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Gene Review

LRP6  -  low density lipoprotein receptor-related...

Homo sapiens

Synonyms: ADCAD2, LRP-6, Low-density lipoprotein receptor-related protein 6
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Disease relevance of LRP6

  • Furthermore, using a retroviral gene transfer system, we find that stable expression of LRP6 in human fibrosarcoma HT1080 cells alters subcellular beta-catenin distribution such that the cytosolic beta-catenin level is significantly increased [1].
  • LRP6 holds the key to the entry of anthrax toxin [2].
  • In the present study, both LRP5 and LRP6 showed significantly higher expression in the UC-Ca group, which suggests the importance of these genes in the development of UC-associated colorectal cancers [3].
  • The Lrp6 mutation in Cd mice provides evidence for a functional connection between Wnt signaling and folate rescue of neural tube defects [4].

High impact information on LRP6

  • The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin [5].
  • Downregulation of LRP6 or coexpression of a truncated LRP6 dominant-negative peptide inhibited cellular uptake of complexes containing the protective antigen (PA) carrier of anthrax toxin moieties and protected targeted cells from death, as did antibodies against epitopes in the LRP6 extracellular domain [5].
  • Here we report that LRP6 functions as a co-receptor for Wnt signal transduction [6].
  • In Xenopus embryos, LRP6 activated Wnt-Fz signalling, and induced Wnt responsive genes, dorsal axis duplication and neural crest formation [6].
  • Thus, unlike Wnt antagonists, which exert their effects by molecular mimicry of Fz or Wnt sequestration through other mechanisms, Dkk-1 specifically inhibits canonical Wnt signalling by binding to the LRP6 component of the receptor complex [7].

Chemical compound and disease context of LRP6

  • A cranial neural tube defect in Crooked tail (Cd) mice is prevented with prenatal dietary folic acid Cd positional cloning reveals a missense mutation of a highly conserved amino acid in the low density lipoprotein receptor-related protein 6 (Lrp6), a coreceptor required for Wnt canonical signaling [4].

Biological context of LRP6

  • In Xenopus and mammalian cell culture assays, we showed that SOST is able to attenuate Wnt signaling and that this attenuation can be rescued by the addition of alpha-Sost antibodies or by the introduction of single amino acid substitution that alter its binding to LRP6 [8].
  • LRP6 maps to human chromosome 12p11-p13 [9].
  • Mouse Lrp6 encodes a protein that has 98% identity to human LRP6 and maps to chromosome 6 [9].
  • LDL receptor-related protein 6 (LRP6) is a Wnt coreceptor in the canonical signaling pathway, which plays essential roles in embryonic development [10].
  • A truncated LRP6 comprising its transmembrane and cytoplasmic domains is expressed as a constitutively active monomer whose signaling ability is inhibited by forced dimerization [10].

Anatomical context of LRP6

  • We report that LRP6 is readily expressed at the transcript level in several human cancer cell lines and human malignant tissues [1].
  • Initial studies have established expression of low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) in vascular smooth muscle cells (VSMCs) [11].
  • We hypothesized that LRP6 is a critical mediator governing the regulation of the canonical Wnt/beta-catenin/T cell factor 4 (Tcf-4) cascade in the vasculature [11].
  • Activation involves binding of secreted members of the Wnt family of proteins with a membrane receptor Frizzled on osteoblasts, an interaction that is facilitated by LRP5/LRP6 co-receptors [12].
  • Wnt11/{beta}-catenin signaling in both oocytes and early embryos acts through LRP6-mediated regulation of axin [13].

Associations of LRP6 with chemical compounds

  • Mutation of LRP6 Ser(1420) and Ser(1430) to alanine strengthens its interaction with axin, suggesting a mechanism by which CKIepsilon may negatively regulate Wnt signaling [14].

Physical interactions of LRP6


Enzymatic interactions of LRP6

  • Now several publications(1-4) indicate that Frizzled receptors are G-protein coupled and kinases were identified that phosphorylate the co-receptor LRP6 [16].

Other interactions of LRP6

  • MATERIALS AND METHODS: We analyzed four variants of LRP5 and one amino acid variant of the LRP6 gene in a large prospective population-based cohort study of elderly subjects [17].
  • 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) [18].
  • Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow [7].
  • SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor [19].
  • Based on this, we hypothesized that the main function of Wnt is to nucleate the formation of a physical complex between LRP6 and a Frizzled [20].
  • Although RSpo1 does not directly activate LRP6, it interferes with DKK1/Kremen-mediated internalization of LRP6 through an interaction with Kremen, resulting in increased LRP6 levels on the cell surface [21].

