Identification of reelin-induced sites of tyrosyl phosphorylation on disabled 1
Identification of reelin-induced sites of tyrosyl phosphorylation on disabled 1
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DOI：
10.1074/jbc.m101422200
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发表时间：
2001-05-11
影响因子：
4.8
通讯作者：
Curran, T
中科院分区：
文献类型：
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作者：
Keshvara, L;Benhayon, D;Curran, T
对小鼠自发和靶向突变的研究发现了哺乳动物大脑发育过程中控制神经元定位的信号通路。reelin, dab1，或vldlr和apoER2均被破坏的小鼠是共济失调的，它们在几个大脑结构中表现出严重的层压缺陷。Reelin是一种分泌的细胞外蛋白，与神经元表面的极低密度脂蛋白受体和载脂蛋白E受体2结合。残疾-1 （Dab1）是一种含有PTB（磷酸酪氨酸结合）结构域的细胞内转换蛋白，在胚胎发生期间被酪氨酸磷酸化，但在缺乏Reelin或极低密度脂蛋白受体和载脂蛋白E受体2的小鼠中，Dab1以低磷酸化的形式积累，当从胚胎大脑分离的神经元受到Reelin刺激时，Dab1迅速磷酸化，并且几种酪氨酸与这种反应有关。所有5种酪氨酸（Tyr（185）、Tyr（198）、Tyr（200）、Tyr（220）和Tyr(232)）被苯丙氨酸取代的小鼠表现出卷轴表型，这表明酪氨酸磷酸化对Dab1功能至关重要。在这里，我们报道，尽管Src可以在体外磷酸化所有5种酪氨酸，Tyr（198）和Tyr（220）代表了reelin诱导的胚胎神经元Dab1磷酸化的主要位点。
The study of mice with spontaneous and targeted mutations has uncovered a signaling pathway that controls neuronal positioning during mammalian brain development. Mice with disruptions in reelin, dab1, or both vldlr and apoER2 are ataxic, and they exhibit severe lamination defects within several brain structures. Reelin is a secreted extracellular protein that binds to the very low density lipoprotein receptor and the apolipoprotein E receptor 2 on the surface of neurons. Disabled-1 (Dab1), an intracellular adapter protein containing a PTB (phosphotyrosine binding) domain, is tyrosyl-phosphorylated during embryogenesis, but it accumulates in a hypophosphorylated form in mice lacking Reelin or both very low density lipoprotein receptor and apolipoprotein E receptor 2, Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons.