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Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia

Official URL:https://doi.org/10.1073/pnas.211291398
PubMed:View item in PubMed
Creators Name:Kozyraki, R. and Fyfe, J. and Verroust, P.J. and Jacobsen, C. and Dautry-Varsat, A. and Gburek, J. and Willnow, T.E. and Christensen, E.I. and Moestrup, S.K.
Journal Title:Proceedings of the National Academy of Sciences of the United States of America
Journal Abbreviation:Proc Natl Acad Sci U S A
Volume:98
Number:22
Page Range:12491-12496
Date:1 January 2001
Keywords:Cell Polarity, Cell Surface Receptors, Endocytosis, Epithelium, Inbred BN Rats, Kidney, LDL-Receptor Related Protein 2, Transferrin, Yolk Sac, Animals, Dogs, Mice, Rats
Abstract:Cubilin is a 460-kDa protein functioning as an endocytic receptor for intrinsic factor vitamin B12 complex in the intestine and as a receptor for apolipoprotein A1 and albumin reabsorption in the kidney proximal tubules and the yolk sac. In the present study, we report the identification of cubilin as a novel transferrin (Tf) receptor involved in catabolism of Tf. Consistent with a cubilinmediated endocytosis of Tf in the kidney, lysosomes of human, dog, and mouse renal proximal tubules strongly accumulate Tf, whereas no Tf is detectable in the endocytic apparatus of the renal tubule epithelium of dogs with deficient surface expression of cubilin. As a consequence, these dogs excrete increased amounts of Tf in the urine. Mice with deficient synthesis of megalin, the putative coreceptor colocalizing with cubilin, also excrete high amounts of Tf and fail to internalize Tf in their proximal tubules. However, in contrast to the dogs with the defective cubilin expression, the megalin-deficient mice accumulate Tf on the luminal cubilin-expressing surface of the proximal tubule epithelium. This observation indicates that megalin deficiency causes failure in internalization of the cubilin-ligand complex. The megalin-dependent, cubilin-mediated endocytosis of Tf and the potential of the receptors thereby to facilitate iron uptake were further confirmed by analyzing the uptake of 125I- and 59Fe-labeled Tf in cultured yolk sac cells.
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Item Type:Article

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