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J. Biol. Chem., Vol. 282, Issue 17, 12547-12556, April 27, 2007

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Evidence That Inhibition of Hemojuvelin Shedding in Response to Iron Is Mediated through Neogenin^*

An-Sheng Zhang¹, Sheila A. Anderson, Kathrin R. Meyers, Catalina Hernandez, Richard S. Eisenstein, and Caroline A. Enns

From the Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239 and the Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706

Hemojuvelin (HJV), encoded by the gene HFE2, is a critical upstream regulator of hepcidin expression. Hepcidin, the central iron regulatory hormone, is secreted from hepatocytes, whereas HFE2 is highly expressed in skeletal muscle and liver. Previous studies demonstrated that HJV is a GPI-anchored protein, binds the proteins neogenin and bone morphogenetic proteins (BMP2 and BMP4), and can be released from the cell membrane (shedding). In this study, we investigated the physiological significance and the underlying mechanism of HJV shedding. In acutely iron-deficient rats with markedly suppressed hepatic hepcidin expression, we detected an early phase increase of serum HJV with no significant change of either HFE2 mRNA or protein levels in gastrocnemius muscle. Studies in both C2C12 (a mouse myoblast cell line) and HepG2 (a human hepatoma cell line) cells showed active HJV shedding, implying that both skeletal muscle and liver could be the source of serum HJV. In agreement with the observations in iron-deficient rats, HJV shedding in these cell lines was down-regulated by holo-transferrin in a concentration-dependent manner. Our present study showing that knock-down of endogenous neogenin, a HJV receptor, in C2C12 cells suppresses HJV shedding and that overexpression of neogenin in HEK293 cells markedly enhances this process, suggests that membrane HJV shedding is mediated by neogenin. The finding that neither BMP4 nor its antagonist, noggin, was able to alter HJV shedding support the lack of involvement of BMP signaling pathway in this process.

Received for publication, September 12, 2006 , and in revised form, February 2, 2007.

^* The research was supported by National Institutes of Health DK54488 (to C. A. E.), National Institutes of Health DK066600 (to R. S. E.), and USDA 2006-35200-16604 (to R. S. E.). 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 Figs. S1–S4.

¹ To whom correspondence should be addressed: Dept. of Cell and Developmental Biology L215, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-5846; Fax: 503-494-4253; E-mail: zhanga{at}ohsu.edu.

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