Mark Peek

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

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 (IC50 21.1 ± 2.7 nM) and HAI‐2 (IC50 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.