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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1573-1579. Prepublished online as a Blood First Edition Paper on October 23, 2003; DOI 10.1182/blood-2003-08-2852. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-08-2852v1 103/5/1573    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fyfe, J. C. Articles by Moestrup, S. K. Search for Related Content PubMed PubMed Citation Articles by Fyfe, J. C. Articles by Moestrup, S. K. Related Collections Hematopoiesis and Stem Cells Red Cells Plenary Papers Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLENARY PAPERS The functional cobalamin (vitamin B12)–intrinsic factor receptor is a novel complex of cubilin and amnionless John C. Fyfe, Mette Madsen, Peter Højrup, Erik I. Christensen, Stephan M. Tanner, Albert de la Chapelle, Qianchuan He, and Søren K. Moestrup From the Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing; Institute of Medical Biochemistry and the Department of Cell Biology, Institute of Anatomy, University of Aarhus, Denmark; Department of Biochemistry and Molecular Biology, Odense University, Denmark; and the Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus. Imerslund-Gräsbeck syndrome (I-GS, megaloblastic anemia 1) is an autosomal recessive disorder characterized by intestinal cobalamin (vitamin B12) malabsorption and proteinuria. I-GS–causing mutations are found in either of 2 genes encoding the epithelial proteins: cubilin and amnionless (AMN). Cubilin recognizes intrinsic factor (IF)–cobalamin and various other proteins to be endocytosed in the intestine and kidney, respectively, whereas the function of AMN is unknown. Here we show that cubilin and AMN colocalize in the endocytic apparatus of polarized epithelial cells and copurify as a tight complex during IF-cobalamin affinity and nondenaturing gel filtration chromatography. In transfected cells expressing either AMN or a truncated IF-cobalamin–binding cubilin construct, neither protein alone conferred ligand endocytosis. In cubilin transfectants, cubilin accumulated in early biosynthetic compartments. However, in cells cotransfected with AMN and the cubilin construct, cubilin trafficked to the cell surface and endosomes, and the cells exhibited IF-cobalamin endocytosis and lysosomal degradation of IF. These data indicate that cubilin and AMN are subunits of a novel cubilin/AMN (cubam) complex, where AMN binds to the amino-terminal third of cubilin and directs subcellular localization and endocytosis of cubilin with its ligand. Therefore, mutations affecting either of the 2 proteins may abrogate function of the cubam complex and cause IG-S. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: "Complex" receptor for vitamin B12-intrinsic factor David Rosenblatt Blood 2004 103: 1565. [Full Text] [PDF] This article has been cited by other articles: N. Dali-Youcef and E. Andres An update on cobalamin deficiency in adults QJM, January 1, 2009; 102(1): 17 - 28. [Abstract] [Full Text] [PDF] S. Dugue-Pujol, X. Rousset, D. 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[Abstract] [Full Text] [PDF] K. Faber, V. Hvidberg, S. K. Moestrup, B. Dahlback, and L. B. Nielsen Megalin Is a Receptor for Apolipoprotein M, and Kidney-Specific Megalin-Deficiency Confers Urinary Excretion of Apolipoprotein M Mol. Endocrinol., January 1, 2006; 20(1): 212 - 218. [Abstract] [Full Text] [PDF] M. Kaare, J. N. Painter, V.-M. Ulander, R. Kaaja, and K. Aittomaki Variations of the Amnionless gene in recurrent spontaneous abortions Mol. Hum. Reprod., January 1, 2006; 12(1): 25 - 29. [Abstract] [Full Text] [PDF] S. Komiya, M. Shimizu, J. Ikenouchi, S. Yonemura, T. Matsui, Y. Fukunaga, H. Liu, F. Endo, S. Tsukita, and A. Nagafuchi Apical membrane and junctional complex formation during simple epithelial cell differentiation of F9 cells Genes Cells, November 1, 2005; 10(11): 1065 - 1080. [Abstract] [Full Text] [PDF] D. S. Rosenblatt "Cubam" goes to the dogs Blood, August 15, 2005; 106(4): 1146 - 1146. [Full Text] [PDF] Q. He, M. Madsen, A. Kilkenney, B. Gregory, E. I. Christensen, H. Vorum, P. Hojrup, A. A. Schaffer, E. F. Kirkness, S. M. Tanner, et al. Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo Blood, August 15, 2005; 106(4): 1447 - 1453. [Abstract] [Full Text] [PDF] G. Coudroy, J. Gburek, R. Kozyraki, M. Madsen, G. Trugnan, S. K. Moestrup, P. J. Verroust, and M. Maurice Contribution of Cubilin and Amnionless to Processing and Membrane Targeting of Cubilin-Amnionless Complex J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2330 - 2337. [Abstract] [Full Text] [PDF] E. Assemat, S. Vinot, F. Gofflot, P. Linsel-Nitschke, F. Illien, F. Chatelet, P. Verroust, S. Louvet-Vallee, F. Rinninger, and R. Kozyraki Expression and Role of Cubilin in the Internalization of Nutrients During the Peri-Implantation Development of the Rodent Embryo Biol Reprod, May 1, 2005; 72(5): 1079 - 1086. [Abstract] [Full Text] [PDF] S. M. Tanner, Z. Li, J. D. Perko, C. Oner, M. Cetin, C. 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