Matriptase is inhibited by extravascular antithrombin in epithelial cells but not in most carcinoma cells
Journal
American Journal of Physiology - Cell Physiology
Journal Volume
301
Journal Issue
5
Pages
C1093-C1103
Date Issued
2011
Author(s)
Abstract
Antithrombin, a major anticoagulant, is robustly transported into extravascular compartments where its target proteases are largely unknown. This serpin was previously detected in human milk as complexes with matriptase, a membrane-bound serine protease broadly expressed in epithelial and carcinoma cells, and under tight regulation by hepatocyte growth factor activator inhibitor (HAI)-1, a transmembrane Kunitz-type serine protease inhibitor that forms heat-sensitive complexes with active matriptase. In the current study, we detect, in addition to matriptase- HAI-1 complexes, heat-resistant matriptase complexes generated by nontransformed mammary, prostate, and epidermal epithelial cells that we show to be matriptase-antithrombin complexes. These findings suggest that in addition to HAI-1, interstitial antithrombin participates in the regulation of matriptase activity in epithelial cells. This physiological mechanism appears, however, to largely be lost in cancer cells since matriptase-antithrombin complexes were not detected in all but two of a panel of seven breast, prostate, and ovarian cancer cell lines. Using purified active matriptase, we further characterize the formation of matriptase-antithrombin complex and show that heparin can significantly potentiate the inhibitory potency of antithrombin against matriptase. Second-order rate constants for the inhibition were determined to be 3.9 × 10 3 M -1s -1 in the absence of heparin and 1.2 × 10 5 M -1s -1 in the presence of heparin, a 30-fold increase, consistent with the established role of heparin in activating antithrombin function. Taken together these data suggest that normal epithelial cells employ a dual mechanism involving HAI-1 and antithrombin to control matriptase and that the antithrombin-based mechanism appears lost in the majority of carcinoma cells. ? 2011 the American Physiological Society.
Subjects
Coagulation; Hepatocyte growth factor activator inhibitor-1; Tumor cells
SDGs
Other Subjects
antithrombin; heparin; matriptase; article; breast cancer; cancer cell culture; carcinoma cell; enzyme activation; enzyme activity; epithelium cell; female; human; human cell; male; ovary cancer; priority journal; prostate cancer; protein purification; Antigens, Nuclear; Antithrombin III; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Epidermis; Epithelial Cells; Female; Heparin; Humans; Male; Mammary Glands, Human; Ovarian Neoplasms; Prostate; Prostatic Neoplasms; Proteinase Inhibitory Proteins, Secretory; Transcription Factors
Type
journal article