Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2

• Published in: FEBS letters 2005-03, Vol.579 (9), p.1945-1950
• Main Authors: Kirchhofer, Daniel, Peek, Mark, Lipari, Michael T., Billeci, Karen, Fan, Bin, Moran, Paul
• Format: Article
• Language: English
• Subjects: Animals; CHO Cells; Cricetinae; Cricetulus; HAI-1, HAI-1B; HAI-2; Hepatocyte growth factor; Hepatocyte Growth Factor - metabolism; Hepsin; HGF; HGF activator; HGFA; HGFA inhibitor-1; HGFA inhibitor-2; Humans; KD1 and KD2; Kunitz domain; Male; Membrane Glycoproteins - pharmacology; Membrane Glycoproteins - physiology; N- and C-terminal Kunitz domain of HAI-1B; Prostate cancer; Prostatic Neoplasms - metabolism; Protein Precursors - drug effects; Protein Precursors - metabolism; Proteinase Inhibitory Proteins, Secretory; Serine Endopeptidases - pharmacology; Serine Endopeptidases - physiology; splice variants of HGFA inhibitor-1; t-PA; tissue-type plasminogen activator; Trypsin Inhibitor, Kunitz Soybean - pharmacology; TTSP; type II transmembrane serine protease; u-PA; urokinase-type plasminogen activator
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2005.01.085

Hepsin, a type II transmembrane serine protease, is highly upregulated in prostate cancer and promotes tumor progression and metastasis. We generated a soluble form of hepsin comprising the entire extracellular domain to show that it efficiently converts single-chain hepatocyte growth factor (pro-HGF) into biologically active two-chain HGF. Hepsin activity was potently inhibited by soluble forms of the bi-Kunitz domain inhibitors HAI-1B (IC 50 21.1 ± 2.7 nM) and HAI-2 (IC 50 1.3 ± 0.3 nM). Enzymatic assays with HAI-1B Kunitz domain mutants (R260A and K401A) further demonstrated that inhibition was due to Kunitz domain-1. The results suggest a functional link between hepsin and the HGF/Met pathway, which may contribute to tumor progression.