Membrane Type 1-Matrix Metalloproteinase Cleaves Off the NH2-Terminal Portion of Heparin-Binding Epidermal Growth Factor and Converts It into a Heparin-Independent Growth Factor
Membrane Type 1-Matrix Metalloproteinase Cleaves Off the NH2-Terminal Portion of Heparin-Binding Epidermal Growth Factor and Converts It into a Heparin-Independent Growth Factor
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DOI：
10.1158/0008-5472.can-10-0346
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Seiki, Motoharu
中科院分区：
文献类型：
--
作者：
Koshikawa, Naohiko;Mizushima, Hiroto;Seiki, Motoharu
表皮生长因子（EGF）受体（ErbB）和EGF家族成员是癌症治疗的有希望的靶点。肝素结合EGF （HB-EGF）是EGF家族的一员，是治疗某些类型人类癌症的重要靶点。蛋白转化酶对HB-EGF进行加工，随后由ADAM家族蛋白酶对HB-EGF进行加工，产生一种需要肝素作为辅助因子的可溶性生长因子。虽然肝素在体外增强HB-EGF的活性，但目前尚不清楚HB-EGF的肝素结合活性是如何被调节的。在这里，我们发现膜型1-基质金属蛋白酶（MT1-MMP; MMP14），一种有效的促进侵袭的蛋白酶，在小鼠中显著促进hb - egf依赖性肿瘤的形成。MT1-MMP还切割HB-EGF并去除对结合肝素很重要的nh2末端20个氨基酸。因此，MT1-MMP对HB-EGF的加工将HB-EGF转化为具有增强的有丝分裂活性的肝素非依赖性生长因子，因此，这两种蛋白的表达在体外和体内共同刺激肿瘤细胞的生长。人胃癌细胞中表达的ErbB受体家族在胶原浸润细胞生长过程中通过MT1-MMP介导HB-EGF活性增强中发挥作用。因此，我们揭示了HB-EGF活性调控的新机制，在设计HB-EGF靶向癌症治疗时应考虑这一机制。癌症Res;70 (14);6093 - 103。(c) 2010年aacr。
Epidermal growth factor (EGF) receptors (ErbB) and EGF family members represent promising targets for cancer therapy. Heparin-binding EGF (HB-EGF) is a member of the EGF family and is an important target for therapy in some types of human cancers. Processing of HB-EGF by proprotein convertases, and successively, by ADAM family proteases, generates a soluble growth factor that requires heparin as a cofactor. Although heparin potentiates HB-EGF activity in vitro, it is not clear how the heparin-binding activity of HB-EGF is regulated. Here, we show that membrane type 1-matrix metalloproteinase (MT1-MMP; MMP14), a potent invasion- promoting protease, markedly enhances HB-EGF-dependent tumor formation in mice. MT1-MMP additionally cleaves HB-EGF and removes the NH2-terminal 20 amino acids that are important for binding heparin. Consequently, the processing of HB-EGF by MT1-MMP converts HB-EGF into a heparin-independent growth factor with enhanced mitogenic activity, and thereby, expression of both proteins costimulates tumor cell growth in vitro and in vivo. The ErbB family of receptors expressed in human gastric carcinoma cells play a role in mediating enhanced HB-EGF activity by MT1-MMP during invasive cell growth in collagen. Thus, we shed light on a new mechanism whereby HB-EGF activity is regulated that should be considered when designing HB-EGF-targeted cancer therapy. Cancer Res; 70(14); 6093-103. (C) 2010 AACR.