title: Activation of hepatocyte growth factor activator zymogen (pro-HGFA) by human kallikrein 1-related peptidases.
abstract: Hepatocyte growth factor activator (HGFA) is a serine protease and a potent activator of prohepatocyte growth factor/scatter factor (pro-HGF/SF), a multifunctional growth factor that is critically involved in tissue morphogenesis, regeneration, and tumor progression. HGFA circulates as a zymogen (pro-HGFA) and is activated in response to tissue injury. Although thrombin is considered to be an activator of pro-HGFA, alternative pro-HGFA activation pathways in tumor microenvironments remain to be identified. In this study, we examined the effects of kallikrein 1-related peptidases (KLKs), a family of extracellular serine proteases, on the activation of pro-HGFA. Among the KLKs examined (KLK2, KLK3, KLK4 and KLK5), we identified KLK4 and KLK5 as novel activators of pro-HGFA. Using N-terminal sequencing, the cleavage site was identified as the normal processing site, Arg407-Ile408. The activation of pro-HGFA by KLK5 required a negatively charged substance such as dextran sulfate, whereas KLK4 could process pro-HGFA without dextran sulfate. KLK5 showed more efficient pro-HGFA processing than KLK4, and was expressed in 50% (13/25) of the tumor cell lines examined. HGFA processed by these KLKs efficiently activated pro-HGF/SF, and led to cellular scattering and invasion in vitro. The activities of both KLK4 and KLK5 were strongly inhibited by HGFA inhibitor type 1, an integral membrane Kunitz-type serine protease inhibitor that inhibits HGFA and other pro-HGF/SF-activating proteases. These data suggest that KLK4 and KLK5 mediate HGFA-induced activation of pro-HGF/SF within tumor tissue, which may thereafter trigger a series of events leading to tumor progression via the MET receptor.
authors.affiliation: Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Mukai
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Daiji
authors.initials: D
authors.lastname: Naka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yukio
authors.initials: Y
authors.lastname: Osada
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kataoka
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism; D020840:Tissue Kallikreins / Q000378:metabolism*
chemical_list: D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; D015843:Serpins; C081092:HGF activator; C400147:KLK5 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases; C120801:kallikrein 4; D020840:Tissue Kallikreins