LRP6

LRP6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3S2K, 3S8V, 3S8Z, 3S94, 3SOB, 3SOQ, 3SOV, 4A0P, 4DG6, 4NM5, 4NM7
Identifiers
Aliases	LRP6, ADCAD2, STHAG7, LDL receptor related protein 6
External IDs	OMIM: 603507; MGI: 1298218; HomoloGene: 1747; GeneCards: LRP6; OMA:LRP6 - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p13.2 Start 12,116,025 bp[1] End 12,267,044 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 G1|6 65.37 cM Start 134,423,439 bp[2] End 134,543,928 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon corpus callosum ventricular zone gonad liver stromal cell of endometrium ganglionic eminence epithelium of colon placenta sural nerve Top expressed in ascending aorta aortic valve stroma of bone marrow cumulus cell choroid plexus of fourth ventricle lactiferous gland secondary oocyte extraocular muscle zygote Gonadal ridge More reference expression data BioGPS More reference expression data
Gene ontology Molecular function low-density lipoprotein particle receptor activity apolipoprotein binding protein homodimerization activity kinase inhibitor activity frizzled binding Wnt-protein binding toxin transmembrane transporter activity protein binding coreceptor activity involved in Wnt signaling pathway identical protein binding Wnt-activated receptor activity signaling receptor binding coreceptor activity involved in canonical Wnt signaling pathway Cellular component integral component of membrane Wnt-Frizzled-LRP5/6 complex Wnt signalosome Golgi apparatus early endosome membrane membrane receptor complex synapse extracellular region cell surface soma early endosome endoplasmic reticulum caveola cytoplasmic vesicle plasma membrane membrane raft Biological process negative regulation of protein phosphorylation Wnt signaling pathway involved in somitogenesis cerebellum morphogenesis roof of mouth development dopaminergic neuron differentiation positive regulation of Wnt signaling pathway involved in dorsal/ventral axis specification regulation of transcription, DNA-templated endocytosis receptor-mediated endocytosis involved in cholesterol transport embryonic pattern specification convergent extension negative regulation of protein kinase activity thalamus development axis elongation involved in somitogenesis canonical Wnt signaling pathway involved in neural crest cell differentiation positive regulation of cytosolic calcium ion concentration response to peptide hormone canonical Wnt signaling pathway involved in regulation of cell proliferation neural crest cell differentiation positive regulation of DNA-binding transcription factor activity Wnt signaling pathway cellular response to cholesterol neural crest formation trachea cartilage morphogenesis positive regulation of transcription, DNA-templated odontogenesis of dentin-containing tooth multicellular organism development midbrain-hindbrain boundary development neural tube closure positive regulation of cell cycle external genitalia morphogenesis Wnt signaling pathway involved in dorsal/ventral axis specification pericardium morphogenesis cerebral cortex development embryonic retina morphogenesis in camera-type eye canonical Wnt signaling pathway negative regulation of protein serine/threonine kinase activity protein localization to plasma membrane negative regulation of canonical Wnt signaling pathway negative regulation of smooth muscle cell apoptotic process face morphogenesis primitive streak formation positive regulation of transcription by RNA polymerase II chemical synaptic transmission toxin transport Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation positive regulation of canonical Wnt signaling pathway beta-catenin destruction complex disassembly midbrain dopaminergic neuron differentiation gastrulation with mouth forming second anterior/posterior pattern specification embryonic limb morphogenesis midbrain development bone remodeling embryonic camera-type eye morphogenesis bone morphogenesis branching involved in mammary gland duct morphogenesis cell-cell adhesion Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 6: 134.42 – 134.54 Mb PubMed search [3] [4]
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.^[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 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

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

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

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

1. ENSG00000281324 GRCh38: Ensembl release 89: ENSG00000070018, ENSG00000281324 – Ensembl, May 2017
2. 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. 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. 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

• 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. S2CID 2297859.
• 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. Bibcode:2000Natur.407..530T. doi:10.1038/35035117. PMID 11029007. S2CID 4400159.
• 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. Bibcode:2001Natur.411..321M. doi:10.1038/35077108. PMID 11357136. S2CID 4323027.
• 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. Bibcode:2001CBio...11..951S. doi:10.1016/S0960-9822(01)00290-1. PMID 11448771. S2CID 15702819.
• 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. Bibcode:2002PNAS...9916899M. 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. S2CID 11159925.
• 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.