title: Plasminogen activator inhibitor type 2 inhibits cell surface associated tissue plasminogen activator in vitro: potential receptor interactions.
abstract: Regulation of cellular plasminogen activation is necessary for maintenance of tissue homeostasis. Despite increasing evidence for co-expression of tissue type plasminogen activator (tPA) and plasminogen activator inhibitor type-2 (PAI-2; SERPINB2) under patho/physiological conditions, the inhibition of cell-bound tPA mediated plasminogen activation by PAI-2 has not been addressed. Here we show that PAI-2 can inhibit cell-bound tPA activity in vitro and thus prevent plasmin formation. We also examined the potential involvement in this inhibition of the annexin II heterotetramer (AIIt), one of the many well characterized cell-surface co/receptors for tPA and plasminogen that efficiently promotes plasminogen activation. This receptor was of interest because AIIt has also been shown to directly bind PAI-2. Characterization of these potential interactions using purified protein systems revealed that PAI-2 directly bound AIIt via the p11 (S100A10) subunit. However, PAI-2 prevented AIIt/tPA-mediated plasminogen activation by its classic serpin inhibitory activity rather than through competition with tPA/plasminogen for binding. Further analysis showed that PAI-2 inhibited cell bound tPA-induced plasmin activity in both an AIIt-dependent and -independent manner. These data open new possibilities for further investigations regarding the regulation of cellular plasmin generation in vivo, especially in tissues where PAI-2 and tPA may be co-expressed.
authors.affiliation: School of Biological Sciences, University of Wollongong, NSW, Australia.
authors.forename: Sergei
authors.initials: S
authors.lastname: Lobov
authors.forename: David R
authors.initials: DR
authors.lastname: Croucher
authors.forename: Darren N
authors.initials: DN
authors.lastname: Saunders
authors.forename: Marie
authors.initials: M
authors.lastname: Ranson
mesh_terms: D017306:Annexin A2 / Q000378:metabolism; D001943:Breast Neoplasms; D005341:Fibrinolysin / Q000378:metabolism*; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D010958:Plasminogen / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D020349:Surface Plasmon Resonance; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D005341:Fibrinolysin; D010958:Plasminogen; D017396:Plasminogen Activator Inhibitor 2; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; D009418:S100 Proteins; D010959:Tissue Plasminogen Activator; D000099248:S100 Calcium Binding Protein A10; C514873:annexin II receptor, human