LRP6

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LRP6
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases LRP6, ADCAD2, STHAG7, LDL receptor related protein 6
External IDs MGI: 1298218 HomoloGene: 1747 GeneCards: LRP6
RNA expression pattern
PBB GE LRP6 34697 at fs.png

PBB GE LRP6 205606 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002336

NM_008514

RefSeq (protein)

NP_002327

NP_032540

Location (UCSC) n/a Chr 6: 134.45 – 134.57 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene.[3][4] LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

Structure[edit]

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.[5]

Function[edit]

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.[5]

Interactions[edit]

Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.[6] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.[7]

LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1[8]), sclerostin, R-spondins and members of the cysteine-knot-type protein family.[5]

Clinical significance[edit]

Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis.[5] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass.[9] LRP6 is critical in bone's anabolic response to parathyroid hormone (PTH) treatment, whereas LRP5 is not involved.[9] On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role.[9] Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.[10][11]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ 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. PMID 9704021. doi:10.1006/bbrc.1998.9061. 
  4. ^ "Entrez Gene: LRP6 low density lipoprotein receptor-related protein 6". 
  5. ^ 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. PMC 3276354Freely accessible. PMID 19072724. doi:10.1359/jbmr.081235. 
  6. ^ 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. PMID 16940750. doi:10.4161/cbt.5.9.3151. 
  7. ^ 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. PMC 2995616Freely accessible. PMID 21098636. doi:10.1242/jcs.067199. 
  8. ^ 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. PMID 11448771. doi:10.1016/s0960-9822(01)00290-1. 
  9. ^ a b c Kang KS, Robling AG (2014). "New Insights into Wnt-Lrp5/6-β-Catenin Signaling in Mechanotransduction". Front Endocrinol (Lausanne). 5: 246. PMC 4299511Freely accessible. PMID 25653639. doi:10.3389/fendo.2014.00246. 
  10. ^ Baron R, Kneissel M (February 2013). "WNT signaling in bone homeostasis and disease: from human mutations to treatments". Nature Medicine. 19 (2): 179–192. PMID 23389618. doi:10.1038/nm.3074. 
  11. ^ Burgers TA, Williams BO (June 2013). "Regulation of Wnt/beta-catenin signaling within and from osteocytes". Bone. 54 (2): 244–249. PMC 3652284Freely accessible. PMID 23470835. doi:10.1016/j.bone.2013.02.022. 

Further reading[edit]