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Gene Review

LRP1  -  low density lipoprotein receptor-related...

Homo sapiens

Synonyms: A2MR, APOER, APR, Alpha-2-macroglobulin receptor, Apolipoprotein E receptor, ...
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Disease relevance of LRP1


Psychiatry related information on LRP1

  • No genetic defect was evident in the LRP1 gene of any of the Alzheimer's disease (AD) patients, further excluding LRP1 as a major genetic problem in AD [7].
  • We thus conclude that one of the neurotoxic mechanisms triggered by ApoE4 is to activate a cell type-specific apoptogenic program involving LRP and the G(i) class of GTPases and that the apoE4 gene may play a direct role in the pathogenesis of AD and other forms of dementia [8].
  • The LRP antagonist receptor-associated protein prevented the APP-KPI internalization and LRP-apolipoprotein E association and this resulted in amnesia [9].

High impact information on LRP1

  • However, interaction of these heads with PAMPs on foreign organisms or damaged cells and presentation of the collagenous tails in an aggregated state to calreticulin/CD91, stimulates phagocytosis and proinflammatory responses [10].
  • By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation [10].
  • We show that the low density lipoprotein (LDL) receptor-related protein (LRP) is responsible for the endocytosis of secreted APP [11].
  • APPs770 degradation is inhibited by an LRP antagonist called the receptor-associated protein (RAP) and by LRP antibodies and is greatly diminished in fibroblasts genetically deficient in LRP [11].
  • The uptake and removal of necrotic or lysed cells involves inflammation and an immune response, due in part to processes that involve members of the collectin family, surface calreticulin and CD91 [12].

Chemical compound and disease context of LRP1


Biological context of LRP1


Anatomical context of LRP1


Associations of LRP1 with chemical compounds

  • Uptake was reduced by the known LRP1 inhibitors RAP, lactoferrin, and suramin, but not by LDL, which exclusively binds to the LDLR [23].
  • The endocytosis-related activity of LRP1 in hRPE cells was examined by assessing the uptake of FITC-labeled, methylamine (MA)-treated alpha(2)-M (alpha(2)-M-MA) [24].
  • No evidence for pathology connected to the LRP1 'mutations' was obtained by subsequent screening for the five LRP1 variants in larger groups of 110 FH patients and 118 patients with molecularly undefined, clinical problems of cholesterol and/or lipid metabolism [7].
  • This article reviews recent work that indicates that LRP1 is phosphorylated on both serine and tyrosine residues [26].
  • LpL-(313-448) and LpL-(347-448) showed similar affinities for binding to both purified alpha2MR/LRP and to heparin [4].

Physical interactions of LRP1

  • Crosslinking experiments on cells with 125I-labeled apoE liposomes or lipoprotein lipase showed that both proteins were able to bind to LRP on the cell surface [27].
  • Studies on the interaction of recombinant human RAP with the LDL receptor family in the chicken revealed that RAP binds with high affinity to the abundant oocyte receptor for yolk precursors (OVR) as well as to the somatic cell-specific LRP/alpha 2MR [28].
  • Inhibition of t-PA but not alpha 2M* binding to LRP/alpha 2MR is also mediated by residues 200-225 and 311-319 [29].
  • In this report, we tested several other LRP ligands for their ability to interact with human and rat gp330 in vitro [3].
  • This is taken as evidence for mediation of internalization and degradation of uPAR-bound uPA.PAI-1 by alpha 2MR/LRP [30].

Regulatory relationships of LRP1

  • This was further supported by observing that an immunoaffinity-isolated polyclonal antibody against LRP blocked cellular degradation of 125I-LPL in a dose-dependent manner [31].
  • We demonstrate that the presentation of LRP and the subsequent uptake of its ligands by malignant cells are both strongly regulated by MT1-MMP [32].
  • The inhibitor-enhanced uPA degradation was blocked by r alpha 2MRAP and inhibited by polyclonal anti-alpha 2MR/LRP antibodies [30].
  • Lactoferrin-induced mitogenesis is also inhibited by an antibody to LRP1 [33].
  • BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor with an important role in regulating the activity of proteinases in extracellular matrix [1].

