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Originally published In Press as doi:10.1074/jbc.M010679200 on January 22, 2001

J. Biol. Chem., Vol. 276, Issue 16, 13295-13301, April 20, 2001
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A Two-receptor Pathway for Catabolism of Clara Cell Secretory Protein in the Kidney*

Regina BurmeisterDagger §, Inger-Margrethe Bøe§, Anders Nykjaer||, Christian Jacobsen||, Soeren K. Moestrup||, Pierre Verroust**, Erik I. ChristensenDagger Dagger , Johan Lund§§, and Thomas E. WillnowDagger ¶¶

From the Dagger  Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany,  Department of Anatomy and Cell Biology, University of Bergen, 5009 Bergen, Norway, Departments of || Medical Biochemistry and Dagger Dagger  Cell Biology, University of Aarhus, 8000 Aarhus, Denmark, ** Institut National de la Santé et de la Recherche Médicale, Unité 538, 75012 Paris, France, and §§ Department of Molecular Science, AstraZeneca, 22187 Lund, Sweden

Clara cell secretory protein (CCSP) is a transport protein for lipophilic substances in bronchio-alveolar fluid, plasma, and uterine secretion. It acts as a carrier for steroid hormones and polychlorinated biphenyl metabolites. Previously, the existence of receptors for uptake of CCSP·ligand complexes into the renal proximal tubules had been suggested. Using surface plasmon resonance analysis, we demonstrate that CCSP binds to cubilin, a peripheral membrane protein on the surface of proximal tubular cells. Binding to cubilin results in uptake and lysosomal degradation of CCSP in cultured cells. Surprisingly, internalization of CCSP is blocked not only by cubilin antagonists but also by antibodies directed against megalin, an endocytic receptor that does not bind CCSP but associates with cubilin. Consistent with a role of both receptors in renal uptake of CCSP in vivo, patients deficient for cubilin or mice lacking megalin exhibit a defect in tubular uptake of the protein and excrete CCSP into the urine. These findings identify a cellular pathway consisting of a CCSP-binding protein (cubilin) and an endocytic coreceptor (megalin) responsible for tissue-specific uptake of CCSP and associated ligands.

* The studies were funded by grants from the Deutsche Forschungsgemeinschaft, the Verbund Klinische Pharmakologie, Berlin-Brandenburg, the Norwegian Research Council, the Norwegian Cancer Society, and the Danish Medical Research Council. T. E. W. is a Heisenberg fellow of the Deutsche Forschungsgemeinschaft.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Contributed equally to this study.

¶¶ To whom correspondence should be addressed: Max-Delbrueck-Center, R.-Roessle-Strasse 10, D-13125 Berlin, Germany. Tel.: 49-30-9406-2569; Fax: 49-30-9406-2110; E-mail: willnow@mdc-berlin.de.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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