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J. Biol. Chem., Vol. 281, Issue 6, 3297-3304, February 10, 2006

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Release of the Soluble Transferrin Receptor Is Directly Regulated by Binding of Its Ligand Ferritransferrin^*

From the Institut für Klinische Chemie und Pathobiochemie, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin 12200, Germany

The human transferrin receptor (TfR) is shed by an integral metalloprotease releasing a soluble form (sTfR) into serum. The sTfR reflects the iron demand of the body and is postulated as a regulator of iron homeostasis via binding to the hereditary hemochromatosis protein HFE. To study the role of transferrin in this process, we investigated TfR shedding in HL60 cells and TfR-deficient Chinese hamster ovary cells transfected with human TfR. Independent of TfR expression, sTfR release decreases with increasing ferritransferrin concentrations, whereas apo-transferrin exhibits no inhibitory effect. To investigate the underlying mechanism, we generated several TfR mutants with different binding affinities for transferrin. Shedding of TfR mutants in transfected cells correlates exactly with their binding affinity, implying that the effect of ferritransferrin on TfR shedding is mediated by a direct molecular interaction. Analysis of sTfR release from purified microsomal membranes revealed that the regulation is independent from intracellular trafficking or cellular signaling events. Our results clearly demonstrated that sTfR does not only reflect the iron demand of the cells but also the iron availability in the bloodstream, mirrored by iron saturation of transferrin, corroborating the important potential function of sTfR as a regulator of iron homeostasis.

Received for publication, October 19, 2005 , and in revised form, December 7, 2005.

^* This work was supported by grants from the Sonnenfeldstiftung (to K. D.) and the Stiftung für Pathobiochemie und Molekulare Diagnostik der Deutsche Vereinte Gesellschaft für Klinische Chemie ünd Laboratoriumsmedizin e.V. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Institut für Biochemie, Freie Universität Berlin, Thielallee 63, D-14195 Berlin, Germany.

² To whom correspondence should be addressed: Hendrik Fuchs, Institut für Klinische Chemie und Pathobiochemie, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. Tel.: 49-30-8445-2559; Fax: 49-30-8445-4152; E-mail: hendrik.fuchs{at}charite.de.

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