Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release?

Abstract

Abstract. Induction of the urokinase type plasminogen activator receptor (uPAR) promotes cell adhesion through its interaction with vitronectin (VN) in the extracellular matrix, and facilitates cell migration and invasion by localizing uPA to the cell surface. We provide evidence that this balance between cell adhesion and cell detachment is governed by PA inhibitor-1 (PAl-l). First, we demonstrate that uPAR and PAL1 bind to the same site in VN (i.e., the amino-terminal somatomedin B domain; SMB), and that PAI-1 competes with uPAR for binding to SMB. Domain swapping and mutagenesis studies indicate that the uPAR-binding sequence is located within the central region of the SMB domain, a region previously shown to contain the PAl-l-binding motif. Second, we show that PAI-1 dissociates bound VN from uPAR and detaches U937 cells from their VN substratum. This PAL1 mediated release of cells from VN appears to occur independently of its ability to function as a protease inhibitor, and may help to explain why high PAI-1 levels indicate a poor prognosis for many cancers. Finally, we show that uPA can rapidly reverse this effect of PAI-1. Taken together, these results suggest a dynamic regulatory role for PAI-1 and uPA in uPAR-mediated cell adhesion and release.

Transforming growth factor beta 1 and sodium butyrate differentially modulate urokinase plasminogen activator and plasminogen activator inhibitor-1 in human breast normal and cancer cells

“…However, recent works have demonstrated that uPA, uPA-R and PAI-I influence cell adhesion in a process independent of uPA-mediated proteolysis (Waltz and Chapman, 1994;Deng et al, 1996). The possibility of such influence on cell adhesion in our model remains unknown and further studies should be performed to understand the mechanism by which TGF-PI and other inhibitory agents regulate cell adhesion/migration in the context of the uPA system.…”

“…The simultaneous upregulation of uPA and PAI-I in the tumour cells should be considered as being complementary: increased cell-associated uPA induces pericellular protein degradation, favouring cell detachment, while increased PAI-1 levels reduce indiscriminant extracellular matrix degradation, which would deprive invasive cells of the anchorage necessary for cell locomotion. Moreover, Deng et al (1996) have recently reported that PAI-I promotes cell detachment by interacting with vitronectin, independent of its activity to function as a protease inhibitor. In our study, although TGF-,B1 strongly increased uPA and PAI-I in MDA-MB-231 cells, it did not inhibit cell proliferation.…”

Role of plasminogen activator-plasmin system in tumor angiogenesis

“…This could explain the release of cells from this matrix protein by an excess of PAI-1. Therefore, the delicate balance between cell adhesion and cell detachment has been proposed to be governed by PAI-1 [53].…”

True

“…There was a significant difference between the cells with and without PAI-1-stab or PAI-1-wt treatment for spontaneous apoptosis (*P < 0.001, n = 7) and for CPTinduced apoptosis (**P < 0.002, n = 7) respectively It has been found that PAI-1 plays an important role in migration and metastasis of tumour cells. PAI-1 may promote tumour cells invasion by regulating uPAR-dependent cell adhesion (Deng et al, 1996;Waltz et al, 1997). On the other hand, PAI-1 may inhibit integrin-and vitronectin-mediated cell migration by blocking α v β 3 binding to vitronectin (Stefansson and Lawrence, 1996;.…”