Elevated plasminogen receptor expression occurs as a degradative phase event in cellular apoptosis

Abstract

Summary Plasminogen activation (PA) is involved in a variety of extracellular proteolytic events, such as fibrinolysis, cell migration (e.g. angiogenesis, tumour cell invasion, inflammation, wound healing, bacterial invasion), ovulation, tissue remodelling and the activation of other protease classes and growth factors. These diverse roles are due to the specific localization of components of the PA system to extracellular matrices, basement membranes, fibrin and cell surfaces. We have previously reported that PA is dramatically elevated during cycloheximide (CHX)-induced apoptosis in U937 cells due to a concomitant increase in both plasminogen receptors (PLG-R; i.e. specific PLG binding) and cell-surface urokinase plasminogen activator. We now extend this study by showing that the increase in PLG-R (resulting in an increase in specific PLG binding) is a late apoptotic event coincident with propidium iodide uptake and internucleosomal DNA fragmentation but occurring after elevations in phosphatidylserine exposure. Plasminogen was also observed to dramatically increase the rate of CHX-induced apoptosis. We conclude that PA may play a role in the degradative (i.e. late-stage) events of cellular apoptosis.

Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

“…The question that arises is how plasminogen exerts its effect on corpse clearance. Previous reports have described an enhanced binding of plasminogen to the surface of apoptotic cells, suggesting that it might function as an opsonin (14)(15)(16)(17). In the current study, however, we did not observe enhanced surface binding of plasminogen to apoptotic cells.…”

“…Instead of acting as an opsonin, we show that plasminogen enhances efferocytosis under crucial contribution of its proteolytic activity, which is acquired after interaction with apoptotic cells. Our data are in line with studies from other groups that have attributed this activation of plasminogen to an increased expression of urokinase-type plasminogen activator, which was specifically detected on the surface of apoptotic, but not necrotic cells (15)(16)(17). Notably, plasmin(ogen)-mediated enhancement of dying cell engulfment was observed in a phase of apoptosis, in which the maximum level of PS externalization had already been reached and the integrity of the plasma membrane was still intact, suggesting that the exposure of "eat-me" signals is a prerequisite for plasmin(ogen)-dependent phagocytosis promotion.…”

Chromatin breakdown during necrosis by serum Dnase1 and the plasminogen system

“…keratin 8 as suggested by published data (39,40), whereas its nuclear accumulation might have been due to binding to chromatin components. Our results amend those of previous reports that have indicated that loss of cell viability dramatically increased plasminogen binding to the cell surface (39,41,42).…”

Plasminogen inhibits TNFα-induced apoptosis in monocytes

“…12,13 Similarly, plasmin-dependent anoikis is observed with adherent smooth muscle cells, 14,15 retinal cells, 16 and fibroblast cell lines. 17 Plasminogen binding capacity is markedly enhanced on late apoptotic/necrotic U937 monocytoid cells following treatment with cycloheximide, 18,19 suggesting a potential role for cellassociated plasminogen in regulation of apoptosis. Monocytoid cells do not depend on adherence for a survival signal.…”