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1 University of Maryland
2 MedImmune, Inc.
3 National Taiwan University
4 National Defense Medical Center
5 Harvard Medical School, Brigham and Women's Hospital
6 University of Maryland School of Medicine
* To whom correspondence should be addressed. E-mail: cylin{at}som.umaryland.edu.
Matriptase, a type 2 transmembrane serine protease, is predominately expressed by epithelial and carcinoma cells, in which hepatocyte growth factor activator inhibitor 1 (HAI-1), a membrane-bound, Kunitz-type serine protease inhibitor, is also expressed. HAI-1 plays dual roles in the regulation of matriptase, as a conventional protease inhibitor, and as a factor required for zymogen activation of matriptase. As a consequence, activation of matriptase is immediately followed by HAI-1-mediated inhibition with all the activated matriptase being sequestered into HAI-1 complexes. Matriptase is also expressed by peripheral blood leukocytes, such as monocytes and macrophages, however, in contrast to epithelial cells, monocytes and macrophages are reported not to express HAI-1, suggesting that these leukocytes possess alternate, HAI-1 independent mechanisms regulating the zymogen activation and protease inhibition of matriptase. In the current study, we characterized matriptase complexes of 110-kDa in human milk, which contained no HAI-1 and which resisted dissociation in boiling SDS in the absence of reducing agents. These complexes were further purified and dissociated into 80-kDa and 45-kDa fragments by treatment with reducing agents. Proteomic and immunological methods identified the 45-kDa fragment as the non-catalytic domains of matriptase and the 80-kDa fragment as the matriptase serine protease domain covalently linked to one of three different secreted serpin inhibitors: antithrombin III, alpha 1 antitrypsin, and alpha 2 antiplasmin. Identification of matriptase-serpin inhibitor complexes provides evidence for the first time that the proteolytic activity of matriptase, from those cells which express no or low levels of HAI-1, may be controlled by secreted serpins.
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