Initiation of plasminogen activation on the surface of monocytes expressing the type II transmembrane serine protease matriptase

Abstract

uPA (urokinase-type plasminogen activator) activates plasminogen with high efficiency when bound to its cellular receptor uPAR, but only after a prolonged lag phase during which generated plasmin activates pro-uPA. How the activity of this proteolytic system might be rapidly initiated is unknown. We have now found that 2 monocytic cell lines display distinct patterns of plasminogen activation. U937 cells, but not THP-1 cells, displayed the expected lag phase, suggesting a constitutive initiation mechanism on the latter. This was shown to be due to the plasmin-independent activation of uPAR-bound pro-uPA by a cell surface-associated protease and to correlate with the expression of matriptase, a type II transmembrane serine protease that was highly expressed in THP-1 cells but undetectable in U937 cells. Kinetic analysis demonstrated that matriptase is a relatively poor activator of pro-uPA in solution, approximately 100-fold less efficient than plasmin (k(cat)/K(m) 1.16 x 10(5) M(-1)s(-1) cf 1.21 x 10(7) M(-1)s(-1)). However, down-regulation of matriptase expression in THP-1 cells by siRNA reduced the activation of cell-associated pro-uPA and the subsequent rapid initiation of plasminogen activation by 76% to 93%. Matriptase was also found to be expressed by peripheral blood monocytes and may therefore be a specific mechanism for the rapid initiation and regulation of plasminogen activation by these cells.

Crystal Structures of Matriptase in Complex with Its Inhibitor Hepatocyte Growth Factor Activator Inhibitor-1

“…ticipate in immune response (6,7). Indeed, knockdown studies in mice have shown that matriptase is important in postnatal survival, the development of the epidermis, hair follicles, and cellular immune system (8).…”

Requirement of the activity of hepatocyte growth factor activator inhibitor type 1 for the extracellular appearance of a transmembrane serine protease matriptase in monkey kidney COS-1 cells

“…HAI-1 might prevent the self-degradation of matriptase in the intracellular environment. It has been shown that matriptase is not co-expressed with HAI-1 in certain cell types and cultured cells (e.g., in ovary granulosa cells and in human monocyte THP-1 cells) (Szabo et al 2008;Kilpatrick et al 2006). In addition, genetic studies using zebrafish indicated that matriptase does not require HAI-1 for biological activity (i.e., for extracellular occurrence) (Carney et al 2007;Mathias et al 2007).…”

Polyserase-1/TMPRSS9 induces pro-tumor effects in pancreatic cancer cells by activation of pro-uPA

“…For example, TMPRSS4 upregulates uPA expression and activation in the DU145 prostate cancer and the NCI-H322 lung cancer cell lines by a mechanism involving modulation of the ERK signaling pathway (23). Matriptase is also able to activate pro-UPA in the ovarian cancer cell line HRA (29) and the monocytic leukemia cell line THP-1 (22). On the other hand, induction of invasive and migratory capacities of PANC-1 cells has been linked to activation of ERK by phosphorylation (30).…”

“…Different reports have emphasized the pro-tumor activities of different TTSPs in pancreatic cancer (9,20,21). Activation (22) or upregulation (23) of pro-uPA may underlie the pro-tumor effects caused by these serine proteases. In the present study, we investigated the effects of the exogenous expression of polyserase-1 in pancreas-derived tumor cells (24,25).…”