LRP6

Low density lipoprotein receptor-related protein 6
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3S2K​, 3S8V​, 3S8Z​, 3S94​, 3SOB​, 3SOQ​, 3SOV​, 4A0P​, 4DG6​, 4NM5​, 4NM7​, 5AIR​
Identifiers
Symbols	LRP6 ; ADCAD2
External IDs	OMIM: 603507 MGI: 1298218 HomoloGene: 1747 GeneCards: LRP6 Gene
Gene ontology Molecular function • low-density lipoprotein receptor activity • receptor binding • frizzled binding • protein binding • Wnt-protein binding • kinase inhibitor activity • toxin transporter activity • apolipoprotein binding • identical protein binding • protein homodimerization activity • Wnt-activated receptor activity • coreceptor activity involved in Wnt signaling pathway Cellular component • extracellular region • early endosome • endoplasmic reticulum • Golgi apparatus • plasma membrane • caveola • cell surface • integral component of membrane • cytoplasmic vesicle • early endosome membrane • neuronal cell body • receptor complex • synapse Biological process • neural tube closure • negative regulation of protein phosphorylation • pericardium morphogenesis • negative regulation of protein kinase activity • synaptic transmission • embryonic pattern specification • neural crest formation • neural crest cell differentiation • Wnt signaling pathway • cerebellum morphogenesis • thalamus development • cerebral cortex development • midbrain development • midbrain-hindbrain boundary development • negative regulation of smooth muscle cell apoptotic process • external genitalia morphogenesis • odontogenesis of dentin-containing tooth • Wnt signaling pathway involved in dorsal/ventral axis specification • canonical Wnt signaling pathway involved in neural crest cell differentiation • canonical Wnt signaling pathway involved in regulation of cell proliferation • positive regulation of cell cycle • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • positive regulation of sequence-specific DNA binding transcription factor activity • palate development • convergent extension • embryonic retina morphogenesis in camera-type eye • canonical Wnt signaling pathway • face morphogenesis • trachea cartilage morphogenesis • cellular response to cholesterol • negative regulation of protein serine/threonine kinase activity • primitive streak formation • negative regulation of canonical Wnt signaling pathway • receptor-mediated endocytosis of low-density lipoprotein particle involved in cholesterol transport • Wnt signaling pathway involved in somitogenesis • axis elongation involved in somitogenesis • positive regulation of canonical Wnt signaling pathway • toxin transport • positive regulation of Wnt signaling pathway involved in dorsal/ventral axis specification Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4040	16974
Ensembl	ENSG00000070018	ENSMUSG00000030201
UniProt	O75581	O88572
RefSeq (mRNA)	NM_002336	NM_008514
RefSeq (protein)	NP_002327	NP_032540
Location (UCSC)	Chr 12: 12.12 – 12.27 Mb	Chr 6: 134.45 – 134.57 Mb
PubMed search

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. 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. 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. PMID 23470835.

Further reading

• He X, Semenov M, Tamai K, Zeng X (2004). "LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way.". Development 131 (8): 1663–77. doi:10.1242/dev.01117. PMID 15084453.
• Hillier LD, Lennon G, Becker M, et al. (1997). "Generation and analysis of 280,000 human expressed sequence tags.". Genome Res. 6 (9): 807–28. doi:10.1101/gr.6.9.807. PMID 8889549.
• Baens M, Wlodarska I, Corveleyn A, et al. (1999). "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).". Genomics 56 (1): 40–50. doi:10.1006/geno.1998.5685. PMID 10036184.
• Tamai K, Semenov M, Kato Y, et al. (2000). "LDL-receptor-related proteins in Wnt signal transduction.". Nature 407 (6803): 530–5. doi:10.1038/35035117. PMID 11029007.
• Mao B, Wu W, Li Y, et al. (2001). "LDL-receptor-related protein 6 is a receptor for Dickkopf proteins.". Nature 411 (6835): 321–5. doi:10.1038/35077108. PMID 11357136.
• Semënov MV, Tamai K, Brott BK, et al. (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.
• Li L, Mao J, Sun L, et al. (2002). "Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled.". J. Biol. Chem. 277 (8): 5977–81. doi:10.1074/jbc.M111131200. PMID 11742004.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Caricasole A, Ferraro T, Iacovelli L, et al. (2003). "Functional characterization of WNT7A signaling in PC12 cells: interaction with A FZD5 x LRP6 receptor complex and modulation by Dickkopf proteins.". J. Biol. Chem. 278 (39): 37024–31. doi:10.1074/jbc.M300191200. PMID 12857724.
• Liu G, Bafico A, Harris VK, Aaronson SA (2003). "A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor.". Mol. Cell. Biol. 23 (16): 5825–35. doi:10.1128/MCB.23.16.5825-5835.2003. PMC 166321. PMID 12897152.
• Zilberberg A, Yaniv A, Gazit A (2004). "The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway.". J. Biol. Chem. 279 (17): 17535–42. doi:10.1074/jbc.M311292200. PMID 14739301.
• Wang X, Adhikari N, Li Q, Hall JL (2005). "LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells.". Am. J. Physiol. Heart Circ. Physiol. 287 (6): H2376–83. doi:10.1152/ajpheart.01173.2003. PMID 15271658.
• Suzuki Y, Yamashita R, Shirota M, et al. (2004). "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions.". Genome Res. 14 (9): 1711–8. doi:10.1101/gr.2435604. PMC 515316. PMID 15342556.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Li Y, Lu W, He X, et al. (2005). "LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution.". Oncogene 23 (56): 9129–35. doi:10.1038/sj.onc.1208123. PMID 15516984.
• Semënov M, Tamai K, He X (2005). "SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor.". J. Biol. Chem. 280 (29): 26770–5. doi:10.1074/jbc.M504308200. PMID 15908424.
• Li Y, Chen J, Lu W, et al. (2006). "Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding.". J. Cell. Sci. 118 (Pt 22): 5305–14. doi:10.1242/jcs.02651. PMID 16263759.
• Mi K, Dolan PJ, Johnson GV (2006). "The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity.". J. Biol. Chem. 281 (8): 4787–94. doi:10.1074/jbc.M508657200. PMID 16365045.