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Gene Review

Lrp2  -  low density lipoprotein receptor-related...

Rattus norvegicus

Synonyms: Glycoprotein 330, LRP-2, Low-density lipoprotein receptor-related protein 2, Megalin, gp330
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Disease relevance of Lrp2

  • Conformation and glycosylation of a megalin fragment correlate with nephritogenicity in Heymann nephritis [1].
  • Rats immunized with the soluble, secreted protein encoded by a baculovirus construct elicited high titer anti-megalin autoantibodies and developed glomerular immune deposits and elevated proteinuria consistent with AHN [1].
  • Recombinant proteins containing a 563-residue N-terminal sequence of megalin were obtained from Escherichia coli and baculovirus-insect cell expression systems [1].
  • Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis [2].
  • The nephritogenic antigen of Heymann's nephritis (HN), gp330, was previously demonstrated (4-9) to be a resident glycoprotein of coated pits in the glomerular and proximal tubule epithelium of rats, and anti-gp330 IgG given intravenously was found to form IDs in glomeruli (passive HN) [3].

High impact information on Lrp2

  • We hypothesized that rats immunized with anti-Fx1A develop autoantibodies (auto-Abs) to Crry as well as to the megalin-containing HN antigenic complex, and that anti-Crry Abs promote the development of injury in HN by neutralizing the complement regulatory activity of Crry [4].
  • In pHN, the formation of subepithelial immune deposits (ID) involves as antigenic targets the membrane glycoprotein gp330/megalin and the 44-kD receptor-associated protein (RAP) [5].
  • Initial events in the formation of immune deposits in passive Heymann nephritis. gp330-anti-gp330 immune complexes form in epithelial coated pits and rapidly become attached to the glomerular basement membrane [3].
  • When the IgG bound to glomeruli was eluted with acid citrate buffer 3 d after injection, it was found to specifically immunoprecipitate only gp330 from detergent-solubilized 125I-labeled kidney microvillar vesicles [3].
  • The present study shows that the antifibrinolytic polypeptide, aprotinin, and the nephro- and ototoxic antibiotics, aminoglycosides, and polymyxin B compete for binding of 125I-urokinase-plasminogen activator inhibitor type-1 complexes to purified rabbit gp330 [6].

Chemical compound and disease context of Lrp2


Biological context of Lrp2


Anatomical context of Lrp2


Associations of Lrp2 with chemical compounds


Physical interactions of Lrp2


Enzymatic interactions of Lrp2

  • These results indicate that autoantibody obtained from the immune deposits in the glomeruli of rats with active Heymann nephritis does not inhibit the binding of plasminogen to gp330 but does significantly alter the urokinase catalyzed activation of plasminogen to plasmin [23].

Regulatory relationships of Lrp2

  • Furthermore, the 210-kDa Tg polypeptide inhibited megalin binding to intact Tg by approximately 70% [11].
  • Megalin expressed in the lower intestine appears not to have a significant role in the absorption of lysozyme [24].

Other interactions of Lrp2

  • Third, megalin and fluorescently labeled MT colocalize in BN-16 cells, as shown by fluorescent microscopic techniques [15].
  • These inhibitory effects and those of a monoclonal antimegalin antibody were not additive, indicating that calmodulin acts on the megalin-mediated pathway [25].
  • Previous studies have identified two high-molecular weight (280 and 330 kd) glycoproteins expressed by coated pits of the proximal renal tubule and yolk sac and have further established that, in vivo, antibodies to gp280 but not to gp330 induce fetal malformations [12].
  • Using nephrectomized rats, we examined changes in mRNA levels of CYP27B1 (25-hydroxyvitamin D3-1 alpha-hydroxylase), CYP24 (25-hydroxyvitamin D3-24-hydroxylase), and vitamin D receptor in relation to megalin, recently found to participate in renal vitamin D metabolism [13].
  • In the thyroid, megalin (a low-density lipoprotein receptor family member) serves as an endocytic receptor for thyroglobulin [26].

