Disease relevance of LRP2

• Of interest, this epitope is homologous to a stretch of amino acids in the protein sequence of low-density lipoprotein receptor-related protein 2 (LRP2), which is a receptor for multiple ligands including beta-very low density lipoprotein and is also an autoantigen responsible for Heymann nephritis in rats [1].
• Autoantibodies to low-density-lipoprotein-receptor-related protein 2 (LRP2) in systemic autoimmune diseases [2].
• The autoAbs to LRP2 were detected in 87% of the patients with rheumatoid arthritis, 40% of those with systemic lupus erythematosus, 35% of those with systemic sclerosis, 15% of those with osteoarthritis, and 3% of those with Behçet's disease [2].
• Using fluorescent microscopy and temperature-shift techniques, we found that T-47D breast cancer cells rapidly internalize DBP via endocytosis, which is blunted by receptor-associated protein, a specific inhibitor of megalin-mediated endocytosis [3].
• Knockout mice lacking the endocytic receptor megalin lose 25(OH) vitamin D(3) in the urine and develop bone disease [4].

High impact information on LRP2

• Megalin and cubilin: multifunctional endocytic receptors [5].
• Apo B-100 of LDL can bind to both the LDL receptor and megalin, but the molecular interactions of apo B-100 with these 2 receptors are not completely understood [6].
• This study suggests that the putative LDL receptor-binding site A on apo B-100 might not by itself be a functional binding domain and that the apo B-binding sites recognized by the LDL receptor and by megalin may be different [6].
• The ability of megalin to mediate cellular endocytosis of Lp B-70.5 was confirmed using retinoic acid/dibutyryl cAMP-treated F9 cells [6].
• 5. On ligand blotting of renal cortical membranes, Lp B-70.5 bound only to megalin [6].

Chemical compound and disease context of LRP2

• Comparative sequence analysis revealed that alpha 2M receptor-associated protein has 73% identity with a rat protein reported to be a pathogenic domain of Heymann nephritis antigen gp 330 and 77% identity to a mouse heparin-binding protein termed HBP-44 [7].

Biological context of LRP2

• The anti-CD69 autoantibody cross-reacted to LRP2 through the homologous amino acid sequence [1].
• The autoAbs to LRP2 are probably produced by the antigen-driven mechanism and the autoimmunity to LRP2 may spread to include CD69 [2].
• Megalin-mediated endocytosis of transcobalamin-vitamin-B12 complexes suggests a role of the receptor in vitamin-B12 homeostasis [8].
• The TC-B12 binding sites in the proximal tubule epithelium colocalized with megalin as shown by ligand binding to cryosections of rat kidney cortex, and the binding was inhibited by anti-megalin polyclonal antibody, EDTA, and RAP [8].
• Megalin-mediated endocytosis of vitamin d binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells [3].

Anatomical context of LRP2

• Ligand blotting of rabbit kidney cortex with rabbit 125I-TC-B12 and human TC-57Co-B12 revealed an exclusive binding to megalin, a 600-kDa endocytic receptor present in renal proximal tubule epithelium and other absorptive epithelia [8].
• 125I-TC-B12 was efficiently endocytosed in a RAP-inhibitable manner in megalin-expressing rat yolk sac carcinoma cells and in vivo microperfused rat proximal tubules [8].
• Megalin is the major receptor in absorptive epithelial cells of the proximal tubules and an antigenic determinant for Heymann nephritis in rats [9].
• Several cultured cell lines that express gp330 and ones that do not express the receptor were examined for their ability to bind and internalize 125I-apoJ [10].
• To identify ligands specific for gp330 and relevant to its localization on epithelia such as in the mammary gland, gp330-Sepharose affinity chromatography was performed [10].

Associations of LRP2 with chemical compounds

• Furthermore, F9 cells treated with retinoic acid and dibutyryl cyclic AMP to increase expression levels of gp330 displayed an increased capacity to internalize and degrade apoJ [10].
• Binding to alpha 2MR and gp330 is a novel kind of molecular recognition of serine proteinases and serpins [11].
• A significant increase in functional affinity for purified megalin was observed when beta2-glycoprotein-I was bound to the acidic phospholipids, phosphatidylserine and cardiolipin [12].
• In 1982, gp330 (now called megalin), a glycoprotein located in clathrin-coated pits of glomerular and proximal tubular epithelia, was identified as a target antigen [13].
• A mutant version of megalin that lacks the terminal valine is unable to bind to GASP, illustrating the PDZ domain-dependent interaction between these two proteins [14].

Physical interactions of LRP2

• In this report, we tested several other LRP ligands for their ability to interact with human and rat gp330 in vitro [15].
• However, we found that gp330 (purified from human or rat) bound the lipolytic enzyme lipoprotein lipase (LPL) with high affinity (Kd = 6.1 and 2.7 nM, respectively) [15].
• The binding of beta2-glycoprotein-I and beta2-glycoprotein-I- phospholipid complexes to megalin was completely blocked by receptor-associated protein [12].
• Circulating thyroglobulin transcytosed by thyroid cells in complexed with secretory components of its endocytic receptor megalin [16].
• Taken together, these findings indicate that a significant pool of NHE3 exists as a multimeric complex with megalin in the brush border of the proximal tubule [17].

Regulatory relationships of LRP2

• Consistent with this possibility, we found that LPL promoted in vitro binding of 125I-lipoproteins to gp330 [15].
• Cubilin is a 460-kDa endocytic receptor coexpressed with megalin, a multiligand receptor of the low-density lipoprotein receptor gene family, at the apical pole of epithelial cells in the renal proximal convoluted tubule, visceral yolk sac, ileum, and placenta [18].
• Furthermore, a rat yolk sac cell line known to express high levels of megalin, endocytosed NGAL by a mechanism completely blocked by an antibody against megalin [19].
• Cubilin and megalin in radiation-induced renal injury with labelled somatostatin analogues: are we just dealing with the kidney [20]?

Other interactions of LRP2

• We recently demonstrated that gp330 and LRP may be functionally related as well; both bind the 39-kDa polypeptide referred to as receptor-associated protein (Kounnas, M. Z., Argraves, W. S., and Strickland, D. K. (1992) J. Biol. Chem. 267, 21162-21166) [15].
• Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin [10].
• The findings support the possibility that LRP-2 can act in vivo to mediate clearance of the complex from biological fluids such as cerebrospinal fluid and thereby play a role in the regulation of Abeta accumulation [21].
• This autoantibody may modulate the function of CD69- and LRP2-expressing cells [1].
• These findings indicate that gp330, like other LDLR family members, mediates endocytosis of its ligands [22].

Analytical, diagnostic and therapeutic context of LRP2

• Enzyme-linked immunosorbent assay was also used to study the interaction of the Abeta1-40-apoJ complex with LRP-2 [21].
• Using gp330 cDNA and previously isolated human RAP cDNA probes, we performed fluorescence in situ hybridization to map the human chromosomal location of the genes for these proteins [23].
• Screening of serum by using a surface plasmon resonance analysis assay identified beta2-glycoprotein-I/apolipoprotein H as a plasma component binding to the renal epithelial endocytic receptor megalin [12].
• Expression of megalin was detected by reverse transcriptase-polymerase chain reaction and visualized by immunofluorescence both at the cell surface (live staining) and intracellularly (permeabilized cells) [24].
• Immunoblotting positively demonstrated expression of LDL receptor-related protein, but not glycoprotein 330 [25].

References