Purification from human milk of matriptase complexes with secreted serpins: mechanism for inhibition of matriptase other than HAI-1
- 1 August 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 295 (2), C423-C431
- https://doi.org/10.1152/ajpcell.00164.2008
Abstract
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, α1-antitrypsin, and α2-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.Keywords
This publication has 33 references indexed in Scilit:
- Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathwayProceedings of the National Academy of Sciences, 2007
- Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental developmentOncogene, 2006
- Shape-shifting serpins – advantages of a mobile mechanismTrends in Biochemical Sciences, 2006
- A Novel Biomarker for Staging Human Prostate Adenocarcinoma: Overexpression of Matriptase with Concomitant Loss of its Inhibitor, Hepatocyte Growth Factor Activator Inhibitor-1Cancer Epidemiology, Biomarkers & Prevention, 2006
- Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformationGenes & Development, 2005
- Simultaneous activation and hepatocyte growth factor activator inhibitor 1-mediated inhibition of matriptase induced at activation foci in human mammary epithelial cellsAmerican Journal of Physiology-Cell Physiology, 2005
- Assembly of adherens junctions is required for sphingosine 1-phosphate-induced matriptase accumulation and activation at mammary epithelial cell-cell contactsAmerican Journal of Physiology-Cell Physiology, 2004
- Sphingosine 1-Phosphate, Present in Serum-derived Lipoproteins, Activates MatriptasePublished by Elsevier BV ,2002
- The kidney is a major site of alpha(2)-antiplasmin production.JCI Insight, 1996
- Immunocytochemical localization of endogenous anti-thrombin III in the vasculature of rat tissues reveals locations of anticoagulantly active heparan sulfate proteoglycans.Journal of Histochemistry & Cytochemistry, 1994