Plasminogen activator inhibitors: hormonally regulated serpins

Andreasen, Peter A.; Georg, Birgitte; Lund, Leif R.; Riccio, Andrea; Stacey, Simon

doi:10.1016/0303-7207(90)90164-4

Cited by 383 publications

(216 citation statements)

References 140 publications

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“…Two plasminogen activating enzymes have been described, urokinase (uPA) and tissue plasminogen activator. Specific inhibitors and receptors for both plasminogen activators and plasminogen [3][4][5][6] add to the complexity of the plasminogen activation system. uPa is secreted as a 411 amino acids proenzyme [7][8][9] (pro-uPA), which can be bound to surface receptors (uPAR) and here be activated by a single proteolytic cleavage [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Serine phosphorylation of biosynthetic pro‐urokinase from human tumor cells

Mastronicola

Stoppelli

Migliaccio³

et al. 1990

FEBS Letters

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Phosphorylation is a potent mechanism regulating the activity of many intracellular enzymes. We have discovered that the product of the human urokinase plasminogen activator gene, pro-uPA, is phosphorylated in serine in at least two human cell lines. Phosphorylation occurs within the cell during biosynthesis, and phosphorylated intracellular pro-uPA is secreted into the medium. Of the secreted pro-uPA molecules, 20-50% are phosphorylated in serine, thus representing a meaningful fraction of the total biosynthetic pro-uPA. Although the sites of phosphorylation have not yet been determined, at least two such sites must exist; in fact plasmin cleavage of phosphorylated single chain pro-uPA yields a two chain uPA in which both chains are phosphorylated. A specific function for pro-uPA phosphorylation has not yet been identified; however, it is tempting to speculate that, as in many other cases, phosphorylation may affect the activity of the enzyme, its response to inhibitors or the conversion of pro-uPA zymogen to active two-chain uPA. This would represent an additional way of regulating extracellular proteolysis, an important pathway involved in both intra-and extravascular phenomena like fibrinolysis, cell migration and invasiveness.

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Section: Introductionmentioning

confidence: 99%

Serine phosphorylation of biosynthetic pro‐urokinase from human tumor cells

Mastronicola

Stoppelli

Migliaccio³

et al. 1990

FEBS Letters

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“…Central to this system is the conversion of the abundant zymogen plasminogen into active plasmin, which is able to degrade several extracellular proteins and to activate latent prometalloproteases (Duffy, 1992;Mignatti and Rifkin, 1993;Andreasen et al, 1997). The activation of plasminogen can be catalysed by urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), the activities of both enzymes being controlled by 2 plasminogen activator inhibitors, PAI-1 and PAI-2 (Andreasen et al, 1990(Andreasen et al, , 1997. Binding of uPA to its specific cellular receptor, uPAR, is considered to be an important step in the proteolytic cascade, since this receptor localizes the proteolytic activities to the cell surface and strongly enhances activation of surface-bound plasminogen (Danø et al, 1994).…”

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confidence: 99%

Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours

et al. 2001

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Summary Using a previously developed enzyme-linked immunosorbent assay (ELISA), the levels of the receptor for urokinase-type plasminogen activator (uPAR) were determined in cytosols and corresponding membrane pellets derived from 878 primary breast tumours. The levels of uPAR in the pellet extracts were more than 3-fold higher than those measured in the cytosols (P < 0.001). Moreover, the uPAR levels in the two types of extracts were weakly, though significantly, correlated with each other (r S = 0.20, P < 0.001). In Cox univariate analysis, high cytosolic levels of uPAR were significantly associated with reduced overall survival (OS) and relapse-free survival (RFS). The levels of uPAR in pellet extracts appeared not to be related with patient survival. In multivariate analysis, elevated levels of uPAR measured in cytosols and pellet extracts were found to be independent predictors of poor OS, not RFS. The prediction of poor prognosis on the basis of high uPAR levels emphasizes its important role in plasmin-mediated degradation of extracellular matrix proteins during cancer invasion and metastasis.

