Different mechanisms define the antiadhesive function of high molecular weight kininogen in integrin- and urokinase receptor–dependent interactions
Open Access
- 15 July 2000
- journal article
- Published by American Society of Hematology in Blood
- Vol. 96 (2) , 514-522
- https://doi.org/10.1182/blood.v96.2.514
Abstract
Proteolytic cleavage of single-chain high molecular weight kininogen (HK) by kallikrein releases the short-lived vasodilator bradykinin and leaves behind 2-chain high molecular weight kininogen (HKa) that has been previously reported to exert antiadhesive properties as well as to bind to the urokinase receptor (uPAR) on endothelial cells. In this study we defined the molecular mechanisms for the antiadhesive effects of HKa related to disruption of integrin- and uPAR-mediated cellular interactions. Vitronectin (VN) but not fibrinogen or fibronectin-dependent vβ3 integrin–mediated adhesion of endothelial cells was blocked by HKa or its isolated domain 5. In a purified system, HKa but not HK competed for the interaction of VN with vβ3 integrin, because HKa and the isolated domain 5 but not HK bound to both multimeric and native VN in a Zn2+-dependent manner. The interaction between HKa or domain 5 with VN was prevented by heparin, plasminogen activator inhibitor-1, and a recombinant glutathione-S-transferase (GST)-fusion peptide GST-VN (1-77) consisting of the amino terminal portion of VN (amino acids 1-77), but not by a cyclic arginyl-glycyl-aspartyl peptide, indicating that HKa interacts with the amino terminal portion of VN (“somatomedin B region”). Furthermore, we have confirmed that HKa but not HK bound to uPAR and to the truncated 2-domain form of uPAR lacking domain 1 in a Zn2+-dependent manner. Through these interactions, HKa or its recombinant His-Gly-Lys–rich domain 5 completely inhibited the uPAR-dependent adhesion of myelomonocytic U937 cells and uPAR-transfected BAF-3 cells to VN and thereby promoted cell detachment. By immunogold electron microscopy, both VN and HK/HKa were found to be colocalized in sections from human atherosclerotic coronary artery, indicating that the described interactions are likely to take place in vivo. Taken together, HK and HKa inhibit different VN-responsive adhesion receptor systems and may thereby influence endothelial cell- or leukocyte-related interactions in the vasculature, particularly under inflammatory conditions.Keywords
This publication has 72 references indexed in Scilit:
- Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor.Journal of Clinical Investigation, 1997
- Urokinase-Type Plasminogen Activator-Induced Monocyte Adhesion Is Modulated by Kininogen, Kallikrein, Factor XII, and PlasminogenExperimental Cell Research, 1996
- Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vesselsCell, 1994
- Wound repair in the context of extracellular matrixCurrent Opinion in Cell Biology, 1994
- Cytokines induce urokinase-dependent adhesion of human myeloid cells. A regulatory role for plasminogen activator inhibitors.Journal of Clinical Investigation, 1993
- Inhibition of cell adhesion by high molecular weight kininogen.The Journal of cell biology, 1992
- The sequence HGLGHGHEQQHGLGHGH in the light chain of high molecular weight kininogen serves as a primary structural feature for zinc‐dependent binding to an anionic surfaceProtein Science, 1992
- High molecular weight kininogen inhibits fibrinogen binding to cytoadhesins of neutrophils and platelets.The Journal of cell biology, 1989
- Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1,3,4,6-tetrachloro-3a,6a-diphenylglycolurilBiochemical and Biophysical Research Communications, 1978