title: Neogenin Facilitates the Induction of Hepcidin Expression by Hemojuvelin in the Liver.
abstract: Hemojuvelin (HJV) regulates iron homeostasis by direct interaction with bone morphogenetic protein (BMP) ligands to induce hepcidin expression through the BMP signaling pathway in the liver. Crystallography studies indicate that HJV can simultaneously bind to both BMP2 and the ubiquitously expressed cell surface receptor neogenin. However, the role of the neogenin-HJV interaction in the function of HJV is unknown. Here we identify a mutation in HJV that specifically lowers its interaction with neogenin. Expression of this mutant Hjv in the liver of Hjv(-/-) mice dramatically attenuated its induction of BMP signaling and hepcidin mRNA, suggesting that interaction with neogenin is critical for the iron regulatory function of HJV. Further studies revealed that neogenin co-immunoprecipitated with ALK3, an essential type-I BMP receptor for hepatic hepcidin expression. Neogenin has also been shown to facilitate the cleavage of HJV by furin in transfected cells. Surprisingly, although cleavage of HJV by furin has been implicated in the regulation of HJV function in cell culture models and furin-cleaved soluble Hjv is detectable in the serum of mice, mutating the furin cleavage site did not alter the stimulation of hepcidin expression by Hjv in mice. In vivo studies validated the important role of HJV-BMP interaction for Hjv stimulation of BMP signaling and hepcidin expression. Together these data support a model in which neogenin acts as a scaffold to facilitate assembly of the HJV·BMP·BMP receptor complex to induce hepcidin expression.
authors.affiliation: From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Ningning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Maxson
authors.affiliation: From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Zhang
authors.affiliation: From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Mastura
authors.initials: M
authors.lastname: Wahedi
authors.affiliation: From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Enns
authors.affiliation: From the Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, Oregon 97239 zhanga@ohsu.edu.
authors.forename: An-Sheng
authors.initials: AS
authors.lastname: Zhang
mesh_terms: D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D000071020:Hemochromatosis Protein; D056945:Hep G2 Cells; D064451:Hepcidins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009154:Mutation; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; C091279:neogenin; D052004:Bone Morphogenetic Protein Receptors
keywords: ALK3; bone morphogenetic protein (BMP); furin; hemojuvelin; hepcidin; iron; liver; matriptase-2; neogenin; signaling