Other interactions of LRP1


Analytical, diagnostic and therapeutic context of LRP1

  • Gel mobility shift assays showed that recombinant SREBP-2-NT protein (1-468) binds to a double-stranded LRP1 DNA fragment (215 to 245) containing a wild-type (wt) SRE sequence but not to a mutated SRE (mt) sequence (5-GAATTCGA-3') [20].
  • Reverse-transcriptase polymerase chain reaction was used to confirm chondrocyte phenotype and the expression of collagenase-3 and LRP1 mRNAs [37].
  • Eighteen previous AD case-control studies have investigated the C766T polymorphism in LRP1 with conflicting results, including a protective effect on AD of the T allele, an increased susceptibility towards AD with both the C and T alleles, or no association at all [38].
  • Overexpression of LRP1 in atherosclerotic lesions has been demonstrated in several animal models and human lesions [2].
  • Further evidence comes from immunoprecipitation experiments using a monoclonal antibody specific for the alpha 2M receptor that show this molecule, like LRP, to contain two polypeptides of approximately 420 and 85 kDa that are noncovalently associated [39].


  1. C766T low-density lipoprotein receptor-related protein 1 (LRP1) gene polymorphism and susceptibility to breast cancer. Benes, P., Jurajda, M., Zaloudík, J., Izakovicová-Hollá, L., Vácha, J. Breast Cancer Res. (2003) [Pubmed]
  2. LDL receptor-related protein and the vascular wall: implications for atherothrombosis. Llorente-Cortés, V., Badimon, L. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  3. Glycoprotein 330, a member of the low density lipoprotein receptor family, binds lipoprotein lipase in vitro. Kounnas, M.Z., Chappell, D.A., Strickland, D.K., Argraves, W.S. J. Biol. Chem. (1993) [Pubmed]
  4. Segments in the C-terminal folding domain of lipoprotein lipase important for binding to the low density lipoprotein receptor-related protein and to heparan sulfate proteoglycans. Nielsen, M.S., Brejning, J., García, R., Zhang, H., Hayden, M.R., Vilaró, S., Gliemann, J. J. Biol. Chem. (1997) [Pubmed]
  5. Regulated expression of the trophoblast alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Differentiation and cAMP modulate protein and mRNA levels. Gåfvels, M.E., Coukos, G., Sayegh, R., Coutifaris, C., Strickland, D.K., Strauss, J.F. J. Biol. Chem. (1992) [Pubmed]
  6. The low-density lipoprotein receptor-related protein regulates cancer cell survival and metastasis development. Montel, V., Gaultier, A., Lester, R.D., Campana, W.M., Gonias, S.L. Cancer Res. (2007) [Pubmed]
  7. Sequencing of the coding exons of the LRP1 and LDLR genes on individual DNA samples reveals novel mutations in both genes. Van Leuven, F., Thiry, E., Lambrechts, M., Stas, L., Boon, T., Bruynseels, K., Muls, E., Descamps, O. Atherosclerosis (2001) [Pubmed]
  8. Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases. Hashimoto, Y., Jiang, H., Niikura, T., Ito, Y., Hagiwara, A., Umezawa, K., Abe, Y., Murayama, Y., Nishimoto, I. J. Neurosci. (2000) [Pubmed]
  9. Amyloid precursor protein expression in the rat hippocampal dentate gyrus modulates during memory consolidation. Conboy, L., Murphy, K.J., Regan, C.M. J. Neurochem. (2005) [Pubmed]
  10. By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Gardai, S.J., Xiao, Y.Q., Dickinson, M., Nick, J.A., Voelker, D.R., Greene, K.E., Henson, P.M. Cell (2003) [Pubmed]
