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PMID:16604073

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Citation

Babitt, JL, Huang, FW, Wrighting, DM, Xia, Y, Sidis, Y, Samad, TA, Campagna, JA, Chung, RT, Schneyer, AL, Woolf, CJ, Andrews, NC and Lin, HY (2006) Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38:531-9

Abstract

Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.

Links

PubMed Online version:10.1038/ng1777

Keywords

Amino Acid Sequence; Animals; Antimicrobial Cationic Peptides/genetics; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins/metabolism; CHO Cells; Cricetinae; GPI-Linked Proteins; Gene Expression Regulation/physiology; Humans; Liver/cytology; Liver/metabolism; Membrane Proteins/genetics; Membrane Proteins/physiology; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Signal Transduction/physiology; Transforming Growth Factor beta/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:BMP2

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BMP2

involved_in

GO:0032092: positive regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q6ZVN8)
  • has_input:(UniProtKB:O00238)

Seeded From UniProt

complete

HUMAN:BMP2

enables

GO:0039706: co-receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q7TQ32

F

Seeded From UniProt

complete

HUMAN:BMP2

part_of

GO:0070724: BMP receptor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BMP2

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q9EQ21)
  • occurs_in:(UBERON:0002107)
  • part_of:(GO:0071773)

Seeded From UniProt

complete

HUMAN:BMP4

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:BMR1A

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1916835
MGI:MGI:88177

P

Seeded From UniProt

complete

MOUSE:BMR1B

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:109452
MGI:MGI:1916835
MGI:MGI:88177

P

Seeded From UniProt

complete

HUMAN:RGMC

involved_in

GO:0030509: BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RGMC

part_of

GO:0070724: BMP receptor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:RGMC

enables

GO:0015026: coreceptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RGMC

involved_in

GO:0071773: cellular response to BMP stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RGMC

contributes_to

GO:0098821: BMP receptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RGMC

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q9EQ21)
  • occurs_in:(UBERON:0002107)

Seeded From UniProt

complete

MOUSE:RGMC

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587746

P

  • occurs_in:(EMAPA:16846)

Seeded From UniProt

complete

MOUSE:RGMC

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:88177

P

  • has_input:(MGI:MGI:1933533)

Seeded From UniProt

complete

HUMAN:BMP4

enables

GO:0039706: co-receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q7TQ32

F

Seeded From UniProt

complete

HUMAN:BMP4

part_of

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RGMC

enables

GO:0015026: coreceptor activity

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:88177

F

Seeded From UniProt

complete

MOUSE:RGMC

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3587746

P

occurs_in:(EMAPA:16846)

Seeded From UniProt

complete

MOUSE:RGMC

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:107191
MGI:MGI:109452
MGI:MGI:1338938
MGI:MGI:88177

P

Seeded From UniProt

complete

MOUSE:RGMC

enables

GO:0036122: BMP binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RGMC

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:88177

P

has_regulation_target:(MGI:MGI:1933533)

Seeded From UniProt

complete

MOUSE:RGMC

enables

GO:0036122: BMP binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12643

F

Seeded From UniProt

complete

MOUSE:RGMC

enables

GO:0036122: BMP binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12644

F

Seeded From UniProt

complete

MOUSE:SMAD1

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:107191
MGI:MGI:1916835
MGI:MGI:88177

P

Seeded From UniProt

complete


See also

References

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