Receptors for plasminogen and t-PA: an update

Over the past decade, the existence of cell-surface receptors for components of the plasminogen system, t-PA, u-PA, plasminogen and plasmin, has been demonstrated. Plasminogen receptors have been detected on virtually all cell types tested, and occupancy has also been demonstrated in biological settings. Characteristic features of plasminogen receptors include their relatively low affinity and their extraordinarily high density on many cells. These receptors recognize the lysine binding sites associated with the kringles of plasminogen. Plasminogen receptors include proteins with carboxyl-terminal lysine residues (enolase and annexin II are representatives) and nonproteins, such as gangliosides. Plasminogen binding to cells enhances plasmin activity by augmenting plasminogen activation, increasing the enzymatic activity of plasmin, and protecting plasmin for inactivation by inhibitors. t-PA receptors serve two major functions, clearance and cell-surface localization. The liver is the main organ for t-PA clearance; parenchymal, endothelial and Kupffer cells are all capable of t-PA uptake. Clearance receptors on these cells are heterogeneous and include ones which recognize the carbohydrate side chains of t-PA and ones which take up t-PA: PAI-1 complexes. Receptors which recognize free t-PA also mediate liver clearance, and alpha 2-MR/LRP is a representative of this latter category. Receptors that localize t-PA on cell surfaces serve a profibrinolytic function. Vascular endothelial cells are rich in such receptors, and annexin II is a representative of these t-PA binding sites. Circulating blood cells also bind t-PA, and some of the sites on these cells are shared with plasminogen. Cells of neuronal origin are capable of binding t-PA with high affinity; and amphoterin, a protein involved in neurite outgrowth, may be a neuronal t-PA receptor. Overall, the plasminogen system is one of the most widely distributed and versatile of the cell surface-proteinase systems. By activating bound plasminogen by cell-bound plasminogen activators, the cell harnesses the broad proteolytic activity of plasmin. Cells can then utilize this activity to perform functions such as assisting in cell migration.