Plasminogen activator inhibitor type 1 promotes the self-association of vitronectin into complexes exhibiting altered incorporation into the extracellular matrix.
Serine proteinase inhibitors, including plasminogen activator inhibitor type 1 (PAI-1) and antithrombin, are key regulators of hemostatic processes such as thrombosis and wound healing. Much evidence suggests that PAI-1 can influence such processes, as well as pathological events like tumor metastasis, through its ability to directly regulate binding of blood platelets and cells to extracellular substrata. One way that PAI-1 influences these processes may be mediated through its binding to the plasma protein vitronectin. Binding to PAI-1 results in the incorporation of vitronectin into a higher order complex with a potential for multivalent interactions (Podor, T. J., Shaughnessy, S. G., Blackburn, M. N., and Peterson, C. B. (2000) J. Biol. Chem. 275, 25402-25410). In this study, evidence is provided to support this concept from studies on the effects of PAI-1-induced multimerization on the interactions of vitronectin with matrix components and cell surface receptors. By monitoring complex formation and stability over time using size-exclusion high performance liquid chromatography, a correlation is made between PAI-1-induced multimerization and enhanced cell/matrix binding properties of vitronectin. This evidence indicates that PAI-1 alters the adhesive functions of vitronectin by converting the protein via the higher order complex to a self-associated, multivalent species that is functionally distinct from the abundant monomeric form found in the circulation.
Minor
Kenneth H
KH
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, USA.
Peterson
Cynthia B
CB
D015153:Blotting, Western; D002448:Cell Adhesion; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry* / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D019096:Vitronectin / Q000737:chemistry* / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; D019096:Vitronectin; D004492:Edetic Acid