Publisher Summary This chapter discusses the role of plasminogen activators in various biological processes. In specific, it describes two types of plasminogen activators—namely, the urokinase-type plasminogen activator (u-PA) and the tissue-type plasminogen activator (t-PA), which are essentially different gene products. The amino acid sequences of these activators and nucleotide sequences of the corresponding cDNAs have largely been determined, and the cDNAs have been cloned using recombinant techniques. A variety of enzymatic as well as immunological assay and detection methods have also been developed that allows a precise quantification of the activators, a distinction between u-PA and t-PA, determination of whether an activator is present in its active or zymogen form, analysis of the kinetics of different steps of the cascade reaction, and immunocytochemical identification of u-PA and t-PA in tissue sections. Much of the studies on plasminogen activators and cancer has been guided by the hypothesis that proteolysis of the components of extracellular matrix, initiated by the release of plasminogen activator from the cancer cells, plays a decisive role for the degradation of normal tissue, and thereby for invasive growth and metastases.

Plasminogen activators, tissue degradation, and cancer.

The secretion of plasminogen activators has been implicated in the controlled extracellular proteolysis that accompanies cell migration and tissue remodeling. We found that the human plasminogen activator urokinase (Uk) (Mr 55,000 form) binds rapidly, specifically, and with high affinity to fresh human blood monocytes and to cells of the monocyte line U937. Upon binding Mr 55,000 Uk was observed to confer high plasminogen activator activity to the cells. Binding of the enzyme did not require a functional catalytic site (located on the B chain of the protein) but did require the noncatalytic A chain of Mr 55,000 Uk, since Mr 33,000 Uk did not bind. These results demonstrate the presence of a membrane receptor for Uk on monocytes and show a hitherto unknown function for the A chain of Uk: binding of secreted enzyme to its receptor results in Uk acting as a membrane protease. This localizes plasminogen activation near the cell surface, an optimal site to facilitate cell migration.

https://rupress.org/jcb/article-pdf/100/1/86/1051168/86.pdf

A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase.

Antibodies to plasminogen activator inhibit human tumor metastasis

N 'Ew information has recently become available that we believe may be of value for a more precise focusing of research on the role of plasminogen activators (PAs) in cellular physiology and pathology. PAs convert the abundant extracellular zymogen plasminogen into plasmin, an active protease that, directly or indirectly, can promote degradation of all components of the extracellular matrix. The urokinase-type PA (u-PA) is one of two activators with similar catalytic specificities that have been described in each mammalian species so far studied. Many cell types synthesize and secrete u-PA at different stages in their life cycle; it has been a consistent finding that the expression of u-PAcatalyzed proteolysis is under the control of hormonal-type mediators, the nature of which depends on the cell population considered, u-PA is thought to play a central role in regulating extracellular proteolysis in a variety of normal and pathological processes involving tissue destruction and cell migration, e.g., organ involution, inflammatory reactions, and invasive growth of trophoblasts and cancer cells (for reviews, see 8, 18, 44, 47, 49, 50). Recent findings show that u-PA is synthesized and released from mammalian cells as a proenzyme with little or no activity (pro-u-PA), that cells possess a specific binding site for u-PA and pro-u-PA, and that they can also synthesize different rapidly acting, high affinity inhibitors of PAs. Thus, activation of pro-u-PA, u-PA receptor occupancy, and PA-inhibitors may finely regulate the location and extent of plasminogen activation.

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T C Wun

Papers

A proenzyme form of human urokinase.