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J. Biol. Chem., Vol. 282, Issue 9, 6201-6209, March 2, 2007

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The Cytoplasmic Domain of Transferrin Receptor 2 Dictates Its Stability and Response to Holo-transferrin in Hep3B Cells^*

From the Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239

Transferrin receptor 2 (TfR2) is a homolog of transferrin receptor 1 (TfR1), the receptor responsible for the uptake of iron-loaded transferrin (holo-Tf) into cells. Unlike the ubiquitous TfR1, TfR2 is predominantly expressed in the liver. Mutations in TfR2 gene cause a rare autosomal recessive form of the iron overload disease, hereditary hemochromatosis. Previous studies demonstrated that holo-Tf increases TfR2 levels by stabilizing TfR2 at the protein level. In this study we constructed two chimeras, one of which had the cytoplasmic domain of TfR2 and the remaining portion of TfR1 and the other with the cytoplasmic and transmembrane domain of TfR1 joined to the ectodomain of TfR2. Similar to TfR2, the levels of the chimera containing only the cytoplasmic domain of TfR2 increased in a time- and dose-dependent manner after the addition of holo-Tf to the medium. The half-life of the chimera increased 2.7-fold in cells exposed to holo-Tf like the endogenous TfR2 in HepG2 cells. Like TfR2 and unlike TfR1, the levels of the chimera did not respond to intracellular iron content. These results suggest that although holo-Tf binding to the ectodomain is necessary, the cytoplasmic domain of TfR2 is largely responsible for its stabilization by holo-Tf.

Received for publication, October 30, 2006 , and in revised form, December 19, 2006.

^* This work was supported by National Institutes of Health Grants RO1-DK072166 (to C. A. E.) and GM-192837 (to the Confocal Microscopy Core Facility). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material including Figs. 1–4.

¹ To whom correspondence should be addressed: Dept. of Cell and Developmental Biology L215, Oregon Health and Science University, 3181 SW Sam Jackson Park Blvd., Portland, OR 97239. Tel.: 503-494-5845; Fax: 503-494-4253; E-mail: ennsca{at}ohsu.edu.

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