LRP1

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Low density lipoprotein receptor-related protein 1
Protein LRP1 PDB 1cr8.png
PDB rendering based on 1cr8.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols LRP1 ; A2MR; APOER; APR; CD91; IGFBP3R; LRP; LRP1A; TGFBR5
External IDs OMIM107770 MGI96828 HomoloGene1744 GeneCards: LRP1 Gene
RNA expression pattern
PBB GE LRP1 200785 s at tn.png
PBB GE LRP1 200784 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4035 16971
Ensembl ENSG00000123384 ENSMUSG00000040249
UniProt Q07954 Q91ZX7
RefSeq (mRNA) NM_002332 NM_008512
RefSeq (protein) NP_002323 NP_032538
Location (UCSC) Chr 12:
57.52 – 57.61 Mb
Chr 10:
127.54 – 127.62 Mb
PubMed search [1] [2]

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene.[1][2]

Function[edit]

LRP-1 is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells.

Clinical significance[edit]

Alzheimer's disease[edit]

Neurons require cholesterol to function. Cholesterol is imported into the neuron by apolipoprotein E (apoE) via LRP1 receptors on the cell surface. It is thought that a causal factor in Alzheimer's is the malfunction of this process which damages neurons by starving them of cholesterol.[3]

Over-accumulation of copper in the brain is associated with reduced LRP1 mediated clearance of amyloid beta across the blood brain barrier. This defective clearance may contribute to the buildup of neurotoxic amyloid-beta that is thought to contribute to Alzheimer's disease.[4]

Cardiovascular disease[edit]

Studies have elucidated different roles for LRP1 in cellular processes relevant for cardiovascular disease. Atherosclerosis is the primary cause of cardiovascular disease such as stroke and heart attacks. In the liver LRP1 is important for the removal of atherogenic lipoproteins (Chylomicron remnants, VLDL) and other proatherogenic ligands from the circulation.[5][6] LRP1 has a cholesterol-independent role in atherosclerosis by modulating the activity and cellular localization of the PDGFR-β in vascular smooth muscle cells.[7][8] Finally, LRP1 in macrophages has an effect on atherosclerosis through the modulation of the extracellular matrix and inflammatory responses.[9][10]

Interactions[edit]

LRP1 has been shown to interact with:

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin_Pathway_WP430 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article
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  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". 

See also[edit]


References[edit]

