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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

Purification from human milk of matriptase complexes with secreted serpins: mechanism for inhibition of matriptase other than HAI-1

¹Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, Maryland; ²MedImmune, Gaithersburg, Maryland; ³Graduated Institute of Biochemistry and Molecular Biology, College of Medicine National Taiwan University, Taipei, Taiwan; ⁴Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, Republic of China; ⁵Brigham and Women's Hospital, Division of Rheumatology, Immunology, and Allergy, Boston, Massachusetts; ⁶Lombardi Cancer Center, Department of Oncology, Georgetown University, Washington, DC

Submitted 20 March 2008 ; accepted in final form 5 June 2008

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 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 were 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 present study, we characterized matriptase complexes of 110 kDa in human milk, which contained no HAI-1 and 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 noncatalytic 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, 1-antitrypsin, and 2-antiplasmin. Identification of matriptase-serpin inhibitor complexes provides evidence for the first time that the proteolytic activity of matriptase, from those cells that express no or low levels of HAI-1, may be controlled by secreted serpins.

protease; type 2 transmembrane serine protease; protease inhibitor; ST-14; hepatocyte growth factor activator inhibitor 1

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