Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine -: Specific requirement of the membrane-bound form of ciliary neurotrophic factor receptor α component
Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine -: Specific requirement of the membrane-bound form of ciliary neurotrophic factor receptor α component
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DOI：
10.1074/jbc.m101681200
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发表时间：
2001-06-22
影响因子：
4.8
通讯作者：
Gascan, H
中科院分区：
文献类型：
--
作者：
Lelièvre, E;Plun-Favreau, H;Gascan, H
睫状神经营养因子（CNTF）是一种支持多种神经细胞分化和存活的细胞因子。其受体复合物由配体结合组分CNTF受体（CNTFR）和两种信号受体组分gp 130和白血病抑制因子受体（LIFR）组成。CNTF和CNTFR缺陷小鼠之间的显著表型差异表明CNTFR作为第二种发育重要配体的受体，我们最近发现，心肌营养素样细胞因子（CLC）与可溶性孤儿受体类胡萝卜素样因子-1（CLF）以形成仅在其表面上表达三重CNTF受体的细胞上显示活性的异源二聚体细胞因子。在本研究中，我们研究了CLC/CLF复合细胞因子的膜结合，并观察到细胞因子与CNTFR亚基的优先相互作用。还详细分析了在人神经母细胞瘤细胞系中由CLC/CLF复合物募集的信号通路。结果显示Janus激酶激活磷酸化的信号受体反过来充当信号转导分子如STAT 3和SHP-2的对接蛋白，体外分析显示，gp 130-LIFR通路也可以刺激磷脂酰肌醇3-激酶和丝裂原-磷酸化酶。激活蛋白激酶途径。与之前报道的CNTF相比，可溶性CNTFR未能促进CLC/CLF的作用，并且需要膜形式的CNTFR的绝对需求来产生对复合细胞因子的功能性应答。这项研究加强了CNTF和CLC/CLF复合细胞因子之间的功能相似性，定义了CNTFR的第二配体。
Ciliary neurotrophic factor (CNTF) is a cytokine sup porting the differentiation and survival of a number of neural cell types. Its receptor complex consists of a ligand-binding component, CNTF receptor (CNTFR), associated with two signaling receptor components, gp130 and leukemia inhibitory factor receptor (LIFR), Striking phenotypic differences between CNTF- and CNTFR-deficient mice suggest that CNTFR serves as a receptor for a second developmentally important ligand, We recently demonstrated that cardiotrophin-like cytokine (CLC) associates with the soluble orphan receptor cytokine-like factor-1 (CLF) to form a heterodimeric cytokine that displayed activities only on cells expressing the tripartite CNTF receptor on their surface. In this present study we examined the membrane binding of the CLC/CLF composite cytokine and observed a preferential interaction of the cytokine with the CNTFR subunit. Signaling pathways recruited by the CLC/CLF complex in human neuroblastoma cell lines were also analyzed in detail. The results obtained showed an activation of Janus kinases (JAK1, JAK2, and TYK2) leading to a tyrosine phosphorylation of the gp130 and LIFR, The phosphorylated signaling receptors served in turn as docking proteins for signal transducing molecules such as STAT3 and SHP-2, In vitro analysis revealed that the gp130-LIFR pathway could also stimulate the phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathways. In contrast to that reported before for CNTF, soluble CNTFR failed to promote the action CLC/CLF, and an absolute requirement of the membrane form of CNTFR was required to generate a functional response to the composite cytokine. This study reinforces the functional similarity between CNTF and the CLC/CLF composite cytokine defining the second ligand for CNTFR.