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Gene Review

CUBN  -  cubilin (intrinsic factor-cobalamin receptor)

Homo sapiens

Synonyms: 460 kDa receptor, Cubilin, IFCR, Intestinal intrinsic factor receptor, Intrinsic factor-cobalamin receptor, ...
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Disease relevance of CUBN


High impact information on CUBN


Biological context of CUBN


Anatomical context of CUBN


Associations of CUBN with chemical compounds

  • Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3) [18].
  • In this study, we analyzed the expression of cubilin in the pre- and early post-implantation rodent embryo and tested its potential function in protein and cholesterol uptake [19].
  • These studies indicate that thyroxine deficiency in rats results in decreased uptake and tissue accumulation of cbl caused mainly by destabilization and deficit of cubilin in the intestinal brush border [20].
  • Endocytosis of the intrinsic factor-cobalamin-receptor complex was inhibited by two ways: at 4 degrees C and at 37 degrees C by incubating the cells with vinblastine, monensin and chloroquine [21].
  • Incubation of cells with tunicamycin decreased the half-life of IFCR from 48 to 24 h, thus causing faster degradation and depletion of the surface receptor [22].

Physical interactions of CUBN

  • In transfected cells expressing either AMN or a truncated IF-cobalamin-binding cubilin construct, neither protein alone conferred ligand endocytosis [15].
  • Using surface plasmon resonance analysis, we demonstrate that CCSP binds to cubilin, a peripheral membrane protein on the surface of proximal tubular cells [17].
  • A receptor has been found in proximal tubular cells (cubilin/megalin complex), which mediates the absorption of LCs and is involved in the pathogenesis of tubulopathies that occurs in these patients [23].
  • IF-mediated import of Cbl is limited to the apical membranes of epithelial cells; it occurs via a multipurpose receptor recently termed "cubilin," and the imported Cbl is usually exported out of these cells bound to endogenous TC II [24].

Regulatory relationships of CUBN

  • 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 [25].

Other interactions of CUBN

  • This observation indicates that megalin deficiency causes failure in internalization of the cubilin-ligand complex [11].
  • In a series of families clinically diagnosed with likely IGS, at least six displayed no evidence of mutations in CUBN or AMN [26].
  • More specific receptors like the folate receptor, IGF-II/Man-6-P receptor, and gp280/IFR, identical to the intrinsic factor receptor, are also functioning in the apical endocytic pathway of renal proximal tubules [27].
  • In this study we used a well established cell culture model (proximal-tubule-derived opossum kidney (OK) cells) in order to test the hypothesis that TGF-beta1 reduces megalin-cubilin-mediated endocytosis [14].
  • It could occur either by receptor-mediated endocytosis via a somatostatin receptor or, alternatively, the multiligand megalin/cubilin tandem receptor, or by fluid-phase endocytosis [28].

