Activation of hepatocyte growth factor by urokinase-type plasminogen activator is ionic strength-dependent

Abstract

The hepatocyte growth factor (HGF) is a multifunctional cytokine that is produced as latent scHGF (single chain HGF). Various proteases reportedly cleave scHGF to generate the active two-chain form (HGF), including u-PA (urokinase-type plasminogen activator), t-PA (tissue-type plasminogen activator), kallikrein, Factor XIa, Factor XIIa, HGF activator and matriptase. Considerable evidence indicates that, in vivo, u-PA activates scHGF in the liver; however, the in vivo results have not been uniformly supported by in vitro experiments. We now report that cleavage of scHGF by high-molecular-mass u-PA (abbreviated u-PA throughout) is sensitive to ionic strength. scHGF cleavage by u-PA was accelerated as the ionic strength was decreased. This result was equivalent irrespective of whether the predominant anion was chloride or acetate. Lmw-u-PA (low-molecular-mass u-PA) was ineffective at cleaving scHGF, regardless of ionic strength. Although scHGF shares homology with plasminogen, EACA (-amino-caproic acid) did not regulate u-PA-mediated scHGF cleavage. Soluble HGF receptor (MET) and soluble u-PAR (u-PA receptor) inhibited the scHGF cleavage. These results support a model in which the ability of u-PA to activate scHGF in vivo may be highly dependent on local conditions within the extracellular space.

Urokinase-type plasminogen activator supports liver repair independent of its cellular receptor

“…Alternatively, the decreased proliferation may be due to impaired activation of growth-related signals in uPAR° livers. This scenario is supported by the role of the ligand uPA in the proteolytic activation of the potent liver cell mitogen hepatocyte growth factor (HGF) into its active heterodimeric form [43,44], and by the recent findings that uPAR is one of the downstream targets of the HGF receptor cMet tyrosine kinase in the KM12L4 human epithelial cell line [45]. However our data did not show significant changes in the activation of cell-associated HGF during early phases of the regenerative response after CCl 4 .…”

Herbal compound triptolide synergistically enhanced antitumor activity of amino-terminal fragment of urokinase

“…Secondly, the binding of uPA and uPAR can also activate multiple cell signalling molecules via some growth factor receptors, such as integrins and EGFR, and then stimulate cell mobility and growth [7,8]. Finally, uPA-uPAR system is implicated in tumour-associated angiogenesis [9,10]. All these crucial roles of uPA-uPAR system in tumour growth and metastasis make it an ideal candidate for targeted cancer therapy.…”

Inhibition of tumor growth and metastasis by ATF-Fc, an engineered antibody targeting urokinase receptor

“…Because the binding of uPA to uPAR can not only induce the migration of endothelial cells, but also promote the release of several angiogenic factors, such as basic fibroblast growth factor, hepatocyte growth factor, transforming growth factor-β, tumor necrosis factor-α and vascular endothelial growth factor. [18][19][20] All these essential roles of uPA-uPAR system in tumor growth and metastasis make it an ideal candidate for targeted cancer therapy. And therapeutic molecules aimed at interrupting the interaction of uPA and uPAR might inhibit both tumor cell invasiveness and tumor-associated angiogenesis, thereby might be effective in the oncotherapy.…”