HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/17/12547    most recent M608788200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, A.-S. Articles by Enns, C. A. Search for Related Content PubMed PubMed Citation Articles by Zhang, A.-S. Articles by Enns, C. A. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Pagani, L. Silvestri, A. Nai, and C. Camaschella Hemojuvelin N-terminal mutants reach the plasma membrane but do not activate the hepcidin response Haematologica, October 1, 2008; 93(10): 1466 - 1472. [Abstract] [Full Text] [PDF]

				J. Gao, N. Zhao, M. D. Knutson, and C. A. Enns The Hereditary Hemochromatosis Protein, HFE, Inhibits Iron Uptake via Down-regulation of Zip14 in HepG2 Cells J. Biol. Chem., August 1, 2008; 283(31): 21462 - 21468. [Abstract] [Full Text] [PDF]

				A.-S. Zhang, F. Yang, K. Meyer, C. Hernandez, T. Chapman-Arvedson, P. J. Bjorkman, and C. A. Enns Neogenin-mediated Hemojuvelin Shedding Occurs after Hemojuvelin Traffics to the Plasma Membrane J. Biol. Chem., June 20, 2008; 283(25): 17494 - 17502. [Abstract] [Full Text] [PDF]

				Y. Xia, J. L. Babitt, Y. Sidis, R. T. Chung, and H. Y. Lin Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin Blood, May 15, 2008; 111(10): 5195 - 5204. [Abstract] [Full Text] [PDF]

				M. J. Wood, L. W. Powell, and G. A. Ramm Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis Blood, May 1, 2008; 111(9): 4456 - 4462. [Abstract] [Full Text] [PDF]

				R. Kuns-Hashimoto, D. Kuninger, M. Nili, and P. Rotwein Selective binding of RGMc/hemojuvelin, a key protein in systemic iron metabolism, to BMP-2 and neogenin Am J Physiol Cell Physiol, April 1, 2008; 294(4): C994 - C1003. [Abstract] [Full Text] [PDF]

				L. Silvestri, A. Pagani, and C. Camaschella Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis Blood, January 15, 2008; 111(2): 924 - 931. [Abstract] [Full Text] [PDF]

				L. Lin, E. V. Valore, E. Nemeth, J. B. Goodnough, V. Gabayan, and T. Ganz Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4 Blood, September 15, 2007; 110(6): 2182 - 2189. [Abstract] [Full Text] [PDF]