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: Shoichiro Mukai, Tsuyoshi Fukushima, Daiji Naka, Hiroyuki Tanaka, Yukio Osada, Hiroaki Kataoka
• Journal: The FEBS journal (FEBS J) Vol. 275 Issue 5 Pg. 1003-17 (Mar 2008) ISSN: 1742-464X [Print] England
• PMID: 18221492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proteinase Inhibitory Proteins, Secretory
• SPINT1 protein, human
• Serpins
• HGF activator
• KLK5 protein, human
• Kallikreins
• Serine Endopeptidases
• kallikrein 4
• Tissue Kallikreins

Topics

• Cell Line, Tumor
• Enzyme Activation
• Humans
• Kallikreins (antagonists & inhibitors, metabolism)
• Proteinase Inhibitory Proteins, Secretory (metabolism)
• Serine Endopeptidases (metabolism)
• Serpins (metabolism)
• Tissue Kallikreins (metabolism)