Activation of hepatocyte growth factor by urokinase-type plasminogen activator is ionic strength-dependent.
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.
Mars
Wendy M
WM
Department of Pathology, University of Pittsburgh, S411-B Biomedical Science Tower, Pittsburgh, PA 15261, USA. wmars@pitt.edu
Jo
Minji
M
Gonias
Steven L
SL
D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000378:metabolism*; D009994:Osmolar Concentration; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D019346:Sodium Acetate; D012965:Sodium Chloride; D012996:Solutions; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000378:metabolism*
D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D012996:Solutions; D012965:Sodium Chloride; D019346:Sodium Acetate; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D014568:Urokinase-Type Plasminogen Activator