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
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

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.[7]

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.[7]

Interactions

Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.[8] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.[9]

LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1[10]), sclerostin, R-spondins and members of the cysteine-knot-type protein family.[7]

Clinical significance

Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis.[7] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass.[11] LRP6 is critical in bone's anabolic response to parathyroid hormone (PTH) treatment, whereas LRP5 is not involved.[11] On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role.[11] Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.[12][13]

References

  1. 1 2 3 ENSG00000281324 GRCh38: Ensembl release 89: ENSG00000070018, ENSG00000281324 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 4 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.
  8. 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.
  9. 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.
  10. 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. S2CID 15702819.
  11. 1 2 3 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.
  12. 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.
  13. 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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