Finn Alexander J, Feng Guoping, Pendergast Ann Marie
Department of Pharmacology and Cancer Biology, Box 3813, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nat Neurosci. 2003 Jul;6(7):717-23. doi: 10.1038/nn1071.
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.
聚集蛋白通过肌肉特异性受体酪氨酸激酶（MuSK）发出信号，使神经肌肉接头（NMJ）突触后膜上的乙酰胆碱受体（AChR）聚集。这是突触前因子诱导突触形成的主流模型，然而，聚集蛋白依赖的MuSK信号级联反应在很大程度上仍不清楚。Abl1（以前称为Abl）和Abl1相关基因产物Abl2（以前称为Arg）定义了一个酪氨酸激酶家族，它们调节肌动蛋白结构和突触前轴突导向。在这里，我们表明Abl激酶是聚集蛋白和MuSK下游突触后组装的关键介质。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，聚集蛋白诱导的AChR聚集和MuSK酪氨酸磷酸化增强需要Abl激酶活性。此外，MuSK和Abl激酶相互进行酪氨酸磷酸化，并在聚集蛋白作用后形成复合物。我们的研究结果表明，Abl激酶为发育中的突触提供信号放大所需的激酶活性以及组装和重塑所需的内在细胞骨架调节能力。
