W, Goodall AH, Samani NJ, Zukowska-Szczechowska E (September 2009). "A Common Variant in Low-Density Lipoprotein Receptor–Related Protein 6 Gene (LRP6) Is Associated With LDL-Cholesterol". Arteriosclerosis, Thrombosis, and Vascular Biology. 29 (9): 1316–1321. doi:10.1161/ATVBAHA.109.185355. PMC 2814817.
  15. ^ Sarzani R, Salvi F, Bordicchia M, Guerra F, Battistoni I, Pagliariccio G, Carbonari L, Dessì-Fulgheri P, Rappelli A (February 2011). "Carotid artery atherosclerosis in hypertensive patients with a functional LDL receptor-related protein 6 gene variant". Nutrition, Metabolism and Cardiovascular Diseases. 21 (2): 150–156. doi:10.1016/j.numecd.2009.08.004.
  16. ^ Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP (2 March 2007). "LRP6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors". Science. 315 (5816): 1278–1282. doi:10.1126/science.1136370. PMC 2945222.
  17. ^ De Ferrari GV, Papassotiropoulos A, Biechele T, Wavrant De-Vrieze F, Avila ME, Major MB, Myers A, Sáez K, Henríquez JP, Zhao A, Wollmer MA, Nitsch RM, Hock C, Morris CM, Hardy J, Moon RT (29 May 2007). "Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease". Proceedings of the National Academy of Sciences. 104 (22): 9434–9439. doi:10.1073/pnas.0603523104. PMC 1890512.
  18. ^ a b c 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.
  19. ^ 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. S2CID 19968640.
  20. ^ 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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