Hemojuvelin

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Hemochromatosis type 2 (juvenile)
Identifiers
SymbolsHFE2 ; HFE2A; HJV; JH; RGMC
External IDsOMIM608374 MGI1916835 HomoloGene17060 GeneCards: HFE2 Gene
Orthologs
SpeciesHumanMouse
Entrez14873869585
EnsemblENSG00000168509ENSMUSG00000038403
UniProtQ6ZVN8Q7TQ32
RefSeq (mRNA)NM_145277NM_027126
RefSeq (protein)NP_660320NP_081402
Location (UCSC)Chr 1:
145.41 – 145.42 Mb
Chr 3:
96.53 – 96.53 Mb
PubMed search[1][2]
 
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Hemochromatosis type 2 (juvenile)
Identifiers
SymbolsHFE2 ; HFE2A; HJV; JH; RGMC
External IDsOMIM608374 MGI1916835 HomoloGene17060 GeneCards: HFE2 Gene
Orthologs
SpeciesHumanMouse
Entrez14873869585
EnsemblENSG00000168509ENSMUSG00000038403
UniProtQ6ZVN8Q7TQ32
RefSeq (mRNA)NM_145277NM_027126
RefSeq (protein)NP_660320NP_081402
Location (UCSC)Chr 1:
145.41 – 145.42 Mb
Chr 3:
96.53 – 96.53 Mb
PubMed search[1][2]

Hemojuvelin (HJV/RGMc/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.[1][2] HJV is also called RGMc, a member of a three gene family (in vertebrates) called the repulsive guidance molecules. Both RGMa and RGMb are found in the nervous system [3][4] while RGMc is found in skeletal muscle and the liver.[4][5]

Function[edit]

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.[6] Associations with BMP2 and BMP4 have been described.[7]

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.[8][9]

A soluble form of HJV may be a molecule that suppresses hepcidin expression.[10]

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.[11][12] Furthermore, aberrant expression of RGMs was indicated in breast cancer. The perturbed expression was associated with disease progression and poor prognosis.[13]

Related gene problems[edit]

Gene structure and transcription[edit]

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).[5] 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.[14]

RGMc/HJV, is transcriptionally regulated during muscle differentiation.[5]

Isoforms[edit]

Two classes of GPI-anchored and glycosylated HJV molecules are targeted to the membrane and undergo distinct fates.[15]

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.[citation needed]

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.[16]

Structure[edit]

The Rosetta ab initio protein structure prediction software has been used to create a three-dimensional model of the RGM family of proteins.[17]

Mechanism of action[edit]

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.[18][19]

Clinical significance[edit]

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.[2] 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[edit]

  1. ^ Roetto A, Totaro A, Cazzola M, Cicilano M, Bosio S, D'Ascola G, Carella M, Zelante L, Kelly AL, Cox TM, Gasparini P, Camaschella C (May 1999). "Juvenile hemochromatosis locus maps to chromosome 1q". Am. J. Hum. Genet. 64 (5): 1388–93. doi:10.1086/302379. PMC 1377875. PMID 10205270. 
  2. ^ a b Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dubé MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP (January 2004). "Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis". Nat. Genet. 36 (1): 77–82. doi:10.1038/ng1274. PMID 14647275. 
  3. ^ Samad TA, Srinivasan A, Karchewski LA, Jeong SJ, Campagna JA, Ji RR, Fabrizio DA, Zhang Y, Lin HY, Bell E, Woolf CJ (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". J. Neurosci. 24 (8): 2027–36. doi:10.1523/JNEUROSCI.4115-03.2004. PMID 14985445. 
  4. ^ a b Schmidtmer J, Engelkamp D (January 2004). "Isolation and expression pattern of three mouse homologues of chick Rgm". Gene Expr. Patterns 4 (1): 105–10. doi:10.1016/S1567-133X(03)00144-3. PMID 14678836. 
  5. ^ a b c 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): 342–51. doi:10.1016/j.ygeno.2010.09.001. PMC 2988867. PMID 20858542. 
  6. ^ Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY (May 2006). "Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression". Nat. Genet. 38 (5): 531–9. doi:10.1038/ng1777. PMID 16604073. 
  7. ^ Zhang AS, Yang F, Meyer K, Hernandez C, Chapman-Arvedson T, Bjorkman PJ, Enns CA (June 2008). "Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane". J. Biol. Chem. 283 (25): 17494–502. doi:10.1074/jbc.M710527200. PMC 2427329. PMID 18445598. 
  8. ^ Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC (August 2005). "A mouse model of juvenile hemochromatosis". J. Clin. Invest. 115 (8): 2187–91. doi:10.1172/JCI25049. PMC 1180543. PMID 16075059. 
  9. ^ Niederkofler V, Salie R, Arber S (August 2005). "Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload". J. Clin. Invest. 115 (8): 2180–6. doi:10.1172/JCI25683. PMC 1180556. PMID 16075058. 
  10. ^ Lin L, Goldberg YP, Ganz T (October 2005). "Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin". Blood 106 (8): 2884–9. doi:10.1182/blood-2005-05-1845. PMID 15998830. 
  11. ^ 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". J Cell Biochem 113 (7): 2523–31. doi:10.1002/jcb.24128. PMID 22415859. 
  12. ^ 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". Int. J. Oncol. 40 (2): 544–50. doi:10.3892/ijo.2011.1251. PMID 22076499. 
  13. ^ Li J, Ye L, Mansel RE, Jiang WG (May 2011). "Potential prognostic value of repulsive guidance molecules in breast cancer". Anticancer Res. 31 (5): 1703–11. PMID 21617229. 
  14. ^ Yao QY, Rickinson AB, Epstein MA (March 1985). "Oropharyngeal shedding of infectious Epstein-Barr virus in healthy virus-immune donors. A prospective study". Chin. Med. J. 98 (3): 191–6. PMID 2988867. 
  15. ^ Kuninger D, Kuns-Hashimoto R, Kuzmickas R, Rotwein P (August 2006). "Complex biosynthesis of the muscle-enriched iron regulator RGMc". J. Cell. Sci. 119 (Pt 16): 3273–83. doi:10.1242/jcs.03074. PMID 16868025. 
  16. ^ 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". Am. J. Physiol., Cell Physiol. 294 (4): C994–C1003. doi:10.1152/ajpcell.00563.2007. PMID 18287331. 
  17. ^ Severyn CJ, Shinde U, Rotwein P (September 2009). "Molecular biology, genetics and biochemistry of the repulsive guidance molecule family". Biochem. J. 422 (3): 393–403. doi:10.1042/BJ20090978. PMID 19698085. 
  18. ^ 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 Mol. Dis. 40 (1): 122–31. doi:10.1016/j.bcmd.2007.06.023. PMC 2211380. PMID 17869549. 
  19. ^ 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 Biochem. 9: 9. doi:10.1186/1471-2091-9-9. PMC 2323002. PMID 18384687. 

Further reading[edit]

External links[edit]