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

Abstract

Dysregulation 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.

SPINT2 inhibits proteases involved in activation of both influenza viruses and metapneumoviruses

“…However, we believe that future research will allow to fully utilize the potential of SPINT2 as a broadspectrum antiviral therapy. Wu et al, recently described that the Kunitz domain I of SPINT2 is responsible for the inhibition of matriptase (Wu et al, 2017a). In future studies we will explore whether the inhibitory capabilities of SPINT2 can be condensed into small peptides that may improve its efficacy.…”

“…However, the finding that SPINT2 is also expressed in brain and lymph node cells indicates that it might regulate other proteases than matriptase (Szabo et al, 2008). Recent reports associated the physiological role of SPINT2 with the inhibition of human serinetype proteases such as matriptase, plasmin, kallikreins (KLK) and coagulation factor XIa (Wu et al, 2017a(Wu et al, , 2019Roversi et al, 2018;Delaria et al, 1997). SPINT2 possesses one transmembrane domain and two kunitz-type inhibitor domains that are exposed to the extracellular space and which are believed to facilitate a potent inhibition of target proteases.…”

“…SPINT2 possesses one transmembrane domain and two kunitz-type inhibitor domains that are exposed to the extracellular space and which are believed to facilitate a potent inhibition of target proteases. Wu et al recently described that the kunitz-type domain 1 of SPINT2 is responsible for matriptase inhibition (Wu et al, 2017a). A major function of SPINT2 is its role as a tumor suppressor because down-regulation diminishes the prospect of survival of several cancers such as hepatocellular carcinoma, gastric cancer, prostate cancer or melanoma (Fukai et al, 2003;Dong et al, 2010;Tsai et al, 2014;Hwang et al, 2015).…”

HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis

“…HAI-2 exhibits two major bands by western blot due to its N-glycosylation. 38,39 HAI-1 expression was only present in H1975 and CL97 cells and showed no correlation with the cell invasion ( Fig. 1a, lower panel).…”

“…Low risk (high HAl-2) (20) 22 (35) 14 (21) 24 (38) 12 (18) 23 (36) 13 (21) 34 (54) 2 (3) 17 (26) 10 (15) 7 (11) 2 (3) 17 (26) 19 (29) 1 (1.5) 18 (28) 17 (27) 11 (17) 20 (31) 8 (13) 25 (39) 3 (5) 22 (34) 6 (9) 28 (43) promote metastasis. 28 During EMT process, the loss of E-cadherin is often accompanied with the up-regulation of mesenchymal neuron cadherin (N-cadherin) or a cytoskeleton protein Vimentin.…”