Hepatocyte Growth Factor Activator: A Proteinase Linking Tissue Injury with Repair

Abstract

Hepatocyte growth factor (HGF) promotes pleiotropic signaling through its specific receptor tyrosine kinase, MET. As such, it has important roles in the regeneration of injured tissues. Since HGF is produced mainly by mesenchymal cells and MET is expressed in most epithelial, endothelial and somatic stem cells, HGF functions as a typical paracrine growth factor. HGF is secreted as an inactive precursor (proHGF) and requires proteolytic activation to initiate HGF-induced MET signaling. HGF activator (HGFAC) is a serum activator of proHGF and produces robust HGF activities in injured tissues. HGFAC is a coagulation factor XII-like serine endopeptidase that circulates in the plasma as a zymogen (proHGFAC). Thrombin, kallikrein-related peptidase (KLK)-4 or KLK-5 efficiently activates proHGFAC. The activated HGFAC cleaves proHGF at Arg494-Val495, resulting in the formation of the active disulfide-linked heterodimer HGF. Macrophage stimulating protein, a ligand of RON, is also activated by HGFAC in vivo. Although HGFAC functions primarily at the site of damaged tissue, a recent report has suggested that activated HGFAC relays a signal to stem cells in non-injured tissues via proHGF activation in the stem cell niche. This review focuses on current knowledge regarding HGFAC-mediated proHGF activation and its roles in tissue regeneration and repair.

Keywords: HGF; MET; hepatocyte growth factor activator; protease; tissue injury; tissue repair.

Figure 1

Tissue injury-induced activations of proHGF by HGFAC in response to tissue injury. Thrombin efficiently activates plasma-derived proHGFAC. KLK-4 and -5 also activate proHGFAC as well. Activated HGFAC is also released into the bloodstream and serves as an “alarmin” for tissue stem cells of non-injured tissue to prepare for the regeneration phase. Injured cell-derived HMGB1 also serves as a similar alarmin through CXCR4, and HGF-MET signaling upregulates CXCR4 expression in stem cells.

Figure 2

Effects of Hgfac deletion on liver regeneration and survival of C57BL6 mice after partial hepatectomy (a) and CCl₄ treatment (b). (a) Effect of Hgfac deletion on liver weight gain after 70% partial hepatectomy. N = 40 for wild-type mice and 28 for Hgfac^−/− mice on the 7th day. No significant differences between two groups (two way repeated-measures analysis of variance). (b) Effect of Hgfac deletion on the survival of mice after CCl₄ administration (2.5 μL/g, intraperitoneal injection). Kaplan-Meier survival curve is shown. *, p = 0.0216 (log-rank test); N = 21 for each group. All mice were maintained, treated, and sacrificed in accordance with the protocols and regulations of Miyazaki University Institutional Animal Care and Use Committee.

Figure 3

Molecular structure of HAI-1/SPINT1 and HAI-2/SPINT2. Whereas the membrane-form HAI-1/SPINT1 and sHAI-1 only with KD1 show high affinity to HGFAC, sHAI-1 having both KD1 and KD2, shows decreased affinity to HGFAC. MANEC, N-terminus with eight-cysteines domain; PKD-like, polycystic kidney disease domain-like domain; LDL-Ra, low density lipoprotein receptor class A domain; KD, Kunitz domain; MMP, matrix metalloprotease.