Postsynaptic requirement for Abl kinases in assembly of the neuromuscular junction
Postsynaptic requirement for Abl kinases in assembly of the neuromuscular junction
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DOI：
10.1038/nn1071
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发表时间：
2003-07-01
影响因子：
25
通讯作者：
Pendergast, AM
中科院分区：
文献类型：
--
作者：
Finn, AJ;Feng, GP;Pendergast, AM
聚集蛋白通过肌肉特异性受体酪氨酸激酶（MuSK）向神经肌肉接头（NMJ）的突触后膜上聚集乙酰胆碱受体（AChR）发出信号。这是突触前因子诱导突触的流行模型，但聚集蛋白依赖的MuSK信号级联在很大程度上是不确定的。AB1（以前称为Abl）和AB1相关基因产物AB2（以前称为Arg）定义了一个酪氨酸激酶家族，调节肌动蛋白结构和突触前轴突导向。在这里，我们表明，Abl激酶的突触后组装的聚集蛋白和MuSK下游的关键介质。在小鼠肌肉中，Abl激酶定位于发育中的NMJ的突触后膜。在培养的肌管中，Abl激酶活性是聚集蛋白诱导的AChR聚集和增强MuSK酪氨酸磷酸化所必需的。此外，MuSK和Abl激酶影响相互酪氨酸磷酸化，并在聚集蛋白接合后形成复合物。我们的研究结果表明，Abl激酶提供的信号放大所需的激酶活性和组装和重塑所需的内在细胞骨架调节能力的发展中的突触。
Agrin signals through the muscle-specific receptor tyrosine kinase (MuSK) to cluster acetylcholine receptors (AChRs) on the postsynaptic membrane of the neuromuscular junction (NMJ). This stands as the prevailing model of synapse induction by a presynaptic factor, yet the agrin-dependent MuSK signaling cascade is largely undefined. Abl1 (previously known as Abl) and the Abl1-related gene product Abl2 (previously known as Arg) define a family of tyrosine kinases that regulate actin structure and presynaptic axon guidance. Here we show that the Abl kinases are critical mediators of postsynaptic assembly downstream of agrin and MuSK. In mouse muscle, Abl kinases were localized to the postsynaptic membrane of the developing NMJ. In cultured myotubes, Abl kinase activity was required for agrin-induced AChR clustering and enhancement of MuSK tyrosine phosphorylation. Moreover, MuSK and Abl kinases effected reciprocal tyrosine phosphorylation and formed a complex after agrin engagement. Our findings suggest that Abl kinases provide the developing synapse with the kinase activity required for signal amplification and the intrinsic cytoskeletal regulatory capacity required for assembly and remodeling.