Hepatocyte growth factor activator inhibitor type 1 inhibits protease activity and proteolytic activation of human airway trypsin-like protease.
Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a Kunitz-type transmembrane serine protease inhibitor initially identified as a potent inhibitor of hepatocyte growth factor activator (HGFA), a serine protease that converts pro-HGF to the active form. HAI-1 also has inhibitory activity against serine proteases such as matriptase, hepsin and prostasin. In this study, we examined effects of HAI-1 on the protease activity and proteolytic activation of human airway trypsin-like protease (HAT), a transmembrane serine protease that is expressed mainly in bronchial epithelial cells. A soluble form of HAI-1 inhibited the protease activity of HAT in vitro. HAT was proteolytically activated in cultured mammalian cells transfected with its expression vector, and a soluble form of active HAT was released into the conditioned medium. The proteolytic activation of HAT required its own serine protease activity. Co-expression of the transmembrane full-length HAI-1 inhibited the proteolytic activation of HAT. In addition, full-length HAI-1 associated with the transmembrane full-length HAT in co-expressing cells. Like other target proteases of HAI-1, HAT converted pro-HGF to the active form in vitro. These results suggest that HAI-1 functions as a physiological regulator of HAT by inhibiting its protease activity and proteolytic activation in airway epithelium.
Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. kato.minoru@mp.mt-pharma.co.jp
Minoru
M
Kato
Tomio
T
Hashimoto
Takeshi
T
Shimomura
Hiroaki
H
Kataoka
Hideyuki
H
Ohi
Naomi
N
Kitamura
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004847:Epithelial Cells / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053491:Proteinase Inhibitory Proteins, Secretory / Q000378:metabolism*; D059748:Proteolysis; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*
D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C112256:human airway trypsin-like protease