A secreted soluble form of ApoE receptor 2 acts as a dominant-negative receptor and inhibits Reelin signaling
A secreted soluble form of ApoE receptor 2 acts as a dominant-negative receptor and inhibits Reelin signaling
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DOI：
10.1093/emboj/cdf599
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发表时间：
2002-11-15
期刊：
影响因子：
11.4
通讯作者：
Nimpf, J
中科院分区：
文献类型：
--
作者：
Koch, S;Strasser, V;Nimpf, J
整个发育中的中枢神经系统的专门神经元分泌Reelin，其结合ApoE受体2（ApoER 2）和极低密度脂蛋白受体（VLDLR），触发引导神经元到其正确位置的信号级联。Reelin与ApoER 2和VLDLR的结合诱导Dab 1的磷酸化，Dab 1与两种受体的细胞内结构域结合。由于差异剪接，存在配体结合和细胞内结构域不同的ApoER 2的几种亚型。一种同种型含有四个结合重复序列加上一个相邻的短的13个氨基酸插入，其中含有一个弗林蛋白酶切割位点。目前尚不清楚这种ApoER 2变体的弗林蛋白酶加工是否真的发生，如果发生，所产生的片段是否被分泌。在这里，我们证明了这种ApoER 2变体的切割确实发生，并且所得到的由整个配体结合结构域组成的受体片段作为可溶性多肽分泌。该受体片段抑制原代神经元中的Reelin信号传导，表明它可以在胚胎脑发育期间以显性负性方式调节Reelin信号传导。
Specialized neurons throughout the developing central nervous system secrete Reelin, which binds to ApoE receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR), triggering a signal cascade that guides neurons to their correct position. Binding of Reelin to ApoER2 and VLDLR induces phosphorylation of Dab1, which binds to the intracellular domains of both receptors. Due to differential splicing, several isoforms of ApoER2 differing in their ligand-binding and intracellular domains exist. One isoform harbors four binding repeats plus an adjacent short 13 amino acid insertion containing a furin cleavage site. It is not known whether furin processing of this ApoER2 variant actually takes place and, if so, whether the produced fragment is secreted. Here we demonstrate that cleavage of this ApoER2 variant does indeed take place, and that the resulting receptor fragment consisting of the entire ligand-binding domain is secreted as soluble polypeptide. This receptor fragment inhibits Reelin signaling in primary neurons, indicating that it can act in a dominant-negative fashion in the regulation of Reelin signaling during embryonic brain development.