Regulation of histidine-rich glycoprotein (HRG) function via plasmin-mediated proteolytic cleavage.
The plasminogen/plasmin system is involved in a variety of normal physiological and pathological processes, including tissue remodelling, angiogenesis and tumour metastasis. Plasminogen activators and receptors for plasminogen/plasminogen activators are essential for the processing of plasminogen to form the active serine protease plasmin. Plasmin can in turn positively or negatively regulate further plasminogen activation via plasmin-mediated cleavage of receptors and activators. HRG (histidine-rich glycoprotein), a relatively abundant (approx. 100-150 microg/ml) plasma glycoprotein, has a multi-domain structure that can interact with many ligands, including Zn2+, heparin, HS (heparan sulfate) and plasminogen. HRG has been shown to function as an adaptor molecule to tether plasminogen to GAG (glycosaminoglycan)-bearing surfaces and to regulate plasminogen activation via various mechanisms. As HRG itself is sensitive to plasmin cleavage, the present study examines in detail the cleavage of human HRG by plasmin and the effect of this cleavage on various functions of HRG. HRG fragments, generated by plasmin cleavage, are held together by disulfide linkages and are not released from the molecule under non-reducing conditions. Plasmin-mediated cleavage partially inhibited HRG binding to cell surface HS, but enhanced HRG binding to necrotic cells and to plasminogen. However, both intact and plasmin-cleaved HRG enhanced the binding of plasminogen to heparin-coated surfaces to a similar extent. Furthermore, the presence of heparin, Zn2+ or acidic pH was found to protect HRG from plasmin cleavage. Thus proteolytic cleavage of HRG by plasmin may provide a feedback mechanism to regulate the effects of HRG on the plasminogen/plasmin system and other functions of HRG.
Poon
Ivan K H
IK
The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
Olsson
Anna-Karin
AK
Hulett
Mark D
MD
Parish
Christopher R
CR
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005341:Fibrinolysin / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism; D000099053:Histidine-Rich Glycoprotein
D005341:Fibrinolysin; D006023:Glycoproteins; D006493:Heparin; D006497:Heparan Sulfate; D010958:Plasminogen; D011506:Proteins; D015032:Zinc; D000099053:Histidine-Rich Glycoprotein