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Hemojuvelin

From Wikipedia, the free encyclopedia

HJV
Identifiers
AliasesHJV, HFE2, hemojuvelin BMP co-receptor, HFE2A, hemochromatosis type 2 (juvenile), JH, RGMC
External IDsOMIM: 608374; MGI: 1916835; GeneCards: HJV
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

148738

69585

Ensembl

ENSG00000168509

ENSMUSG00000038403

UniProt

Q6ZVN8

Q7TQ32

RefSeq (mRNA)

NM_027126

RefSeq (protein)

NP_081402

Location (UCSC)Chr 1: 146.02 – 146.04 MbChr 3: 96.43 – 96.44 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Hemojuvelin (HJV), also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2), is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene.[5][6] Hemojuvelin is a member of the repulsive guidance molecule family of proteins.[7][8] Both RGMa and RGMb are found in the nervous system,[9][10] while hemojuvelin is found in skeletal muscle and the liver.[10][11]

Function

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For many years the signal transduction pathways that regulate systemic iron homeostasis have been unknown. However it has been demonstrated that hemojuvelin interacts with bone morphogenetic protein (BMP), possibly as a co-receptor, and may signal via the SMAD pathway to regulate hepcidin expression.[12] Associations with BMP2 and BMP4 have been described.[13]

Mouse HJV knock-out models confirmed that HJV is the gene responsible for juvenile hemochromatosis. Hepcidin levels in the liver are dramatically depressed in these knockout animals.[14][15]

A soluble form of HJV may be a molecule that suppresses hepcidin expression.[16]

RGMs may play inhibitory roles in prostate cancer by suppressing cell growth, adhesion, migration and invasion. RGMs can coordinate Smad-dependent and Smad-independent signalling of BMPs in prostate cancer and breast cancer cells.[17][18] Furthermore, aberrant expression of RGMs was indicated in breast cancer. The perturbed expression was associated with disease progression and poor prognosis.[19]

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Gene structure and transcription

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RGMc/HJV is a 4-exon gene in mammals that undergoes alternative RNA splicing to yield 3 mRNAs with different 5’ untranslated regions (5’UTRs).[11] Gene transcription is induced during myoblast differentiation, producing all 3 mRNAs. There are three critical promoter elements responsible for transcriptional activation in skeletal muscle (the tissue that has the highest level of RGMc expressesion per weight), comprising paired E-boxes, a putative Stat and/or Ets element, and a MEF2 site, and muscle transcription factors myogenin and MEF2C stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, these results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history.[11]

RGMc/HJV, is transcriptionally regulated during muscle differentiation.[11]

Isoforms

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Two classes of GPI-anchored and glycosylated HJV molecules are targeted to the membrane and undergo distinct fates.[20]

  • Full-length HJV is released from the cell surface and accumulates in extracellular fluid, where its half-life exceeds 24 hours. There appears to be two potential soluble isoforms and two membrane-associated isoforms.[20]
  • The predominant membrane-associated isoform, a disulfide-linked two-chain form composed of N- and C-terminal fragments, is not found in the extracellular fluid, and is short-lived, as it disappears from the cell surface with a half-life of < 3 hours after interruption of protein synthesis.[20]

RGMc appears to undergo a complex processing that generates 2 soluble, single-chain forms, and two membrane-bound forms found as a (i) single-chain, and (ii) two-chain species which appears to be cleaved at a site within a partial von Willebrand factor domain.[20]

Using a combination of biochemical and cell-based approaches, it has demonstrated that BMP-2 could interact in biochemical assays with the single-chain HJV species, and also could bind to cell-associated HJV. Two mouse HJV amino acid substitution mutants, D165E and G313V (corresponding to human D172E and G320V), also could bind BMP-2, but less effectively than wild-type HJV, while G92V (human G99V) could not. In contrast, the membrane-spanning protein, neogenin, a receptor for the related molecule, RGMa, preferentially bound membrane-associated heterodimeric RGMc and was able to interact on cells only with wild-type RGMc and G92V. These results show that different isoforms of RGMc/HJV may play unique physiological roles through defined interactions with distinct signaling proteins and demonstrate that, in some disease-linked HJV mutants, these interactions are defective.[21]

Structure

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In 2009, the Rosetta ab initio protein structure prediction software has been used to create a three-dimensional model of the RGM family of proteins.,[8] In 2011, a crystal structure of a fragment of hemojuvelin binding to neogenin was completed [22] showing similar structures to the ab initio model and further informing the view of the RGM family of proteins.

Mechanism of action

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Furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.[23][24]

Clinical significance

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Mutations in HJV are responsible for the vast majority of juvenile hemochromatosis patients. A small number of patients have mutations in the hepcidin (HAMP) gene. The gene was positionally cloned.[6] Hemojuvelin is highly expressed in skeletal muscle and heart, and to a lesser extent in the liver. One insight into the pathogenesis of juvenile hemochromatosis is that patients have low to undetectable urinary hepcidin levels, suggesting that hemojuvelin is a positive regulator of hepcidin, the central iron regulatory hormone. As a result, low hepcidin levels would result in increased intestinal iron absorption. Thus, HJV/RGMc appears to play a critical role in iron metabolism.[citation needed]

