The Kunitz Domain i of Hepatocyte Growth Factor Activator Inhibitor-2 Inhibits Matriptase Activity and Invasive Ability of Human Prostate Cancer Cells

Wu S.-R.Teng C.-H.Tu Y.-T.Chun-Jung KoCheng T.-S.Lan S.-W.Lin H.-Y.Lin H.-H.Tu H.-F.Hsiao P.-W.HSIANG-PO HUANGCHUNG-HSIN CHENMING-SHYUE LEE2020-02-062020-02-0620172045-2322https://www.scopus.com/inward/record.uri?eid=2-s2.0-85033370838&doi=10.1038%2fs41598-017-15415-4&partnerID=40&md5=5c55d7fcf304872f4bc352d0bf3b1e82https://scholars.lib.ntu.edu.tw/handle/123456789/454720Dysregulation of pericellular proteolysis is often required for tumor invasion and cancer progression. It has been shown that down-regulation of hepatocyte growth factor activator inhibitor-2 (HAI-2) results in activation of matriptase (a membrane-anchored serine protease), human prostate cancer cell motility and tumor growth. In this study, we further characterized if HAI-2 was a cognate inhibitor for matriptase and identified which Kunitz domain of HAI-2 was required for inhibiting matriptase and human prostate cancer cell motility. Our results show that HAI-2 overexpression suppressed matriptase-induced prostate cancer cell motility. We demonstrate that HAI-2 interacts with matriptase on cell surface and inhibits matriptase proteolytic activity. Moreover, cellular HAI-2 harnesses its Kunitz domain 1 (KD1) to inhibit matriptase activation and prostate cancer cell motility although recombinant KD1 and KD2 of HAI-2 both show an inhibitory activity and interaction with matriptase protease domain. The results together indicate that HAI-2 is a cognate inhibitor of matriptase, and KD1 of HAI-2 plays a major role in the inhibition of cellular matritptase activation as well as human prostate cancer invasion. ? 2017 The Author(s).[SDGs]SDG3matriptase; membrane protein; serine proteinase; serine proteinase inhibitor; SPINT2 protein, human; amino acid sequence; animal; Bagg albino mouse; cell motion; chemistry; genetics; HEK293 cell line; human; male; metabolism; pathology; prostate tumor; protein degradation; protein domain; RNA interference; sequence homology; tumor cell line; Amino Acid Sequence; Animals; Cell Line, Tumor; Cell Movement; HEK293 Cells; Humans; Male; Membrane Glycoproteins; Mice, Inbred BALB C; Prostatic Neoplasms; Protein Domains; Proteolysis; RNA Interference; Sequence Homology, Amino Acid; Serine Endopeptidases; Serine Proteinase InhibitorsThe Kunitz Domain i of Hepatocyte Growth Factor Activator Inhibitor-2 Inhibits Matriptase Activity and Invasive Ability of Human Prostate Cancer Cellsjournal article10.1038/s41598-017-15415-42-s2.0-85033370838