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“…There are two main types of inhibitors of plasminogen activator, PAI-1 and PAI-2. The urokinase receptor (uPAR) serves to localize plasminogen activation to cell surfaces (Dan0 et al, 1985;Andreasen et al, 1990Andreasen et al, , 1997Mignatti and Rifkin, 1993 Recent studies have shown that the levels of uPA and PAI-I in malignant tumours vary considerably and are related to the prognosis of the patient (Andreasen et al, 1997). Whether uPA and PAI-I are related to local recurrence, metastatic spread or both is not clear.…”

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confidence: 99%

Prognostic significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in primary breast cancer

Knoop

Andreasen²,

Hansen³

et al. 1998

Br J Cancer

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Summary The uPA-mediated pathway of plasminogen activation is central to cancer metastasis. Whether uPA and PAI-1 are related to local recurrence, metastatic spread or both is not clear. We present a retrospective study of 429 primary breast cancer patients with a median followup of 5.1 years, in which the levels of uPA and PAI-1 in tumour extracts were analysed by means of an enzyme-linked immunosorbent assay.The median values of uPA and PAI-1, which were used as cut-off points, were 4.5 and 11.1 ng mg-1 protein respectively. The levels of uPA and PAI-1 were correlated with tumour size, degree of anaplasia, steroid receptor status and number of positive nodes. Patients with high content of either uPA or PAI-1 had increased risk of relapse and death. We demonstrated an independent ability of PAI-1 to predict distant metastasis (relative risk 1.7, confidence limits 1.22 and 2.46) and that neither uPA nor PAI-1 provided any information regarding local recurrence.Keywords: urokinase; plasminogen; PAI-1; breast neoplasm mortality; prognosis Cancer cells undergo the following steps during metastasis: detachment from the primary tumour; migration; invasion of the blood and lymphatic vessels; adhesion to and penetration of the endothelium, allowing colonization at distant sites (Liotta et al, 1991). Tumour progression and metastasis also involve various processes that may be called cancer cell-directed tissue remodelling. Examples are angiogenesis (Folkman, 1995) and desmoplasia (Dvorak et al, 1995).Extracellular proteolysis has been implicated in cancer metastasis for many years, with the basic idea that release of proteolytic enzymes from a tumour leads to breakdown of basement membranes and extracellular matrix (ECM), thus allowing cancer cell invasion into the surrounding normal tissue. This is true for plasminogen activators and metalloproteinases (Dan0 et al, 1985;Liotta et al, 1991;Mignatti and Rifkin, 1993;Andreasen et al, 1997). There are two types of plasminogen activator, the urokinase-type uPA and the tissue-type tPA. Both are capable of catalysing the formation of the broad spectrum proteinase plasmin from the inactive zymogen plasminogen. There seems to be general agreement that uPA is most important for generation of plasmin in events involving degradation of ECM, while the primary role of tPA is to generate plasmin for thrombolysis. In relation to cancer metastasis, therefore, uPA is of main interest. There are two main types of inhibitors of plasminogen activator, PAI-1 and PAI-2. The urokinase receptor (uPAR) serves to localize plasminogen activation to cell surfaces (Dan0 et al, 1985;Andreasen et al, 1990Andreasen et al, , 1997Mignatti and Rifkin, 1993 Recent studies have shown that the levels of uPA and PAI-I in malignant tumours vary considerably and are related to the prognosis of the patient (Andreasen et al, 1997). Whether uPA and PAI-I are related to local recurrence, metastatic spread or both is not clear. None of the research groups has to our knowledge looked specifically into the levels of...

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Plasminogen activator inhibitors: hormonally regulated serpins

Cited by 383 publications

References 140 publications

Serine phosphorylation of biosynthetic pro‐urokinase from human tumor cells

Serine phosphorylation of biosynthetic pro‐urokinase from human tumor cells

Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours

Prognostic significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in primary breast cancer

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