STRUCTURE, FUNCTION AND EXPRESSION ON BLOOD AND BONE-MARROW CELLS OF THE UROKINASE-TYPE PLASMINOGEN-ACTIVATOR RECEPTOR, UPAR

Several important functions have been assigned to the receptor for uro kinase-type plasminogen activator, uPAR. As implied by the name, uPAR was first identified as a high affinity cellular receptor for urokinas e plasminogen activator (uPA). It mediates the binding of the zymogen, pro uPA, to the plasma membrane where trace amounts of plasmin will i nitiate a series of events referred to as ''reciprocal zymogen activat ion'' where plasmin converts pro-uPA to the active enzyme, uPA, which in turn converts plasma membrane-associated plasminogen to plasmin. Th is is an efficient machinery to generate broad-spectrum proteolytic ac tivity which is spatially restricted to the plasma membrane, since pla smin that diffuses away hom the plasma membrane is rapidly inactivated by circulating inhibitors (i.e., alpha(2)-antiplasmin). The system is controlled by a series of plasminogen activator inhibitors (PAIs), mo st importantly PAI-1 and PAI-2, providing means of temporally restrict ing the process of plasminogen activation. In addition to its role in plasminogen activation, compelling evidence has demonstrated a role fo r uPAR in cell-cell and cell-extracellular matrix adhesion, both direc tly and indirectly. uPAR is directly involved in binding to the extrac ellular matrix molecule, vitronectin, and the affinity of this binding is increased when uPAR is occupied by (pro-)uPA. A more indirect but presumably very important role of uPAR in cell adhesion seems to be me diated through interactions between uPAR and beta(1) or beta(2)-integr ins. It has been demonstrated that uPAR may bind physically to integri ns in a reversible manner. The interaction seems to be of functional i mportance since the affinity of the integrin for its corresponding lig and is modulated by the association of integrin with uPAR. In some exp erimental setups uPAR has been shown to reduce the affinity of the ass ociated integrin for certain ligands, while other experimental systems have demonstrated an increased affinity of the interaction between in tegrin and ligand after binding of uPAR to the integrin. Finally, uPAR has also been shown to participate in signal transduction events. Sin ce uPAR is not a transmembrane molecule but belongs to the group of pr oteins that are tethered to the plasma membrane via a glycosyl-phospha tidylinositol anchor, association with a transmembrane adaptor is requ ired for transmission of signals via uPAR. Integrins may serve as such signal transducers, and indeed uPAR has been shown to be associated i n the plasma membrane with complexes of integrins and (phosphorylated) tyrosin kinases suggesting a role for these complexes in transmembran e transmission of signals via uPAR. In the hematopoietic system it has been shown that urokinase-type plasminogen activator (uPAR) is expres sed as a differentiation antigen on cells of the myelomonocytic Lineag e and as an activation antigen on monocytes and T lymphocytes. Neutrop hils contain intracellular reservoirs of uPAR that are translocated to the plasma membrane upon activation, and neutrophils from patients wi th the rare blood disease paroxysmal nocturnal hemoglobinuria (PNH) th at fail to express glycosyl-phosphatidylinositol-anchored proteins inc luding uPAR, show a very significantly reduced transmigration over an endothelial barrier. Cell-associated plasminogen activation by PNH-aff ected neutrophils is severely impaired, and it has been proposed that this may be causally related to the propensity for thrombosis in PNH. The pattern of expression of uPAR in hematological malignancies mirror s the expression by normal blood and bone marrow counterparts with som e exceptions (differentiated myeloid leukemias are positive, undiffere ntiated myeloid may be negative and the majority of lymphoid leukemias and lymphomas are negative). The potential clinical relevance of uPAR expression in leukemias and lymphomas has not been determined.