Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin.
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.
Xia
Yin
Y
Program in Membrane Biology and Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Babitt
Jodie L
JL
Sidis
Yisrael
Y
Chung
Raymond T
RT
Lin
Herbert Y
HY
D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000473:pathology; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D008024:Ligands; D008099:Liver / Q000737:chemistry; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D016212:Transforming Growth Factor beta
D023181:Antimicrobial Cationic Peptides; C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525816:BMP6 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008024:Ligands; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta; C091279:neogenin; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; C425585:activin receptor type II-A