Analytical, diagnostic and therapeutic context of LRP6


  1. LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution. Li, Y., Lu, W., He, X., Schwartz, A.L., Bu, G. Oncogene (2004) [Pubmed]
  2. LRP6 holds the key to the entry of anthrax toxin. Bann, J.G., Cegelski, L., Hultgren, S.J. Cell (2006) [Pubmed]
  3. Gene expression signature and the prediction of ulcerative colitis-associated colorectal cancer by DNA microarray. Watanabe, T., Kobunai, T., Toda, E., Kanazawa, T., Kazama, Y., Tanaka, J., Tanaka, T., Yamamoto, Y., Hata, K., Kojima, T., Yokoyama, T., Konishi, T., Okayama, Y., Sugimoto, Y., Oka, T., Sasaki, S., Ajioka, Y., Muto, T., Nagawa, H. Clin. Cancer Res. (2007) [Pubmed]
  4. Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6. Carter, M., Chen, X., Slowinska, B., Minnerath, S., Glickstein, S., Shi, L., Campagne, F., Weinstein, H., Ross, M.E. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  5. The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin. Wei, W., Lu, Q., Chaudry, G.J., Leppla, S.H., Cohen, S.N. Cell (2006) [Pubmed]
  6. LDL-receptor-related proteins in Wnt signal transduction. Tamai, K., Semenov, M., Kato, Y., Spokony, R., Liu, C., Katsuyama, Y., Hess, F., Saint-Jeannet, J.P., He, X. Nature (2000) [Pubmed]
  7. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Bafico, A., Liu, G., Yaniv, A., Gazit, A., Aaronson, S.A. Nat. Cell Biol. (2001) [Pubmed]
  8. Bone Density Ligand, Sclerostin, Directly Interacts With LRP5 but Not LRP5(G171V) to Modulate Wnt Activity. Ellies, D.L., Viviano, B., McCarthy, J., Rey, J.P., Itasaki, N., Saunders, S., Krumlauf, R. J. Bone Miner. Res. (2006) [Pubmed]
  9. Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family. Brown, S.D., Twells, R.C., Hey, P.J., Cox, R.D., Levy, E.R., Soderman, A.R., Metzker, M.L., Caskey, C.T., Todd, J.A., Hess, J.F. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  10. A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor. Liu, G., Bafico, A., Harris, V.K., Aaronson, S.A. Mol. Cell. Biol. (2003) [Pubmed]
  11. LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells. Wang, X., Adhikari, N., Li, Q., Hall, J.L. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  12. 1,25-Dihydroxyvitamin D(3) induces expression of the Wnt signaling co-regulator LRP5 via regulatory elements located significantly downstream of the gene's transcriptional start site. Fretz, J.A., Zella, L.A., Kim, S., Shevde, N.K., Pike, J.W. J. Steroid Biochem. Mol. Biol. (2007) [Pubmed]
  13. Wnt11/{beta}-catenin signaling in both oocytes and early embryos acts through LRP6-mediated regulation of axin. Kofron, M., Birsoy, B., Houston, D., Tao, Q., Wylie, C., Heasman, J. Development (2007) [Pubmed]
  14. Negative Regulation of LRP6 Function by Casein Kinase I {epsilon} Phosphorylation. Swiatek, W., Kang, H., Garcia, B.A., Shabanowitz, J., Coombs, G.S., Hunt, D.F., Virshup, D.M. J. Biol. Chem. (2006) [Pubmed]
  15. The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity. Mi, K., Dolan, P.J., Johnson, G.V. J. Biol. Chem. (2006) [Pubmed]
  16. Kinases and G proteins join the Wnt receptor complex. Quaiser, T., Anton, R., Kühl, M. Bioessays (2006) [Pubmed]
  17. Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. van Meurs, J.B., Rivadeneira, F., Jhamai, M., Hugens, W., Hofman, A., van Leeuwen, J.P., Pols, H.A., Uitterlinden, A.G. J. Bone Miner. Res. (2006) [Pubmed]
  18. 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). Baens, M., Wlodarska, I., Corveleyn, A., Hoornaert, I., Hagemeijer, A., Marynen, P. Genomics (1999) [Pubmed]
  19. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. Semënov, M., Tamai, K., He, X. J. Biol. Chem. (2005) [Pubmed]
  20. Wnt-independent activation of beta-catenin mediated by a Dkk1-Fz5 fusion protein. Holmen, S.L., Robertson, S.A., Zylstra, C.R., Williams, B.O. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  21. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Binnerts, M.E., Kim, K.A., Bright, J.M., Patel, S.M., Tran, K., Zhou, M., Leung, J.M., Liu, Y., Lomas, W.E., Dixon, M., Hazell, S.A., Wagle, M., Nie, W.S., Tomasevic, N., Williams, J., Zhan, X., Levy, M.D., Funk, W.D., Abo, A. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  22. Activation of the canonical wingless/t-cell factor signaling pathway promotes invasive differentiation of human trophoblast. Pollheimer, J., Loregger, T., Sonderegger, S., Saleh, L., Bauer, S., Bilban, M., Czerwenka, K., Husslein, P., Knöfler, M. Am. J. Pathol. (2006) [Pubmed]
  23. Altering interface detector positioning in combination with prestorage filtration to achieve a better quality of single donor platelet concentrates using the CS 3000 Plus blood separator. Lydaki, E., Nikoloudi, E., Bolonaki, E., Mavroudis, D., Kandidaki, E. Journal of clinical apheresis. (2002) [Pubmed]
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