  11. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Kounnas, M.Z., Moir, R.D., Rebeck, G.W., Bush, A.I., Argraves, W.S., Tanzi, R.E., Hyman, B.T., Strickland, D.K. Cell (1995) [Pubmed]
  12. The phosphatidylserine receptor: a crucial molecular switch? Henson, P.M., Bratton, D.L., Fadok, V.A. Nat. Rev. Mol. Cell Biol. (2001) [Pubmed]
  13. The low density lipoprotein receptor-related protein contributes to selective uptake of high density lipoprotein cholesteryl esters by SW872 liposarcoma cells and primary human adipocytes. Vassiliou, G., Benoist, F., Lau, P., Kavaslar, G.N., McPherson, R. J. Biol. Chem. (2001) [Pubmed]
  14. Modulation of the LDL receptor and LRP levels by HIV protease inhibitors. Tran, H., Robinson, S., Mikhailenko, I., Strickland, D.K. J. Lipid Res. (2003) [Pubmed]
  15. Effects of apolipoprotein E on the human immunodeficiency virus protein Tat in neuronal cultures and synaptosomes. Pocernich, C.B., Sultana, R., Hone, E., Turchan, J., Martins, R.N., Calabrese, V., Nath, A., Butterfield, D.A. J. Neurosci. Res. (2004) [Pubmed]
  16. The expression of the LDL receptor-related protein (LRP) correlates with the differentiation of human neuroblastoma cells. Fabrizi, C., Businaro, R., Persichini, T., Fumagalli, L., Lauro, G.M. Brain Res. (1997) [Pubmed]
  17. Estradiol regulation of astroglia and apolipoprotein E: An important role in neuronal regeneration. Struble, R.G., Nathan, B.P., Cady, C., Cheng, X., McAsey, M. Exp. Gerontol. (2007) [Pubmed]
  18. Normal development and fertility of knockout mice lacking the tumor suppressor gene LRP1b suggest functional compensation by LRP1. Marschang, P., Brich, J., Weeber, E.J., Sweatt, J.D., Shelton, J.M., Richardson, J.A., Hammer, R.E., Herz, J. Mol. Cell. Biol. (2004) [Pubmed]
  19. LRP-DIT, a putative endocytic receptor gene, is frequently inactivated in non-small cell lung cancer cell lines. Liu, C.X., Musco, S., Lisitsina, N.M., Forgacs, E., Minna, J.D., Lisitsyn, N.A. Cancer Res. (2000) [Pubmed]
  20. Sterol regulatory element-binding protein-2 negatively regulates low density lipoprotein receptor-related protein transcription. Llorente-Cortés, V., Costales, P., Bernués, J., Camino-Lopez, S., Badimon, L. J. Mol. Biol. (2006) [Pubmed]
  21. Association study of the A2M and LRP1 Genes with Alzheimer disease in the Han Chinese. Bian, L., Yang, J.D., Guo, T.W., Duan, Y., Qin, W., Sun, Y., Feng, G.Y., He, L. Biol. Psychiatry (2005) [Pubmed]
  22. Characterization of the soluble form of the low density lipoprotein receptor-related protein (LRP). Quinn, K.A., Pye, V.J., Dai, Y.P., Chesterman, C.N., Owensby, D.A. Exp. Cell Res. (1999) [Pubmed]
  23. Expression of LRP1 by human osteoblasts: a mechanism for the delivery of lipoproteins and vitamin K1 to bone. Niemeier, A., Kassem, M., Toedter, K., Wendt, D., Ruether, W., Beisiegel, U., Heeren, J. J. Bone Miner. Res. (2005) [Pubmed]
  24. Expression of LRP1 in retinal pigment epithelial cells and its regulation by growth factors. Hollborn, M., Birkenmeier, G., Saalbach, A., Iandiev, I., Reichenbach, A., Wiedemann, P., Kohen, L. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  25. Lactoferrin potently inhibits osteoblast apoptosis, via an LRP1-independent pathway. Grey, A., Zhu, Q., Watson, M., Callon, K., Cornish, J. Mol. Cell. Endocrinol. (2006) [Pubmed]