  1. ^ Herz J, Hamann U, Rogne S, Myklebost O, Gausepohl H, Stanley KK (December 1988). "Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor". EMBO J. 7 (13): 4119–27. PMC 455121. PMID 3266596. 
  2. ^ Myklebost O, Arheden K, Rogne S, Geurts van Kessel A, Mandahl N, Herz J, Stanley K, Heim S, Mitelman F (July 1989). "The gene for the human putative apoE receptor is on chromosome 12 in the segment q13-14". Genomics 5 (1): 65–9. doi:10.1016/0888-7543(89)90087-6. PMID 2548950. 
  3. ^ Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, Bu G (2007). "Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1". Neuron 56 (1): 66–78. doi:10.1016/j.neuron.2007.08.008. PMC 2045076. PMID 17920016. 
  4. ^ Singh I, Sagare AP, Coma M, Perlmutter D, Gelein R, Bell RD, Deane RJ, Zhong E, Parisi M, Ciszewski J, Kasper RT, Deane R (September 2013). "Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance". Proc. Natl. Acad. Sci. U.S.A. 110 (36): 14771–6. doi:10.1073/pnas.1302212110. PMC 3767519. PMID 23959870. 
  5. ^ Gordts PL, Reekmans S, Lauwers A, Van Dongen A, Verbeek L, Roebroek AJ (September 2009). "Inactivation of the LRP1 intracellular NPxYxxL motif in LDLR-deficient mice enhances postprandial dyslipidemia and atherosclerosis". Arterioscler. Thromb. Vasc. Biol. 29 (9): 1258–64. doi:10.1161/ATVBAHA.109.192211. PMID 19667105. 
  6. ^ Rohlmann A, Gotthardt M, Hammer RE, Herz J (February 1998). "Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants". J. Clin. Invest. 101 (3): 689–95. doi:10.1172/JCI1240. PMC 508614. PMID 9449704. 
  7. ^ Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J (April 2003). "LRP: role in vascular wall integrity and protection from atherosclerosis". Science 300 (5617): 329–32. doi:10.1126/science.1082095. PMID 12690199. 
  8. ^ Boucher P, Li WP, Matz RL, Takayama Y, Auwerx J, Anderson RG, Herz J (2007). "LRP1 functions as an atheroprotective integrator of TGFbeta and PDFG signals in the vascular wall: implications for Marfan syndrome". PLoS ONE 2 (5): e448. doi:10.1371/journal.pone.0000448. PMC 1864997. PMID 17505534.  open access publication - free to read
  9. ^ Yancey PG, Ding Y, Fan D, Blakemore JL, Zhang Y, Ding L, Zhang J, Linton MF, Fazio S (July 2011). "Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6Chigh monocytosis: evidence that the effects are not apolipoprotein E dependent". Circulation 124 (4): 454–64. doi:10.1161/CIRCULATIONAHA.111.032268. PMC 3144781. PMID 21730304. 
  10. ^ Overton CD, Yancey PG, Major AS, Linton MF, Fazio S (March 2007). "Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse". Circ. Res. 100 (5): 670–7. doi:10.1161/01.RES.0000260204.40510.aa. PMID 17303763. 
  11. ^ Trommsdorff M, Borg JP, Margolis B, Herz J (1998). "Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein". J. Biol. Chem. 273 (50): 33556–60. doi:10.1074/jbc.273.50.33556. PMID 9837937. 
  12. ^ Poswa M (1977). "[Team growth by acquiring an apprentice]". Quintessenz J 7 (3): 21–3. PMID 277965. 
  13. ^ Kowal RC, Herz J, Goldstein JL, Esser V, Brown MS (1989). "Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins". Proc. Natl. Acad. Sci. U.S.A. 86 (15): 5810–4. Bibcode:1989PNAS...86.5810K. doi:10.1073/pnas.86.15.5810. PMC 297720. PMID 2762297. 
  14. ^ Orr AW, Pedraza CE, Pallero MA, Elzie CA, Goicoechea S, Strickland DK, Murphy-Ullrich JE (2003). "Low density lipoprotein receptor-related protein is a calreticulin coreceptor that signals focal adhesion disassembly". J. Cell Biol. 161 (6): 1179–89. doi:10.1083/jcb.200302069. PMC 2172996. PMID 12821648. 
  15. ^ a b c d e f g Gotthardt M, Trommsdorff M, Nevitt MF, Shelton J, Richardson JA, Stockinger W, Nimpf J, Herz J (2000). "Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction". J. Biol. Chem. 275 (33): 25616–24. doi:10.1074/jbc.M000955200. PMID 10827173. 
  16. ^ Williams SE, Inoue I, Tran H, Fry GL, Pladet MW, Iverius PH, Lalouel JM, Chappell DA, Strickland DK (1994). "The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP". J. Biol. Chem. 269 (12): 8653–8. PMID 7510694. 
  17. ^ Nykjaer A, Nielsen M, Lookene A, Meyer N, Røigaard H, Etzerodt M, Beisiegel U, Olivecrona G, Gliemann J (1994). "A carboxyl-terminal fragment of lipoprotein lipase binds to the low density lipoprotein receptor-related protein and inhibits lipase-mediated uptake of lipoprotein in cells". J. Biol. Chem. 269 (50): 31747–55. PMID 7989348. 
  18. ^ Chappell DA, Fry GL, Waknitz MA, Iverius PH, Williams SE, Strickland DK (1992). "The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor binds and mediates catabolism of bovine milk lipoprotein lipase". J. Biol. Chem. 267 (36): 25764–7. PMID 1281473. 
  19. ^ Zhuo M, Holtzman DM, Li Y, Osaka H, DeMaro J, Jacquin M, Bu G (2000). "Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation". J. Neurosci. 20 (2): 542–9. PMID 10632583. 
  20. ^ Orth K, Madison EL, Gething MJ, Sambrook JF, Herz J (1992). "Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor". Proc. Natl. Acad. Sci. U.S.A. 89 (16): 7422–6. doi:10.1073/pnas.89.16.7422. PMC 49722. PMID 1502153. 
  21. ^ Czekay RP, Kuemmel TA, Orlando RA, Farquhar MG (2001). "Direct binding of occupied urokinase receptor (uPAR) to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity". Mol. Biol. Cell 12 (5): 1467–79. doi:10.1091/mbc.12.5.1467. PMC 34598. PMID 11359936. 
  22. ^ Barnes H, Ackermann EJ, van der Geer P (2003). "v-Src induces Shc binding to tyrosine 63 in the cytoplasmic domain of the LDL receptor-related protein 1". Oncogene 22 (23): 3589–97. doi:10.1038/sj.onc.1206504. PMID 12789267. 
  23. ^ Loukinova E, Ranganathan S, Kuznetsov S, Gorlatova N, Migliorini MM, Loukinov D, Ulery PG, Mikhailenko I, Lawrence DA, Strickland DK (2002). "Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP). Evidence for integrated co-receptor function between LRP and the PDGF". J. Biol. Chem. 277 (18): 15499–506. doi:10.1074/jbc.M200427200. PMID 11854294. 
  24. ^ Wang S, Herndon ME, Ranganathan S, Godyna S, Lawler J, Argraves WS, Liau G (2004). "Internalization but not binding of thrombospondin-1 to low density lipoprotein receptor-related protein-1 requires heparan sulfate proteoglycans". J. Cell. Biochem. 91 (4): 766–76. doi:10.1002/jcb.10781. PMID 14991768. 
  25. ^ Mikhailenko I, Krylov D, Argraves KM, Roberts DD, Liau G, Strickland DK (1997). "Cellular internalization and degradation of thrombospondin-1 is mediated by the amino-terminal heparin binding domain (HBD). High affinity interaction of dimeric HBD with the low density lipoprotein receptor-related protein". J. Biol. Chem. 272 (10): 6784–91. doi:10.1074/jbc.272.10.6784. PMID 9045712. 
  26. ^ Godyna S, Liau G, Popa I, Stefansson S, Argraves WS (1995). "Identification of the low density lipoprotein receptor-related protein (LRP) as an endocytic receptor for thrombospondin-1". J. Cell Biol. 129 (5): 1403–10. doi:10.1083/jcb.129.5.1403. PMC 2120467. PMID 7775583. 

