Tyrosine phosphorylation of disabled-1 is essential for reelinstimulated activation of Akt and Src family kinases
Tyrosine phosphorylation of disabled-1 is essential for reelinstimulated activation of Akt and Src family kinases
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DOI：
10.1016/s0169-328x(03)00295-x
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发表时间：
2003-10-07
期刊：
影响因子：
--
通讯作者：
Cooper, JA
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文献类型：
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作者：
Ballif, BA;Arnaud, L;Cooper, JA
Reelin是一种分泌型信号蛋白，在哺乳动物脑发育过程中对迁移神经元的正确定位至关重要。Reelin信号通过脂蛋白受体VLDLR和ApoER 2转导到细胞中，导致相关细胞内衔接蛋白Disabled-1（Dab 1）的酪氨酸磷酸化。Dab 1的酪氨酸磷酸化对于响应Reelin是必需的，因为表达不能在酪氨酸上磷酸化的Dab 1形式的敲入小鼠与缺乏Reelin、Reelin受体或Dab 1的小鼠是不可区分的。依赖于Dahl酪氨酸磷酸化的分子事件是未知的。然而，Reelin最近已被证明激活磷酸肌醇-3-激酶（PI 3-K）依赖性激酶，Akt，以及Src家族激酶在野生型，但不是Dab 1（-/-）的原代胚胎神经元培养物。使用药理学抑制剂和小鼠窝藏突变等位基因的Dab 1，我们在这里表明，酪氨酸磷酸化，但不是羧基末端区域，Dab 1是所需的Reelin诱导激活Akt和Src家族激酶。此外，虽然Fyn是Dab 1的重要调节因子，但Fyn缺乏并不能阻止急性Reelin诱导的Akt激活。最后，而一些生长因子传播信号同时通过PI 3-K和丝裂原活化蛋白激酶（MAPK）级联，我们发现Reelin不从事典型的MAPK级联。这些结果定义了第一个分子事件严格依赖于Reelin诱导的Dab 1酪氨酸磷酸化，并表明Reelin信号的传播是由Akt介导的，Src家族激酶的底物和/或与这些激酶共享磷酸化Dahl的共同分子连接的未鉴定分子。(C)2003 Elsevier B. V.保留所有权利。
Reelin is a large secreted signaling protein that is essential for proper positioning of migratory neurons during mammalian brain development. The Reelin signal is transduced into the cell by the lipoprotein receptors VLDLR and ApoER2, leading to tyrosine phosphorylation of the associated intracellular adaptor protein Disabled-1 (Dab1). Tyrosine phosphorylation of Dab1 is essential for responding to Reelin, as knock-in mice expressing a form of Dab1 that cannot be phosphorylated on tyrosine are indistinguishable from mice lacking Reelin, Reelin-receptors or Dab1. Molecular events dependent on Dahl tyrosine phosphorylation are unknown. However, Reelin has recently been shown to activate the phosphoinositide-3-kinase (PI 3-K)-dependent kinase, Akt, as well as Src family kinases in wild type but not Dab1(-/-) primary embryonic neuronal cultures. Using pharmacological inhibitors and mice harboring mutant alleles of Dab1, we show here that tyrosine phosphorylation, but not the carboxyl-terminal region, of Dab1 is required for Reelin-induced activation of Akt and Src family kinases. Additionally, although Fyn is an important regulator of Dab1, Fyn deficiency does not prevent acute Reelin-induced Akt activation. Finally, whereas a number of growth factors propagate signals simultaneously through PI 3-K and mitogen-activated protein kinase (MAPK) cascades, we find Reelin does not engage the canonical MAPK cascade. These results define the first molecular events strictly dependent on Reelin-induced Dab1 tyrosine phosphorylation, and suggest that propagation of the Reelin signal is mediated by Akt, substrates of Src family kinases and/or unidentified molecules that share with these a common molecular link to phosphorylated Dahl. (C) 2003 Elsevier B.V. All rights reserved.