The integral membrane

Kunitz-type serine protease inhibitors HAI-1 and HAI-2

can suppress the proteolytic activity of the type 2 transmembrane serine protease matriptase with high specificity and potency. High levels of extracellular matriptase proteolytic activity have

however

been observed in some neoplastic B-cells with high levels of endogenous HAI-2

indicating that HAI-2 may be an ineffective matriptase inhibitor at the cellular level. The different effectiveness of the HAIs in the control of extracellular matriptase proteolytic activity is examined here. Upon inducing matriptase zymogen activation in the HAI Teton Daudi Burkitt lymphoma cells

which naturally express matriptase with very low levels of HAI-2 and no HAI-1

nascent active matriptase was rapidly inhibited or shed as an enzymatically active enzyme. With increasing HAI-1 expression

cellular matriptase-HAI-1 complex increased

and extracellular active matriptase decreased proportionally. Increasing HAI-2 expression

however

resulted in cellular matriptase-HAI-2 complex levels reaching a plateau

while extracellular active matriptase remained high. In contrast to this differential effect

both HAI-1 and HAI-2

even at very low levels

were shown to promote the expression and cell-surface translocation of endogenous matriptase. The difference in the suppression of extracellular active matriptase by the two closely related serine protease inhibitors could result from the primarily cell surface expression of HAI-1 compared to the mainly intracellular localization of HAI-2. The HAIs

therefore

resemble one another with respect to promoting matriptase expression and surface translocation but differ in their effectiveness in the control of extracellular matriptase enzymatic activity.