title: Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2.
abstract: 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.
authors.affiliation: Department of Physiology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. dak@gne.com
authors.forename: Daniel
authors.initials: D
authors.lastname: Kirchhofer
authors.forename: Mark
authors.initials: M
authors.lastname: Peek
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lipari
authors.forename: Karen
authors.initials: K
authors.lastname: Billeci
authors.forename: Bin
authors.initials: B
authors.lastname: Fan
authors.forename: Paul
authors.initials: P
authors.lastname: Moran
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011498:Protein Precursors / Q000187:drug effects / Q000378:metabolism*; D053491:Proteinase Inhibitory Proteins, Secretory; D012697:Serine Endopeptidases / Q000494:pharmacology / Q000502:physiology*; D014360:Trypsin Inhibitor, Kunitz Soybean / Q000494:pharmacology
chemical_list: D008562:Membrane Glycoproteins; D011498:Protein Precursors; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; C109148:SPINT2 protein, human; C086013:pro-hepatocyte growth factor; D017228:Hepatocyte Growth Factor; D014360:Trypsin Inhibitor, Kunitz Soybean; D012697:Serine Endopeptidases; C055645:hepsin