Histidine-rich glycoprotein

Histidine-rich glycoprotein
Identifiers
Symbols	HRG ; HPRG; HRGP; THPH11
External IDs	OMIM: 142640 MGI: 2146636 HomoloGene: 133557 GeneCards: HRG Gene
Gene ontology Molecular function • cysteine-type endopeptidase inhibitor activity • receptor binding • protein binding • heparin binding • zinc ion binding • immunoglobulin binding • heme binding • heparan sulfate proteoglycan binding • metal ion binding Cellular component • extracellular region • plasma membrane • platelet alpha granule lumen • extracellular exosome • blood microparticle Biological process • angiogenesis • platelet degranulation • positive regulation of immune response to tumor cell • chemotaxis • negative regulation of cell adhesion • blood coagulation • negative regulation of cell proliferation • regulation of gene expression • regulation of platelet activation • negative regulation of lamellipodium assembly • negative regulation of endopeptidase activity • negative regulation of angiogenesis • platelet activation • regulation of blood coagulation • negative regulation of cell growth • regulation of actin cytoskeleton organization • negative regulation of cell adhesion mediated by integrin • fibrinolysis • positive regulation of apoptotic process • regulation of protein complex assembly • negative regulation of blood vessel endothelial cell migration • regulation of peptidyl-tyrosine phosphorylation • defense response to fungus • positive regulation of focal adhesion assembly • negative regulation of vascular endothelial growth factor signaling pathway • positive regulation of blood vessel remodeling • negative regulation of endothelial cell chemotaxis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3273	94175
Ensembl	ENSG00000113905	ENSMUSG00000022877
UniProt	P04196	Q9ESB3
RefSeq (mRNA)	NM_000412	NM_053176
RefSeq (protein)	NP_000403	NP_444406
Location (UCSC)	Chr 3: 186.66 – 186.68 Mb	Chr 16: 22.95 – 22.96 Mb
PubMed search

Histidine-rich glycoprotein (HRG)is a glycoprotein that in humans is encoded by the HRG gene.^[1][2] It possesses a multi-domain structure which makes it capable of binding to numerous ligands, modulating various biological processes including immunity, vascularization and coagulation.^[3]

Function

This histidine-rich glycoprotein contains two cystatin-like domains and is located in plasma and platelets. The physiological function has not been determined but it is known that the protein binds heme, dyes and divalent metal ions. It can inhibit rosette formation and interacts with heparin, thrombospondin and plasminogen. Two of the protein's effects, the inhibition of fibrinolysis and the reduction of inhibition of coagulation, indicate a potential prothrombotic effect. Mutations in this gene lead to thrombophilia due to abnormal histidine-rich glycoprotein levels.^[2]

HRG is thought to have multiple roles as a protein in the human blood, including roles in immunity, angiogenesis and coagulation.^[4]

Clinical significance

The implications of HRG in cancer have been described as "multi-faceted".^[5] For example, the protein appears to have both pro- and anyi-angiogenic effecs. In biomarker studies, the protein has been found to have (weak) prognostic and diagnostic value for cancer.^[5] The absence of the protein is associated with thrombophilia.^[5] HRG has been shown to inhibit the M2-like phenotype of tumor-associated macrophages.^[6]

In addition, HRG has been discovered to play a role in infection. Some studies have found HRG to react to infection with Streptococcus pyogenes and a direct interaction between a S. pyogenes virulence factor (sHIP) and the human HRG has been identified.^[5][7]

References

1. Hennis BC, Kluft C (Aug 1991). "KpnI RFLP in the human histidine-rich glycoprotein gene". Nucleic Acids Research 19 (15): 4311. doi:10.1093/nar/19.15.4311-a. PMC 328603. PMID 1678514.
2. "Entrez Gene: HRG histidine-rich glycoprotein".
3. Blank M, Shoenfeld Y (Jun 2008). "Histidine-rich glycoprotein modulation of immune/autoimmune, vascular, and coagulation systems". Clinical Reviews in Allergy & Immunology 34 (3): 307–12. doi:10.1007/s12016-007-8058-6. PMID 18219588.
4. Poon IK, Patel KK, Davis DS, Parish CR, Hulett MD (Feb 2011). "Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma". Blood 117 (7): 2093–101. doi:10.1182/blood-2010-09-303842. PMID 20971949.
5. Johnson LD, Goubran HA, Kotb RR (Feb 2014). "Histidine rich glycoprotein and cancer: a multi-faceted relationship". Anticancer Research 34 (2): 593–603. PMID 24510988.
6. Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Åkerud P, De Mol M, Salomäki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P (Jan 2011). "HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF". Cancer Cell 19 (1): 31–44. doi:10.1016/j.ccr.2010.11.009. PMID 21215706.
7. Wisniewska M, Happonen L, Kahn F, Varjosalo M, Malmström L, Rosenberger G, Karlsson C, Cazzamali G, Pozdnyakova I, Frick IM, Björck L, Streicher W, Malmström J, Wikström M (Jun 2014). "Functional and structural properties of a novel protein and virulence factor (Protein sHIP) in Streptococcus pyogenes". The Journal of Biological Chemistry 289 (26): 18175–88. doi:10.1074/jbc.M114.565978. PMID 24825900.

