Hepatocyte growth factor (HGF)/NK1 is a naturally occurring HGF scatter factor variant with partial agonist antagonist activity
Hepatocyte growth factor (HGF)/NK1 is a naturally occurring HGF scatter factor variant with partial agonist antagonist activity
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DOI：
10.1074/jbc.271.22.13110
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发表时间：
1996-05-31
影响因子：
4.8
通讯作者：
Rubin, JS
中科院分区：
文献类型：
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作者：
Cioce, V;Csaky, KG;Rubin, JS
肝细胞生长因子/分散因子（HGF/SF）通过激活其受体c-Met酪氨酸激酶来刺激细胞增殖、运动和形态发生。HGF/SF在结构上与纤溶酶原相关，包括一个氨基末端发夹环、四个kringle结构域和一个丝氨酸蛋白酶样区域。截断的HGF/SF异构体，称为HGF/NK2，它延伸到第二kringle结构域，并作为竞争性的HGF/SF拮抗剂，先前被证明是由替代的HGF/SF转录物编码的。在这项研究中，我们描述了第二种自然发生的HGF/SF变体HGF/NK1，由HGF/SF氨基末端序列和第一个kringle结构域组成。该产物由一个2千碱基的替代转录本编码，该转录本包含与外显子K1b相邻的内含子序列。对杆状病毒表达的HGF/NR1的分析表明，该亚型具有HGF/SF的肝素结合特性，并且相对于HGF/SF具有适度的有丝分裂和散射活性。然而，在40倍摩尔过量时，HGF/NK1抑制HGF/ sf依赖性DNA合成。HGF/NK1刺激酪氨酸磷酸化Met，共价亲和交联表明HGF/NK1受体直接相互作用。这些发现表明，HGF/SF基因编码多种替代产物，不仅包括有丝分裂激动剂（HGF/SF）和纯拮抗剂（HGF/NK2），还包括具有部分激动剂/拮抗剂特性的分子。
Hepatocyte growth factor/scatter factor (HGF/SF) stimulates cell proliferation, motility, and morphogenesis by activation of its receptor, the c-Met tyrosine kinase. HGF/SF is structurally related to plasminogen, including an amino-terminal hairpin loop, four kringle domains, and a serine protease-like region. A truncated HGF/SF isoform, designated HGF/NK2, which extends through the second kringle domain and behaves as a competitive HGF/SF antagonist, was previously shown to be encoded by an alternative HGF/SF transcript. In this study, we describe a second naturally occurring HGF/SF variant, HGF/NK1, consisting of the HGF/SF amino-terminal sequence and first kringle domain. This product is encoded by a 2-kilobase alternative transcript containing intronic sequence that was contiguous with exon K1b. Analysis of baculovirus-expressed HGF/NR1 revealed that this isoform possesses the heparin binding properties of HGF/SF and modest mitogenic and scattering activity relative to HGF/SF. However, at a 40-fold molar excess, HGF/NK1 inhibited HGF/SF-dependent DNA synthesis. HGF/NK1 stimulated tyrosine phosphorylation of Met, and covalent affinity crosslinking demonstrated a direct HGF/NK1-receptor interaction. These findings establish that the HGF/SF gene encodes multiple alternative products, which include not only a mitogenic agonist (HGF/SF) and a pure antagonist (HGF/NK2) but also a molecule with partial agonist/antagonist properties.