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Originally published In Press as doi:10.1074/jbc.M203461200 on August 5, 2002

J. Biol. Chem., Vol. 277, Issue 41, 38494-38502, October 11, 2002
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Shedding of the Transferrin Receptor Is Mediated Constitutively by an Integral Membrane Metalloprotease Sensitive to Tumor Necrosis Factor alpha  Protease Inhibitor-2*

Matthias KaupDagger , Katrin DasslerDagger , Christoph Weise§, and Hendrik FuchsDagger

From the Dagger  Institut für Klinische Chemie und Pathobiochemie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin and the § Institut für Chemie-Biochemie, Freie Universität Berlin, Thielallee 63, D-14195 Berlin, Germany

The transferrin receptor (TfR) is a transmembrane protein that mediates cellular uptake of iron. Although the serum concentration of the soluble TfR (sTfR) is altered in several diseases and used for diagnostic purposes, the identity and regulation of the shedding protease is unknown. In this study we quantified sTfR release from microsomal membranes and leukocytic cell lines in the presence of numerous protease inhibitors and cell activating compounds. We show that sTfR release is mediated by an integral membrane metalloprotease and can be inhibited by matrix metalloproteinase inhibitor 2 and tumor necrosis factor alpha  protease inhibitor-2 (TAPI-2). Cleavage is also inhibited by a specific furin inhibitor, indicating that the protease is activated by a furin-like proprotein convertase. Whereas stimulation of the cells by the ectodomain shedding activator phorbol 12-N-myristate 13-acetate did not alter sTfR release significantly, the phosphatase inhibitor pervanadate led to an increase of TfR shedding in several leukocytic cell lines. Our results suggest that TfR shedding is constitutively mediated by a member of the metalloprotease family known as ADAM (for a disintegrin and metalloprotease).

* This work was supported by Deutsche Forschungsgemeinschaft Grants FU 408/1-1 and FU 408/1-3 and by a Fonds der Chemischen Industrie grant (to K. D.) The work at the Institute of Biochemistry (C. W., Neurochemistry Department, Prof. F. Hucho) was supported by the Fonds der Chemischen Industrie.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.

To whom correspondence should be addressed. Tel.: 49-30-8445-2559; Fax: 49-30-8445-4152; E-mail: hendrik.fuchs@ukbf.fu-berlin.de.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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