Plasminogen receptors and their role in the pathogenesis of inflammatory, autoimmune and malignant disease

Abstract

Summary. Plasminogen is the proenzyme of plasmin, the key protease of the fibrinolytic system, but its role is not limited to fibrinolysis regulation. Plasminogen binds not only to fibrin, but also to different receptors on cell surfaces, including the heterotetrameric complex Annexin A2-S100A10, enolase-1, histone H2B and the plasminogen receptor Plg-R KT . These receptors localize plasmin generation to the cell surface and provide a broad spectrum of reactions including proteolytic activity, cell migration and recruitment as well as signaling pathway activation. These plasminogen-binding proteins are involved in both physiologic and pathologic processes such as inflammation, thrombosis and cancer. Thus, plasminogen is at the center of a complex tightly controlled and regulated system where plasminogen-binding proteins have a crucial role, suggesting new therapeutic and diagnostic strategies. This review will discuss currently available information on plasminogen receptors, particularly their mechanisms of action and their roles in inflammatory, autoimmune and malignant disease.

Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)

“…The strong LBS present in plasminogen allows for its binding and subsequent activation to occur on various receptors containing carboxyl-terminal lysines including annexin A2 A100A10 heterotetramer, enolase-1, and Plg-R KT ( 38 ). For example, treatment of monocytoid cells with carboxypeptidase B (CpB), which removes carboxyl-terminal lysines, leads to a decrease of 64% for plasminogen binding and >95% for plasminogen activation ( 39 ).…”

“…Plasminogen receptors are a heterogeneous and ubiquitously present group of cell-surface proteins ( 38 ). Plasminogen receptors have been shown to contain carboxyl-terminal lysine residues that bind plasminogen ( 38 ).…”

“…Plasminogen receptors have been shown to contain carboxyl-terminal lysine residues that bind plasminogen ( 38 ). Removal of these carboxyl-terminal lysines destroys the ability of this subset of receptors to bind to plasminogen and support its activation ( 38 ).…”

“…Plasminogen receptors have been shown to contain carboxyl-terminal lysine residues that bind plasminogen ( 38 ). Removal of these carboxyl-terminal lysines destroys the ability of this subset of receptors to bind to plasminogen and support its activation ( 38 ). However, not all plasminogen receptors contain a carboxyl-terminal lysine, with examples of this type being actin, amphoterin, ␣ V ␤ 3 , ␣ M ␤ 2 , and ␣ IIb ␤ 3 ( 57 ).…”

“…However, not all plasminogen receptors contain a carboxyl-terminal lysine, with examples of this type being actin, amphoterin, ␣ V ␤ 3 , ␣ M ␤ 2 , and ␣ IIb ␤ 3 ( 57 ). Binding of plasminogen to these receptors presumably converts plasminogen from its native closed conformation into a more open and highly activatable form ( 38 ). The initial plasmin generated on the cell surface begins to catalyze the positive feedback mechanism of converting Glu-to Lysplasminogen, the latter of which is itself more readily activatable ( 32 ).…”