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Regulation of HAM function by proteolytic processing

通过蛋白水解过程调节 HAM 功能

基本信息

批准号：
13680709
负责人：
MIYAZAWA Keiji
金额：
$ 2.3万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13680709/
关键词：
growth factors protease inhibitor processing インイビター

项目摘要

HGF activator inhibitor (HAI-1) is a proteinaceous inhibitor of HGF activator (HGFA), which proteolytically activates hepatocyte growth factor (HGF). HGF is a multifunctional cytokine that is involved in regeneration and tissue repair after injury. HAI-1 is synthesized as a type I membrane protein, and secreted as a 40 kD HAI-1 or 58 kD HAI-1 by proteolytic processing. 40kD HAI-1 contains one Kunitz domain (Kunitz 1), whereas 58 kD HAI-1 contains two Kunitz domains (Kunitz 1 and 2). We generated deletion mutants of each Kunitz domains, and found that Kunitz 1is mainly involved in inhibition of HGFA. Although 58 kD HAI-1contains two Kunitz domains, its inhibitory activity for HGFA is very weak. We found that two Kunitz domains masked each other, thus lowering the inhibitory activity of the whole protein.When two-thirds of rat liver is resected, pro-HGF in the residual liver increases dramatically, but the active HGF is present in only a small amount. We then administered active HGFA via portal vein 24 h after partial hepatectomy, and examined the effect on liver regeneration. Administration of HGFA caused activation of pro-HGF in the residual liver and induced tyrosine phosphorylation of c-Met (HGF receptor). In addition, labeling index of hepatocytes was increased, and recovery of liver mass was promoted. We needed, however, a large amount of HGFA to obtain significant enhancement of liver regeneration, indicating that tissue-derived inhibitors such as HAI-1 play important roles in regulating activity of HGFA in vivo.

HGF 激活剂抑制剂 (HAI-1) 是 HGF 激活剂 (HGFA) 的蛋白质抑制剂，可通过蛋白水解激活肝细胞生长因子 (HGF)。 HGF是一种多功能细胞因子，参与损伤后的再生和组织修复。 HAI-1 被合成为 I 型膜蛋白，并通过蛋白水解加工分泌为 40 kD HAI-1 或 58 kD HAI-1。 40kD HAI-1 包含一个 Kunitz 结构域（Kunitz 1），而 58 kD HAI-1 包含两个 Kunitz 结构域（Kunitz 1 和 2）。我们生成了每个 Kunitz 结构域的缺失突变体，发现 Kunitz 1 主要参与 HGFA 的抑制。虽然58 kD HAI-1含有两个Kunitz结构域，但其对HGFA的抑制活性非常弱。我们发现两个Kunitz结构域相互掩蔽，从而降低了整个蛋白的抑制活性。当切除三分之二的大鼠肝脏时，残余肝脏中的pro-HGF急剧增加，但活性HGF仅存在少量。然后，我们在部分肝切除术后 24 小时通过门静脉注射活性 HGFA，并检查其对肝再生的影响。施用 HGFA 引起残余肝脏中 HGF 前体的激活，并诱导 c-Met（HGF 受体）酪氨酸磷酸化。此外，肝细胞标记指数增加，促进肝脏质量恢复。然而，我们需要大量的HGFA才能显着增强肝再生，这表明HAI-1等组织源性抑制剂在调节体内HGFA活性方面发挥着重要作用。