Mars Wendy M, Jo Minji, Gonias Steven L
Department of Pathology, University of Pittsburgh, S411-B Biomedical Science Tower, Pittsburgh, PA 15261, USA.
Biochem J. 2005 Aug 15;390(Pt 1):311-5. doi: 10.1042/BJ20042028.
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.
肝细胞生长因子（HGF）是一种多功能细胞因子，以无活性的单链HGF（scHGF）形式产生。据报道，多种蛋白酶可切割scHGF以生成活性双链形式（HGF），包括尿激酶型纤溶酶原激活剂（u-PA）、组织型纤溶酶原激活剂（t-PA）、激肽释放酶、因子XIa、因子XIIa、HGF激活剂和matriptase。大量证据表明，在体内，u-PA在肝脏中激活scHGF；然而，体内实验结果并未得到体外实验的一致支持。我们现在报道，高分子量u-PA（以下简称u-PA）对scHGF的切割对离子强度敏感。随着离子强度降低，u-PA对scHGF的切割加速。无论主要阴离子是氯离子还是醋酸根离子，该结果都是相同的。低分子量u-PA（Lmw-u-PA）无论离子强度如何，都无法有效切割scHGF。尽管scHGF与纤溶酶原有同源性，但ε-氨基己酸（EACA）并不调节u-PA介导的scHGF切割。可溶性HGF受体（MET）和可溶性u-PA受体（u-PAR）抑制scHGF的切割。这些结果支持了一种模型，即u-PA在体内激活scHGF的能力可能高度依赖于细胞外空间的局部条件。
