HRG

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. The encoded protein also has a peptide that displays antimicrobial activity against C. albicans, E. coli, S. aureus, P. aeruginosa, and E. faecalis. 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.

Full Name

histidine-rich glycoprotein

Function

Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Binds heparin and heparin/glycosaminoglycans in a zinc-dependent manner. Binds heparan sulfate on the surface of liver, lung, kidney and heart endothelial cells. Binds to N-sulfated polysaccharide chains on the surface of liver endothelial cells. Inhibits rosette formation. Acts as an adapter protein and is implicated in regulating many processes such as immune complex and pathogen clearance, cell chemotaxis, cell adhesion, angiogenesis, coagulation and fibrinolysis. Mediates clearance of necrotic cells through enhancing the phagocytosis of necrotic cells in a heparan sulfate-dependent pathway. This process can be regulated by the presence of certain HRG ligands such as heparin and zinc ions. Binds to IgG subclasses of immunoglobins containing kappa and lambda light chains with different affinities regulating their clearance and inhibiting the formation of insoluble immune complexes. Tethers plasminogen to the cell surface. Binds T-cells and alters the cell morphology. Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2. Acts as a regulator of the vascular endothelial growth factor (VEGF) signaling pathway; inhibits endothelial cell motility by reducing VEGF-induced complex formation between PXN/paxillin and ILK/integrin-linked protein kinase and by promoting inhibition of VEGF-induced tyrosine phosphorylation of focal adhesion kinases and alpha-actinins in endothelial cells. Also plays a role in the regulation of tumor angiogenesis and tumor immune surveillance. Normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis.

Biological Process

Angiogenesis Source: UniProtKB-KW
Antimicrobial humoral immune response mediated by antimicrobial peptide Source: UniProtKB
Chemotaxis Source: UniProtKB-KW
Cytolysis by host of symbiont cells Source: UniProtKB
Defense response to fungus Source: UniProtKB
Fibrinolysis Source: UniProtKB-KW
Heme transport Source: GO_Central
Negative regulation of angiogenesis Source: UniProtKB
Negative regulation of blood vessel endothelial cell migration Source: UniProtKB
Negative regulation of cell adhesion Source: UniProtKB
Negative regulation of cell adhesion mediated by integrin Source: UniProtKB
Negative regulation of cell growth Source: UniProtKB
Negative regulation of cell population proliferation Source: UniProtKB
Negative regulation of endopeptidase activity Source: GO_Central
Negative regulation of endothelial cell chemotaxis Source: UniProtKB
Negative regulation of fibrinolysis Source: GO_Central
Negative regulation of lamellipodium assembly Source: UniProtKB
Negative regulation of vascular endothelial growth factor signaling pathway Source: UniProtKB
Platelet activation Source: UniProtKB
Positive regulation of apoptotic process Source: UniProtKB
Positive regulation of blood vessel remodeling Source: UniProtKB
Positive regulation of focal adhesion assembly Source: UniProtKB
Positive regulation of immune response to tumor cell Source: UniProtKB
Regulation of actin cytoskeleton organization Source: UniProtKB
Regulation of blood coagulation Source: UniProtKB
Regulation of gene expression Source: UniProtKB
Regulation of peptidyl-tyrosine phosphorylation Source: UniProtKB
Regulation of platelet activation Source: UniProtKB
Regulation of protein-containing complex assembly Source: UniProtKB

Cellular Location

Secreted

Involvement in disease

Thrombophilia due to histidine-rich glycoprotein deficiency (THPH11):
A hemostatic disorder characterized by a tendency to thrombosis.

PTM

Proteolytic cleavage produces several HRG fragments which are mostly disulfide-linked and, therefore, not released. Cleavage by plasmin is inhibited in the presence of heparin, zinc ions or in an acidic environment. Cleavage reduces binding of HRG to heparan sulfate, but enhances the ability of HRG to bind and tether plasminogen to the cell surface. On platelet activation, releases a 33 kDa antiangiogenic peptide which encompasses the HRR. Also cleaved in the C-terminal by plasmin.
N-glycosylated.