Splice-Mediated Motif Switching Regulates Disabled-1 Phosphorylation and SH2 Domain Interactions
Splice-Mediated Motif Switching Regulates Disabled-1 Phosphorylation and SH2 Domain Interactions
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DOI：
10.1128/mcb.00570-12
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发表时间：
2012-07-01
影响因子：
5.3
通讯作者：
Godbout, Roseline
中科院分区：
文献类型：
--
作者：
Gao, Zhihua;Poon, Ho Yin;Godbout, Roseline
Disabled-1（Dab 1）在大脑发育过程中reelin介导的神经元迁移中发挥关键作用。Dab 1在两个YQXI和两个YXVP基序的酪氨酸磷酸化募集多个SH 2结构域，导致广泛的信号级联的激活。然而，Dab 1下游效应子协调调控的分子机制仍然知之甚少。在这里，我们表明，选择性剪接的结果包括不同组合的YQXI和YXVP基序在Dab 1亚型在发展过程中。具有部分或完全丧失YQXI基序的Dab 1变体优先在早期发育阶段表达，而通常研究的Dab 1主要在晚期发育阶段表达。Dab 1变体在293 T和Neuro 2a细胞中的表达揭示了在已经失去一个或两个YQXI基序的变体中酪氨酸磷酸化水平降低或不存在。我们进一步证明，Dab 1的变体在激活Src和招募参与特定下游信号通路的不同SH 2结构域的能力不同。我们建议，协调表达的特定Dab 1亚型在不同群体的细胞在发育中的大脑有助于精确的神经元迁移，通过调节Dab 1下游效应子的子集的活动。
Disabled-1 (Dab1) plays a key role in reelin-mediated neuronal migration during brain development. Tyrosine phosphorylation of Dab1 at two YQXI and two YXVP motifs recruits multiple SH2 domains, resulting in activation of a wide range of signaling cascades. However, the molecular mechanisms underlying the coordinated regulation of Dab1 downstream effectors remain poorly understood. Here, we show that alternative splicing results in inclusion of different combinations of YQXI and YXVP motifs in Dab1 isoforms during development. Dab1 variants with partial or complete loss of YQXI motifs are preferentially expressed at early developmental stages, whereas the commonly studied Dab1 is predominantly expressed at late developmental stages. Expression of Dab1 variants in 293T and Neuro2a cells reveals reduced levels or absence of tyrosine phosphorylation in variants that have lost one or both YQXI motifs. We further demonstrate that Dab1 variants differ in their abilities to activate Src and recruit distinct SH2 domains involved in specific downstream signaling pathways. We propose that coordinated expression of specific Dab1 isoforms in different populations of cells in the developing brain contributes to precise neuronal migration by modulating the activity of subsets of Dab1 downstream effectors.