Differential interaction of the Pafah1b alpha subunits with the Reelin transducer Dab1.
Differential interaction of the Pafah1b alpha subunits with the Reelin transducer Dab1.
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DOI：
10.1016/j.brainres.2009.02.059
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发表时间：
2009-04-24
期刊：
影响因子：
2.9
通讯作者：
D'Arcangelo G
中科院分区：
文献类型：
--
作者：
Zhang G;Assadi AH;Roceri M;Clark GD;D'Arcangelo G
Reelin信号通路控制发育中的大脑径向神经元的迁移和成熟。血小板活化因子（PAF）乙酰水解酶1b （Pafah1b）复合物也参与大脑发育的多个方面。我们之前的研究表明，Reelin通路和Pafah1b复合物在遗传和生化上相互作用。Pafah1b的调控亚基Lis1与phosphoDab1相互作用，后者是Reelin信号传导的重要介质。携带Reelin通路和Lis1突变的复合突变体表现为脑积水，这是一种被编码Pafah1b的Alpha2亚基的基因突变抑制的表型。这个亚基，像其他的Pafah1b催化亚基Alpha1一样，也结合Reelin受体VLDLR。本文研究了Pafah1b催化亚基与Dab1的分子相互作用。我们发现，从缺乏Reelin的正常和Reelin突变小鼠的脑提取物，以及含有正常或磷酸化突变形式的Dab1的无细胞提取物中，Alpha2与Dab1共沉淀，这表明Dab1的磷酸化不是与Alpha2结合所必需的。这种相互作用仅针对Alpha2而非Alpha1，并且依赖于Alpha2独特的酪氨酸残基。使用缺乏Alpha2的突变小鼠进行的生化分析进一步证明，该亚基不是reelin诱导的Dab1磷酸化所必需的。然而，在无细胞系统中增加Alpha2的量会破坏Dab1- lis1复合物的形成，而不会影响Dab1与VLDLR的关联。我们的数据表明，Alpha2亚基可能在影响大脑发育和脑积水的蛋白质复合物的形成中发挥调节作用。
The Reelin signaling pathway controls radial neuronal migration and maturation in the developing brain. The platelet activating factor (PAF) acetyl hydrolase 1b (Pafah1b) complex is also involved in multiple aspects of brain development. We previously showed that the Reelin pathway and the Pafah1b complex interact genetically and biochemically. Lis1, the regulatory subunit of Pafah1b interacts with phosphoDab1, an essential mediator of Reelin signaling. Compound mutants carrying mutations in both, the Reelin pathway and Lis1 exhibit hydrocephalus, a phenotype that is suppressed by mutations in the gene encoding the Alpha2 subunit of Pafah1b. This subunit, like to other Pafah1b catalytic subunit Alpha1, also binds the Reelin receptor VLDLR. Here we investigated the molecular interactions of the Pafah1b catalytic subunits with Dab1. We found that Alpha2 coprecipitates with Dab1 from brain extracts of normal and reeler mutant mice lacking Reelin, and from cell-free extracts containing normal or a phosphorylation mutant form of Dab1, suggesting that Dab1 phosphorylation is not necessary for binding to Alpha2. This interaction is specific for Alpha2 and not Alpha1, and depends on a unique tyrosine residue of Alpha2. Biochemical assays using mutant mice lacking Alpha2 further demonstrated that this subunit is not required for Reelin-induced Dab1 phosphorylation. However, increasing amounts of Alpha2 in a cell free system disrupted the formation of Dab1-Lis1 complexes without affecting the association of Dab1 with VLDLR. Our data suggest that the Alpha2 subunit may play a modulatory role in the formation of protein complexes that affect brain development and hydrocephalus.
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影响因子：
30.8
作者：
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