Further reading[edit]

  • Li Z, Dai J, Zheng H, Liu B, Caudill M (2002). "An integrated view of the roles and mechanisms of heat shock protein gp96-peptide complex in eliciting immune response". Front. Biosci. 7: d731–51. PMID 11861214. 
  • van der Geer P (2002). "Phosphorylation of LRP1: regulation of transport and signal transduction". Trends Cardiovasc. Med. 12 (4): 160–5. doi:10.1016/S1050-1738(02)00154-8. PMID 12069755. 
  • May P, Herz J (2004). "LDL receptor-related proteins in neurodevelopment". Traffic 4 (5): 291–301. doi:10.1034/j.1600-0854.2003.00086_4_5.x. PMID 12713657. 
  • Llorente-Cortés V, Badimon L (2005). "LDL receptor-related protein and the vascular wall: implications for atherothrombosis". Arterioscler. Thromb. Vasc. Biol. 25 (3): 497–504. doi:10.1161/01.ATV.0000154280.62072.fd. PMID 15705932. 
  • Huang SS, Huang JS (2005). "TGF-beta control of cell proliferation". J. Cell. Biochem. 96 (3): 447–62. doi:10.1002/jcb.20558. PMID 16088940. 
  • Lillis AP, Mikhailenko I, Strickland DK (2005). "Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability". J. Thromb. Haemost. 3 (8): 1884–93. doi:10.1111/j.1538-7836.2005.01371.x. PMID 16102056. 

External links[edit]