A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity
A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity
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DOI：
10.1038/sj.onc.1209803
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发表时间：
2007-01-01
期刊：
影响因子：
8
通讯作者：
Iozzo, R. V.
中科院分区：
文献类型：
--
作者：
Goldoni, S.;Iozzo, R. A.;Iozzo, R. V.
富含亮氨酸重复序列和免疫球蛋白样结构域-1（Leucine-rich repeats and immunoglobulin-like domains-1，LRIG 1）是一种跨膜蛋白，其胞外域含有15个富含亮氨酸重复序列（Leucine-rich repeats，LRR），与哺乳动物核心蛋白聚糖和果蝇kekkon 1基因同源。在这项研究中，我们证明了LRIG 1的可溶性胞外域，只含有LRR，抑制配体非依赖性表皮生长因子受体（EGFR）的激活，并导致A431，HeLa和MDA-468癌细胞的生长抑制。相反，不表达可检测水平的EGFR的细胞不能对可溶性LRIG 1应答。然而，当在这些细胞中引入功能性EGFR基因时，它们会受到可溶性LRIG 1蛋白的生长抑制。此外，我们证明了A431细胞上存在高亲和力（Kd = 10 nM）结合位点，这些位点可以被摩尔过量的EGF竞争性取代（高达75%）。用含有核心蛋白聚糖N-末端的嵌合蛋白聚糖获得甚至更强大的效果，所述嵌合蛋白聚糖被单个糖胺聚糖链取代，与LRIG 1胞外域融合。两种蛋白质还以快速和剂量依赖性方式抑制EGFR和细胞外信号调节蛋白激酶1/2信号的配体依赖性活化。这些结果表明，LRIG 1蛋白的可溶性胞外域引起的一种新的作用机制，可以调节EGFR信号传导及其促生长活性。EGFR活性的衰减而不对受体进行物理下调可能代表一种针对恶性肿瘤的新治疗方法，其中EGFR在肿瘤生长和存活中起主要作用。
Leucine-rich repeats and immunoglobulin-like domains-1 (LRIG1) is a transmembrane protein with an ectodomain containing 15 leucine-rich repeats (LRRs) homologous to mammalian decorin and the Drosophila kekkon1 gene. In this study, we demonstrate that a soluble ectodomain of LRIG1, containing only the LRRs, inhibits ligand-independent epidermal growth factor receptor (EGFR) activation and causes growth inhibition of A431, HeLa and MDA-468 carcinoma cells. In contrast, cells that do not express detectable levels of EGFR fail to respond to soluble LRIG1. However, when a functional EGFR gene is introduced in these cells, they become growth-inhibited by soluble LRIG1 protein. Furthermore, we demonstrate the existence of high-affinity (K-d = 10 nM) binding sites on the A431 cells that can be competitively displaced (up to 75%) by molar excess of EGF. Even more powerful effects are obtained with a chimeric proteoglycan harboring the N-terminus of decorin, substituted with a single glycosaminoglycan chain, fused to the LRIG1 ectodomain. Both proteins also inhibit ligand-dependent activation of the EGFR and extracellular signal-regulated protein kinase 1/2 signaling in a rapid and dose-dependent manner. These results suggest a novel mechanism of action evoked by a soluble ectodomain of LRIG1 protein that could modulate EGFR signaling and its growth-promoting activity. Attenuation of EGFR activity without physical downregulation of the receptor could represent a novel therapeutic approach toward malignancies in which EGFR plays a primary role in tumor growth and survival.