References

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  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000168509 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000038403 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Roetto A, Totaro A, Cazzola M, Cicilano M, Bosio S, D'Ascola G, et al. (May 1999). "Juvenile hemochromatosis locus maps to chromosome 1q". American Journal of Human Genetics. 64 (5): 1388–1393. doi:10.1086/302379. PMC 1377875. PMID 10205270.
  6. 1 2 Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dubé MP, et al. (January 2004). "Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis". Nature Genetics. 36 (1): 77–82. doi:10.1038/ng1274. PMID 14647275.
  7. ↑ Corradini E, Babitt JL, Lin HY (2009). "The RGM/DRAGON family of BMP co-receptors". Cytokine & Growth Factor Reviews. 20 (5–6): 389–398. doi:10.1016/j.cytogfr.2009.10.008. PMC 3715994. PMID 19897400.
  8. 1 2 Severyn CJ, Shinde U, Rotwein P (September 2009). "Molecular biology, genetics and biochemistry of the repulsive guidance molecule family". The Biochemical Journal. 422 (3): 393–403. doi:10.1042/BJ20090978. PMC 4242795. PMID 19698085.
  9. ↑ Samad TA, Srinivasan A, Karchewski LA, Jeong SJ, Campagna JA, Ji RR, et al. (February 2004). "DRAGON: a member of the repulsive guidance molecule-related family of neuronal- and muscle-expressed membrane proteins is regulated by DRG11 and has neuronal adhesive properties". The Journal of Neuroscience. 24 (8): 2027–2036. doi:10.1523/JNEUROSCI.4115-03.2004. PMC 6730385. PMID 14985445.
  10. 1 2 Schmidtmer J, Engelkamp D (January 2004). "Isolation and expression pattern of three mouse homologues of chick Rgm". Gene Expression Patterns. 4 (1): 105–110. doi:10.1016/S1567-133X(03)00144-3. PMID 14678836.
  11. 1 2 3 4 Severyn CJ, Rotwein P (December 2010). "Conserved proximal promoter elements control repulsive guidance molecule c/hemojuvelin (Hfe2) gene transcription in skeletal muscle". Genomics. 96 (6): 342–351. doi:10.1016/j.ygeno.2010.09.001. PMC 2988867. PMID 20858542.
  12. ↑ Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, et al. (May 2006). "Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression". Nature Genetics. 38 (5): 531–539. doi:10.1038/ng1777. PMID 16604073. S2CID 19282860.
  13. ↑ Zhang AS, Yang F, Meyer K, Hernandez C, Chapman-Arvedson T, Bjorkman PJ, et al. (June 2008). "Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane". The Journal of Biological Chemistry. 283 (25): 17494–17502. doi:10.1074/jbc.M710527200. PMC 2427329. PMID 18445598.
  14. ↑ Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC (August 2005). "A mouse model of juvenile hemochromatosis". The Journal of Clinical Investigation. 115 (8): 2187–2191. doi:10.1172/JCI25049. PMC 1180543. PMID 16075059.
  15. ↑ Niederkofler V, Salie R, Arber S (August 2005). "Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload". The Journal of Clinical Investigation. 115 (8): 2180–2186. doi:10.1172/JCI25683. PMC 1180556. PMID 16075058.
  16. ↑ Lin L, Goldberg YP, Ganz T (October 2005). "Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin". Blood. 106 (8): 2884–2889. doi:10.1182/blood-2005-05-1845. PMID 15998830.
  17. ↑ Li J, Ye L, Sanders AJ, Jiang WG (March 2012). "Repulsive guidance molecule B (RGMB) plays negative roles in breast cancer by coordinating BMP signaling". Journal of Cellular Biochemistry. 113 (7): 2523–2531. doi:10.1002/jcb.24128. PMID 22415859. S2CID 35629616.
  18. ↑ Li J, Ye L, Kynaston HG, Jiang WG (February 2012). "Repulsive guidance molecules, novel bone morphogenetic protein co-receptors, are key regulators of the growth and aggressiveness of prostate cancer cells". International Journal of Oncology. 40 (2): 544–550. doi:10.3892/ijo.2011.1251. PMID 22076499.
  19. ↑ Li J, Ye L, Mansel RE, Jiang WG (May 2011). "Potential prognostic value of repulsive guidance molecules in breast cancer". Anticancer Research. 31 (5): 1703–1711. PMID 21617229.
  20. 1 2 3 4 Kuninger D, Kuns-Hashimoto R, Kuzmickas R, Rotwein P (August 2006). "Complex biosynthesis of the muscle-enriched iron regulator RGMc". Journal of Cell Science. 119 (Pt 16): 3273–3283. doi:10.1242/jcs.03074. PMID 16868025. S2CID 15574534.
  21. ↑ Kuns-Hashimoto R, Kuninger D, Nili M, Rotwein P (April 2008). "Selective binding of RGMc/hemojuvelin, a key protein in systemic iron metabolism, to BMP-2 and neogenin". American Journal of Physiology. Cell Physiology. 294 (4): C994–C1003. doi:10.1152/ajpcell.00563.2007. PMID 18287331. S2CID 32158124.
  22. ↑ Yang F, West AP, Bjorkman PJ (April 2011). "Crystal structure of a hemojuvelin-binding fragment of neogenin at 1.8Å". Journal of Structural Biology. 174 (1): 239–244. doi:10.1016/j.jsb.2010.10.005. PMC 3074981. PMID 20971194.
  23. ↑ Lin L, Nemeth E, Goodnough JB, Thapa DR, Gabayan V, Ganz T (2008). "Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site". Blood Cells, Molecules & Diseases. 40 (1): 122–131. doi:10.1016/j.bcmd.2007.06.023. PMC 2211380. PMID 17869549.
  24. ↑ Kuninger D, Kuns-Hashimoto R, Nili M, Rotwein P (2008). "Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin". BMC Biochemistry. 9 9. doi:10.1186/1471-2091-9-9. PMC 2323002. PMID 18384687.

Further reading

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  • Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al. (1993). "Juvenile Hereditary Hemochromatosis.". GeneReviews. PMID 20301349.
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