Analytical, diagnostic and therapeutic context of Lrp2

  • All three recombinant proteins were reactive in Western blots with rabbit anti-megalin antiserum, whereas the insect cell-derived proteins reacted preferentially in Western blot and ELISA with anti-megalin autoantibodies from rats with AHN induced by native megalin [1].
  • Furthermore, megalin affinity chromatography and surface plasmon resonance analysis revealed a calcium-dependent high affinity binding of the 460-kDa receptor to megalin, which thereby may mediate its vesicular trafficking [27].
  • We developed an assay, based on flow cytometry, to measure binding of serum IgGs to L2 cells, a rat carcinoma cell line that expresses abundant megalin [2].
  • To identify megalin's apical sorting signal, we generated deletion mutants and chimeric minireceptors composed of complementary regions of megalin and LDL receptor-related protein (LRP) and assessed the distribution of the mutants in Madin-Darby canine kidney (MDCK) cells by immunofluorescence and cell surface biotinylation [28].
  • Cubilin and megalin expression and their interaction in the rat intestine: effect of thyroidectomy [17].


  1. Conformation and glycosylation of a megalin fragment correlate with nephritogenicity in Heymann nephritis. Tramontano, A., Makker, S.P. J. Immunol. (2004) [Pubmed]
  2. Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis. Marinò, M., Chiovato, L., Friedlander, J.A., Latrofa, F., Pinchera, A., McCluskey, R.T. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  3. Initial events in the formation of immune deposits in passive Heymann nephritis. gp330-anti-gp330 immune complexes form in epithelial coated pits and rapidly become attached to the glomerular basement membrane. Kerjaschki, D., Miettinen, A., Farquhar, M.G. J. Exp. Med. (1987) [Pubmed]
  4. Inhibition of complement regulation is key to the pathogenesis of active Heymann nephritis. Schiller, B., He, C., Salant, D.J., Lim, A., Alexander, J.J., Quigg, R.J. J. Exp. Med. (1998) [Pubmed]
  5. Induction of passive Heymann nephritis with antibodies specific for a synthetic peptide derived from the receptor-associated protein. Kerjaschki, D., Ullrich, R., Exner, M., Orlando, R.A., Farquhar, M.G. J. Exp. Med. (1996) [Pubmed]
  6. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. Moestrup, S.K., Cui, S., Vorum, H., Bregengård, C., Bjørn, S.E., Norris, K., Gliemann, J., Christensen, E.I. J. Clin. Invest. (1995) [Pubmed]
  7. Studies with monoclonal antibodies against brush border antigens in Heymann nephritis. Bhan, A.K., Schneeberger, E.E., Baird, L.G., Collins, A.B., Kamata, K., Bradford, D., Erikson, M.E., McCluskey, R.T. Lab. Invest. (1985) [Pubmed]
  8. Passive Heymann nephritis with acute and severe proteinuria induced by heterologous antibody against renal tubular brush border glycoprotein gp108. Natori, Y., Hayakawa, I., Shibata, S. Lab. Invest. (1986) [Pubmed]
  9. Treatment with mycophenolate mofetil attenuates the development of Heymann nephritis. Luca, M.E., Paul, L.C., van Der Wal, A.M., Bruijn, J.A., de Heer, E. Exp. Nephrol. (2000) [Pubmed]
  10. Megalin (gp330) is an endocytic receptor for thyroglobulin on cultured fisher rat thyroid cells. Marinò, M., Zheng, G., McCluskey, R.T. J. Biol. Chem. (1999) [Pubmed]
  11. Identification of a heparin-binding region of rat thyroglobulin involved in megalin binding. Marinò, M., Friedlander, J.A., McCluskey, R.T., Andrews, D. J. Biol. Chem. (1999) [Pubmed]
  12. Antibodies to the 280-kd coated pit protein, target of teratogenic antibodies, produce alterations in the traffic of internalized proteins. Le Panse, S., Ayani, E., Mulliez, N., Chatelet, F., Cywiner-Golenzer, C., Galceran, M., Citadelle, D., Roux, C., Ronco, P., Verroust, P. Am. J. Pathol. (1994) [Pubmed]