Analytical, diagnostic and therapeutic context of CUBN


  1. Imerslund-Gräsbeck syndrome (selective vitamin B12 malabsorption with proteinuria). Gräsbeck, R. Orphanet journal of rare diseases [electronic resource]. (2006) [Pubmed]
  2. Recent insights into the molecular genetics of the homocysteine metabolism. Födinger, M., Wagner, O.F., Hörl, W.H., Sunder-Plassmann, G. Kidney Int. Suppl. (2001) [Pubmed]
  3. Megalin-mediated endocytosis of vitamin d binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. Rowling, M.J., Kemmis, C.M., Taffany, D.A., Welsh, J. J. Nutr. (2006) [Pubmed]
  4. Myeloma light chains are ligands for cubilin (gp280). Batuman, V., Verroust, P.J., Navar, G.L., Kaysen, J.H., Goda, F.O., Campbell, W.C., Simon, E., Pontillon, F., Lyles, M., Bruno, J., Hammond, T.G. Am. J. Physiol. (1998) [Pubmed]
  5. Expression of cobalamin transport proteins and cobalamin transcytosis by colon adenocarcinoma cells. Ramanujam, K.S., Seetharam, S., Ramasamy, M., Seetharam, B. Am. J. Physiol. (1991) [Pubmed]
  6. Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Aminoff, M., Carter, J.E., Chadwick, R.B., Johnson, C., Gräsbeck, R., Abdelaal, M.A., Broch, H., Jenner, L.B., Verroust, P.J., Moestrup, S.K., de la Chapelle, A., Krahe, R. Nat. Genet. (1999) [Pubmed]
  7. The intrinsic factor-vitamin B12 receptor, cubilin, is a high-affinity apolipoprotein A-I receptor facilitating endocytosis of high-density lipoprotein. Kozyraki, R., Fyfe, J., Kristiansen, M., Gerdes, C., Jacobsen, C., Cui, S., Christensen, E.I., Aminoff, M., de la Chapelle, A., Krahe, R., Verroust, P.J., Moestrup, S.K. Nat. Med. (1999) [Pubmed]
  8. Megalin and cubilin: multifunctional endocytic receptors. Christensen, E.I., Birn, H. Nat. Rev. Mol. Cell Biol. (2002) [Pubmed]
  9. Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. Birn, H., Fyfe, J.C., Jacobsen, C., Mounier, F., Verroust, P.J., Orskov, H., Willnow, T.E., Moestrup, S.K., Christensen, E.I. J. Clin. Invest. (2000) [Pubmed]
  10. Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East. Tanner, S.M., Li, Z., Bisson, R., Acar, C., Oner, C., Oner, R., Cetin, M., Abdelaal, M.A., Ismail, E.A., Lissens, W., Krahe, R., Broch, H., Gräsbeck, R., de la Chapelle, A. Hum. Mutat. (2004) [Pubmed]
  11. Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Kozyraki, R., Fyfe, J., Verroust, P.J., Jacobsen, C., Dautry-Varsat, A., Gburek, J., Willnow, T.E., Christensen, E.I., Moestrup, S.K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  12. Evidence for auto/paracrine actions of vitamin D in bone: 1alpha-hydroxylase expression and activity in human bone cells. van Driel, M., Koedam, M., Buurman, C.J., Hewison, M., Chiba, H., Uitterlinden, A.G., Pols, H.A., van Leeuwen, J.P. FASEB J. (2006) [Pubmed]
  13. Genetic evidence of an accessory activity required specifically for cubilin brush-border expression and intrinsic factor-cobalamin absorption. Xu, D., Kozyraki, R., Newman, T.C., Fyfe, J.C. Blood (1999) [Pubmed]
  14. Transforming growth factor-beta1 reduces megalin- and cubilin-mediated endocytosis of albumin in proximal-tubule-derived opossum kidney cells. Gekle, M., Knaus, P., Nielsen, R., Mildenberger, S., Freudinger, R., Wohlfarth, V., Sauvant, C., Christensen, E.I. J. Physiol. (Lond.) (2003) [Pubmed]
  15. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Fyfe, J.C., Madsen, M., Højrup, P., Christensen, E.I., Tanner, S.M., de la Chapelle, A., He, Q., Moestrup, S.K. Blood (2004) [Pubmed]
  16. Mouse amnionless, which is required for primitive streak assembly, mediates cell-surface localization and endocytic function of cubilin on visceral endoderm and kidney proximal tubules. Strope, S., Rivi, R., Metzger, T., Manova, K., Lacy, E. Development (2004) [Pubmed]
  17. A two-receptor pathway for catabolism of Clara cell secretory protein in the kidney. Burmeister, R., Boe, I.M., Nykjaer, A., Jacobsen, C., Moestrup, S.K., Verroust, P., Christensen, E.I., Lund, J., Willnow, T.E. J. Biol. Chem. (2001) [Pubmed]
  18. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Nykjaer, A., Fyfe, J.C., Kozyraki, R., Leheste, J.R., Jacobsen, C., Nielsen, M.S., Verroust, P.J., Aminoff, M., de la Chapelle, A., Moestrup, S.K., Ray, R., Gliemann, J., Willnow, T.E., Christensen, E.I. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  19. Expression and role of cubilin in the internalization of nutrients during the peri-implantation development of the rodent embryo. Assémat, E., Vinot, S., Gofflot, F., Linsel-Nitschke, P., Illien, F., Châtelet, F., Verroust, P., Louvet-Vallée, S., Rinninger, F., Kozyraki, R. Biol. Reprod. (2005) [Pubmed]
  20. 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]
  21. Receptor-mediated endocytosis of the intrinsic factor-cobalamin complex in HT 29, a human colon carcinoma cell line. Guéant, J.L., Masson, C., Schohn, H., Girr, M., Saunier, M., Nicolas, J.P. FEBS Lett. (1992) [Pubmed]
  22. Effect of processing inhibitors on cobalamin (vitamin B12) transcytosis in polarized opossum kidney cells. Ramanujam, K.S., Seetharam, S., Dahms, N.M., Seetharam, B. Arch. Biochem. Biophys. (1994) [Pubmed]
  23. Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns. Teng, J., Russell, W.J., Gu, X., Cardelli, J., Jones, M.L., Herrera, G.A. Lab. Invest. (2004) [Pubmed]
  24. Cellular import of cobalamin (Vitamin B-12). Seetharam, B., Bose, S., Li, N. J. Nutr. (1999) [Pubmed]
  25. Cubilin, a multifunctional epithelial receptor: an overview. Kozyraki, R. J. Mol. Med. (2001) [Pubmed]
  26. Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Tanner, S.M., Li, Z., Perko, J.D., Oner, C., Cetin, M., Altay, C., Yurtsever, Z., David, K.L., Faivre, L., Ismail, E.A., Gräsbeck, R., de la Chapelle, A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  27. Membrane receptors for endocytosis in the renal proximal tubule. Christensen, E.I., Birn, H., Verroust, P., Moestrup, S.K. Int. Rev. Cytol. (1998) [Pubmed]
  28. Endocytosis of the somatostatin analogue, octreotide, by the proximal tubule-derived opossum kidney (OK) cell line. Barone, R., Van Der Smissen, P., Devuyst, O., Beaujean, V., Pauwels, S., Courtoy, P.J., Jamar, F. Kidney Int. (2005) [Pubmed]
  29. The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region. Kozyraki, R., Kristiansen, M., Silahtaroglu, A., Hansen, C., Jacobsen, C., Tommerup, N., Verroust, P.J., Moestrup, S.K. Blood (1998) [Pubmed]
  30. Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin. Kristiansen, M., Aminoff, M., Jacobsen, C., de La Chapelle, A., Krahe, R., Verroust, P.J., Moestrup, S.K. Blood (2000) [Pubmed]
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