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首页> 外文期刊>The FEBS journal >TMPRSS13, a type II transmembrane serine protease, is inhibited by hepatocyte growth factor activator inhibitor type 1 and activates pro-hepatocyte growth factor
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TMPRSS13, a type II transmembrane serine protease, is inhibited by hepatocyte growth factor activator inhibitor type 1 and activates pro-hepatocyte growth factor

机译：II型跨膜丝氨酸蛋白酶TMPRSS13被1型肝细胞生长因子激活抑制剂抑制并激活前肝细胞生长因子

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摘要

Type II transmembrane serine proteases (TTSPs) are structurally defined by the presence of a transmembrane domain located near the N-terminus and a C-terminal extracellular serine protease domain. The human TTSP family consists of 17 members. Some members of the family have pivotal functions in development and homeostasis, and are involved in tumorigenesis and viral infections. The activities of TTSPs are regulated by endogenous protease inhibitors. However, protease inhibitors of most TTSPs have not yet been identified. In this study, we investigated the inhibitory effect of hepatocyte growth factor activator inhibitor type 1 (HAI-1), a Kunitz-type serine protease inhibitor, on several members of the TTSP family. We found that the protease activity of a member, TMPRSS13, was inhibited by HAI-1. A detailed analysis revealed that a soluble form of HAI-1 with one Kunitz domain (NK1) more strongly inhibited TMPRSS13 than another soluble form of HAI-1 with two Kunitz domains (NK1LK2). In addition, an in vitro protein binding assay showed that NK1 formed complexes with TMPRSS13, but NK1LK2 did not. TMPRSS13 converted single-chain pro-hepatocyte growth factor (pro-HGF) to a two-chain form in vitro, and the pro-HGF converting activity of TMPRSS13 was inhibited by NK1. The two-chain form of HGF exhibited biological activity, assessed by phosphorylation of the HGF receptor (c-Met) and extracellular signal-regulated kinase, and scattered morphology in human hepatocellular carcinoma cell line HepG2. These results suggest that TMPRSS13 functions as an HGF-converting protease, the activity of which may be regulated by HAI-1.
机译：II型跨膜丝氨酸蛋白酶（TTSP）在结构上由位于N端附近的跨膜结构域和C端细胞外丝氨酸蛋白酶结构域的存在来定义。 TTSP人类家族由17个成员组成。该家族的一些成员在发育和体内平衡中起着关键作用，并参与肿瘤发生和病毒感染。 TTSPs的活性受内源性蛋白酶抑制剂的调节。然而，大多数TTSP的蛋白酶抑制剂尚未被鉴定。在这项研究中，我们调查了1型肝细胞生长因子激活剂抑制剂（HAI-1），一种Kunitz型丝氨酸蛋白酶抑制剂，对TTSP家族的几个成员的抑制作用。我们发现HAI-1抑制了成员TMPRSS13的蛋白酶活性。详细分析显示，具有一个Kunitz域（NK1）的HAI-1可溶性形式比具有两个Kunitz域（NK1LK2）的HAI-1另一种可溶性形式对TMPRSS13的抑制作用更强。另外，体外蛋白结合试验显示NK1与TMPRSS13形成复合物，而NK1LK2没有。 TMPRSS13在体外将单链促肝细胞生长因子（pro-HGF）转化为两链形式，而NK1抑制了TMPRSS13的促HGF转化活性。 HGF的两链形式具有生物活性，可以通过HGF受体（c-Met）和细胞外信号调节激酶的磷酸化来评估，并在人肝癌细胞系HepG2中具有分散的形态。这些结果表明TMPRSS13充当HGF转换蛋白酶，其活性可能受HAI-1调节。

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