  13. Gene expression of vitamin D hydroxylase and megalin in the remnant kidney of nephrectomized rats. Takemoto, F., Shinki, T., Yokoyama, K., Inokami, T., Hara, S., Yamada, A., Kurokawa, K., Uchida, S. Kidney Int. (2003) [Pubmed]
  14. Role of megalin (gp330) in transcytosis of thyroglobulin by thyroid cells. A novel function in the control of thyroid hormone release. Marinò, M., Zheng, G., Chiovato, L., Pinchera, A., Brown, D., Andrews, D., McCluskey, R.T. J. Biol. Chem. (2000) [Pubmed]
  15. Megalin mediates renal uptake of heavy metal metallothionein complexes. Klassen, R.B., Crenshaw, K., Kozyraki, R., Verroust, P.J., Tio, L., Atrian, S., Allen, P.L., Hammond, T.G. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  16. Megalin (gp330): a putative endocytic receptor for thyroglobulin (Tg). Zheng, G., Marino', M., Zhao, J., McCluskey, R.T. Endocrinology (1998) [Pubmed]
  17. Cubilin and megalin expression and their interaction in the rat intestine: effect of thyroidectomy. Yammani, R.R., Seetharam, S., Seetharam, B. Am. J. Physiol. Endocrinol. Metab. (2001) [Pubmed]
  18. Phosphoinositide 3-kinase inhibits megalin-mediated transcytosis of thyroglobulin across thyroid epithelial cells at a post-sorting level. Marinò, M., Chiovato, L., Lisi, S., Pinchera, A., McCluskey, R.T. Eur. J. Endocrinol. (2001) [Pubmed]
  19. Functional characterization of rat gp600/megalin promoter: combination of proximal Sp1 site and JCV repeat is important in rat gp600/megalin promoter activation. Zhao, J., Oleinikov, A.V., Oleinikova, I., Makker, S.P. Gene (2001) [Pubmed]
  20. Identification of the rat Heymann nephritis autoantigen (GP330) as a receptor site for plasminogen. Kanalas, J.J., Makker, S.P. J. Biol. Chem. (1991) [Pubmed]
  21. Evidence indicating that renal tubular metabolism of leptin is mediated by megalin but not by the leptin receptors. Hama, H., Saito, A., Takeda, T., Tanuma, A., Xie, Y., Sato, K., Kazama, J.J., Gejyo, F. Endocrinology (2004) [Pubmed]
  22. Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules. Oyama, Y., Takeda, T., Hama, H., Tanuma, A., Iino, N., Sato, K., Kaseda, R., Ma, M., Yamamoto, T., Fujii, H., Kazama, J.J., Odani, S., Terada, Y., Mizuta, K., Gejyo, F., Saito, A. Lab. Invest. (2005) [Pubmed]
  23. Effect of the nephritogenic autoantibody of Heymann's nephritis on plasminogen-binding to gp330 and activation by urokinase. Kanalas, J.J. Biochim. Biophys. Acta (1993) [Pubmed]
  24. Segment-selective absorption of lysozyme in the intestine. Takano, M., Koyama, Y., Nishikawa, H., Murakami, T., Yumoto, R. Eur. J. Pharmacol. (2004) [Pubmed]
  25. Megalin-mediated transcytosis of thyroglobulin by thyroid cells is a calmodulin-dependent process. Marinò, M., McCluskey, R.T. Thyroid (2000) [Pubmed]
  26. Binding of the low density lipoprotein receptor-associated protein (RAP) to thyroglobulin (Tg): putative role of RAP in the Tg secretory pathway. Marinò, M., Chiovato, L., Lisi, S., Pinchera, A., McCluskey, R.T. Mol. Endocrinol. (2001) [Pubmed]
  27. The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins. Moestrup, S.K., Kozyraki, R., Kristiansen, M., Kaysen, J.H., Rasmussen, H.H., Brault, D., Pontillon, F., Goda, F.O., Christensen, E.I., Hammond, T.G., Verroust, P.J. J. Biol. Chem. (1998) [Pubmed]
  28. Identification of an apical sorting determinant in the cytoplasmic tail of megalin. Takeda, T., Yamazaki, H., Farquhar, M.G. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
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