Further reading

• Hughes GJ, Frutiger S, Paquet N, Ravier F, Pasquali C, Sanchez JC, James R, Tissot JD, Bjellqvist B, Hochstrasser DF (1993). "Plasma protein map: an update by microsequencing". Electrophoresis 13 (9-10): 707–14. doi:10.1002/elps.11501301150. PMID 1459097.
• Hutchens TW, Yip TT, Morgan WT (Mar 1992). "Identification of histidine-rich glycoprotein in human colostrum and milk". Pediatric Research 31 (3): 239–46. doi:10.1203/00006450-199203000-00009. PMID 1561009.
• van den Berg EA, le Clercq E, Kluft C, Koide T, van der Zee A, Oldenburg M, Wijnen JT, Meera Khan P (Jun 1990). "Assignment of the human gene for histidine-rich glycoprotein to chromosome 3". Genomics 7 (2): 276–9. doi:10.1016/0888-7543(90)90551-5. PMID 2347592.
• Shatsky M, Saigo K, Burdach S, Leung LL, Levitt LJ (May 1989). "Histidine-rich glycoprotein blocks T cell rosette formation and modulates both T cell activation and immunoregulation". The Journal of Biological Chemistry 264 (14): 8254–9. PMID 2524479.
• Saigo K, Shatsky M, Levitt LJ, Leung LK (May 1989). "Interaction of histidine-rich glycoprotein with human T lymphocytes". The Journal of Biological Chemistry 264 (14): 8249–53. PMID 2566603.
• Koide T, Foster D, Yoshitake S, Davie EW (Apr 1986). "Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA". Biochemistry 25 (8): 2220–5. doi:10.1021/bi00356a055. PMID 3011081.
• Hajjar DP, Boyd DB, Harpel PC, Nachman RL (Mar 1987). "Histidine-rich glycoprotein inhibits the antiproliferative effect of heparin on smooth muscle cells". The Journal of Experimental Medicine 165 (3): 908–13. doi:10.1084/jem.165.3.908. PMC 2188292. PMID 3819648.
• Leung LL (Apr 1986). "Interaction of histidine-rich glycoprotein with fibrinogen and fibrin". The Journal of Clinical Investigation 77 (4): 1305–11. doi:10.1172/JCI112435. PMC 424483. PMID 3958188.
• Heimburger N, Haupt H, Kranz T, Baudner S (Jul 1972). "[Human serum proteins with high affinity to carboxymethylcellulose. II. Physico-chemical and immunological characterization of a histidine-rich 3,8S- 2 -glycoportein (CM-protein I)]". Hoppe-Seyler's Zeitschrift Für Physiologische Chemie 353 (7): 1133–40. PMID 4116337.
• Silverstein RL, Leung LL, Harpel PC, Nachman RL (Nov 1984). "Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator". The Journal of Clinical Investigation 74 (5): 1625–33. doi:10.1172/JCI111578. PMC 425339. PMID 6438154.
• Hennis BC, Frants RR, Bakker E, Vossen RH, van der Poort EW, Blonden LA, Cox S, Khan PM, Spurr NK, Kluft C (Jan 1994). "Evidence for the absence of intron H of the histidine-rich glycoprotein (HRG) gene: genetic mapping and in situ localization of HRG to chromosome 3q28-q29". Genomics 19 (1): 195–7. doi:10.1006/geno.1994.1046. PMID 8188234.
• Sørensen CB, Krogh-Pedersen H, Petersen TE (Aug 1993). "Determination of the disulphide bridge arrangement of bovine histidine-rich glycoprotein". FEBS Letters 328 (3): 285–90. doi:10.1016/0014-5793(93)80945-Q. PMID 8348977.
• Leung L (May 1993). "Histidine-rich glycoprotein: an abundant plasma protein in search of a function". The Journal of Laboratory and Clinical Medicine 121 (5): 630–1. PMID 8478589.
• Angles-Cano E, Gris JC, Loyau S, Schved JF (May 1993). "Familial association of high levels of histidine-rich glycoprotein and plasminogen activator inhibitor-1 with venous thromboembolism". The Journal of Laboratory and Clinical Medicine 121 (5): 646–53. PMID 8478593.
• Gorgani NN, Parish CR, Easterbrook Smith SB, Altin JG (Jun 1997). "Histidine-rich glycoprotein binds to human IgG and C1q and inhibits the formation of insoluble immune complexes". Biochemistry 36 (22): 6653–62. doi:10.1021/bi962573n. PMID 9184145.
• Schinke T, Koide T, Jahnen-Dechent W (Aug 1997). "Human histidine-rich glycoprotein expressed in SF9 insect cells inhibits apatite formation". FEBS Letters 412 (3): 559–62. doi:10.1016/S0014-5793(97)00827-2. PMID 9276466.
• Shigekiyo T, Yoshida H, Matsumoto K, Azuma H, Wakabayashi S, Saito S, Fujikawa K, Koide T (Jan 1998). "HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency". Blood 91 (1): 128–33. PMID 9414276.
• Wakabayashi S, Takahashi K, Koide T (Mar 1999). "Structural characterization of the gene for human histidine-rich glycoprotein, reinvestigation of the 5'-terminal region of cDNA and a search for the liver specific promoter in the gene". Journal of Biochemistry 125 (3): 522–30. doi:10.1093/oxfordjournals.jbchem.a022316. PMID 10050040.
• Gorgani NN, Altin JG, Parish CR (Aug 1999). "Histidine-rich glycoprotein regulates the binding of monomeric IgG and immune complexes to monocytes". International Immunology 11 (8): 1275–82. doi:10.1093/intimm/11.8.1275. PMID 10421785.