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Blood, 15 May 2008, Vol. 111, No. 10, pp. 5195-5204. Prepublished online as a Blood First Edition Paper on March 7, 2008; DOI 10.1182/blood-2007-09-111567. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures Additional Supplemental Figures All Versions of this Article: blood-2007-09-111567v1 111/10/5195    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Xia, Y. Articles by Lin, H. Y. Search for Related Content PubMed PubMed Citation Articles by Xia, Y. Articles by Lin, H. Y. Related Collections Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin Yin Xia1, Jodie L. Babitt1, Yisrael Sidis2, Raymond T. Chung3, and Herbert Y. Lin1 1 Program in Membrane Biology and Division of Nephrology, Department of Medicine; 2 Reproductive Endocrine Unit, Department of Medicine; and 3 Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston Hemojuvelin (HJV) is a coreceptor for bone morphogenetic protein (BMP) signaling that regulates hepcidin expression and iron metabolism. However, the precise combinations of BMP ligands and receptors used by HJV remain unknown. HJV has also been demonstrated to bind to neogenin, but it is not known whether this interaction has a role in regulating hepcidin expression. In the present study, we show that BMP-2, BMP-4, and BMP-6 are endogenous ligands for HJV in hepatoma-derived cell lines, and that all 3 of these ligands are expressed in human liver. We demonstrate in vitro that HJV selectively uses the BMP type II receptors ActRIIA and BMPRII, but not ActRIIB, and HJV enhances utilization of ActRIIA by BMP-2 and BMP-4. Interestingly, ActRIIA is the predominant BMP type II receptor expressed in human liver. While HJV can use all 3 BMP type I receptors (ALK2, ALK3, and ALK6) in vitro, only ALK2 and ALK3 are detected in human liver. Finally, we show that HJV-induced BMP signaling and hepcidin expression are not altered by neogenin overexpression or by inhibition of endogenous neogenin expression. Thus, HJV-mediated BMP signaling and hepcidin regulation occur via a distinct subset of BMP ligands and BMP receptors, independently of neogenin. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. J. Ramsay, V. Quesada, M. Sanchez, C. Garabaya, M. P. Sarda, M. Baiget, A. Remacha, G. Velasco, and C. Lopez-Otin Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms Hum. Mol. Genet., October 1, 2009; 18(19): 3673 - 3683. [Abstract] [Full Text] [PDF] A.-S. Zhang, F. Yang, J. Wang, H. Tsukamoto, and C. A. Enns Hemojuvelin-Neogenin Interaction Is Required for Bone Morphogenic Protein-4-induced Hepcidin Expression J. Biol. Chem., August 21, 2009; 284(34): 22580 - 22589. [Abstract] [Full Text] [PDF] A. J. Ramsay, J. D. Hooper, A. R. Folgueras, G. Velasco, and C. Lopez-Otin Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis Haematologica, June 1, 2009; 94(6): 840 - 849. [Abstract] [Full Text] [PDF] J. E. Maxson, C. A. Enns, and A.-S. Zhang Processing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells Blood, February 19, 2009; 113(8): 1786 - 1793. [Abstract] [Full Text] [PDF] S. Pelucchi, R. Mariani, P. Trombini, S. Coletti, M. Pozzi, V. Paolini, D. Barisani, and A. Piperno Expression of hepcidin and other iron-related genes in type 3 hemochromatosis due to a novel mutation in transferrin receptor-2 Haematologica, February 1, 2009; 94(2): 276 - 279. [Abstract] [Full Text] [PDF] 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] L. Kautz, D. Meynard, A. Monnier, V. Darnaud, R. Bouvet, R.-H. Wang, C. Deng, S. Vaulont, J. Mosser, H. Coppin, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver Blood, August 15, 2008; 112(4): 1503 - 1509. [Abstract] [Full Text] [PDF] M. D. Fleming The Regulation of Hepcidin and Its Effects on Systemic and Cellular Iron Metabolism Hematology, January 1, 2008; 2008(1): 151 - 158. [Abstract] [Full Text] [PDF]

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