  26. Phosphorylation of LRP1: regulation of transport and signal transduction. van der Geer, P. Trends Cardiovasc. Med. (2002) [Pubmed]
  27. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Beisiegel, U., Weber, W., Bengtsson-Olivecrona, G. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  28. The chicken oocyte receptor for yolk precursors as a model for studying the action of receptor-associated protein and lactoferrin. Hiesberger, T., Hermann, M., Jacobsen, L., Novak, S., Hodits, R.A., Bujo, H., Meilinger, M., Hüttinger, M., Schneider, W.J., Nimpf, J. J. Biol. Chem. (1995) [Pubmed]
  29. Identification of domains on the 39-kDa protein that inhibit the binding of ligands to the low density lipoprotein receptor-related protein. Warshawsky, I., Bu, G., Schwartz, A.L. J. Biol. Chem. (1993) [Pubmed]
  30. Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase.plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. Nykjaer, A., Petersen, C.M., Møller, B., Jensen, P.H., Moestrup, S.K., Holtet, T.L., Etzerodt, M., Thøgersen, H.C., Munch, M., Andreasen, P.A. J. Biol. Chem. (1992) [Pubmed]
  31. The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor binds and mediates catabolism of bovine milk lipoprotein lipase. Chappell, D.A., Fry, G.L., Waknitz, M.A., Iverius, P.H., Williams, S.E., Strickland, D.K. J. Biol. Chem. (1992) [Pubmed]
  32. The low density lipoprotein receptor-related protein LRP is regulated by membrane type-1 matrix metalloproteinase (MT1-MMP) proteolysis in malignant cells. Rozanov, D.V., Hahn-Dantona, E., Strickland, D.K., Strongin, A.Y. J. Biol. Chem. (2004) [Pubmed]
  33. The low-density lipoprotein receptor-related protein 1 is a mitogenic receptor for lactoferrin in osteoblastic cells. Grey, A., Banovic, T., Zhu, Q., Watson, M., Callon, K., Palmano, K., Ross, J., Naot, D., Reid, I.R., Cornish, J. Mol. Endocrinol. (2004) [Pubmed]
  34. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. Ogden, C.A., deCathelineau, A., Hoffmann, P.R., Bratton, D., Ghebrehiwet, B., Fadok, V.A., Henson, P.M. J. Exp. Med. (2001) [Pubmed]
  35. The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor. Warshawsky, I., Broze, G.J., Schwartz, A.L. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  36. Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the alpha 2-macroglobulin receptor/low-density-lipoprotein receptor-related protein. Rebeck, G.W., Harr, S.D., Strickland, D.K., Hyman, B.T. Ann. Neurol. (1995) [Pubmed]
  37. Impairment of the collagenase-3 endocytotic receptor system in cells from patients with osteoarthritis. Walling, H.W., Raggatt, L.J., Irvine, D.W., Barmina, O.Y., Toledano, J.E., Goldring, M.B., Hruska, K.A., Adkisson, H.D., Burdge, R.E., Gatt, C.J., Harwood, D.A., Partridge, N.C. Osteoarthr. Cartil. (2003) [Pubmed]
  38. Association study and meta-analysis of low-density lipoprotein receptor related protein in Alzheimer's disease. Pritchard, A., Harris, J., Pritchard, C.W., St Clair, D., Lemmon, H., Lambert, J.C., Chartier-Harlin, M.C., Hayes, A., Thaker, U., Iwatsubo, T., Mann, D.M., Lendon, C. Neurosci. Lett. (2005) [Pubmed]
  39. Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. Strickland, D.K., Ashcom, J.D., Williams, S., Burgess, W.H., Migliorini, M., Argraves, W.S. J. Biol. Chem. (1990) [Pubmed]
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