Apel Elizabeth D, Glass David J, Moscoso Lisa M, Yancopoulos George D, Sanes Joshua R
Department of Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Neuron. 1997 Apr;18(4):623-35. doi: 10.1016/s0896-6273(00)80303-7.
Agrin-induced clustering of acetylcholine receptors (AChRs) in the postsynaptic membrane is a key step in synaptogenesis at the neuromuscular junction. The receptor tyrosine kinase MuSK is a component of the agrin receptor, while the cytoplasmic protein rapsyn is necessary for the clustering of AChRs and all other postsynaptic membrane components studied to date. We show here that MuSK remains concentrated at synaptic sites in rapsyn-deficient mutant mice, suggesting that MuSK forms a primary structural scaffold to which rapsyn attaches other synaptic components. Using nonmuscle cells, we show that rapsyn-MuSK interactions are mediated by the ectodomain of MuSK, suggesting the existence of a transmembrane intermediate. In addition to rapsyn's structural role, we demonstrate that it is required for an early step in MuSK signaling, AChR phosphorylation. This signaling requires the kinase domain of MuSK, but not its ectodomain. Thus, MuSK may interact with rapsyn in multiple ways to play both structural and signaling roles in agrin-induced differentiation.
聚集蛋白诱导的乙酰胆碱受体（AChRs）在突触后膜上的簇集是神经肌肉接头处突触形成的关键步骤。受体酪氨酸激酶MuSK是聚集蛋白受体的一个组成部分，而胞质蛋白rapsyn是AChRs以及迄今为止所研究的所有其他突触后膜成分簇集所必需的。我们在此表明，在缺乏rapsyn的突变小鼠中，MuSK仍集中在突触部位，这表明MuSK形成了一个主要的结构支架，rapsyn将其他突触成分附着于其上。利用非肌肉细胞，我们表明rapsyn与MuSK的相互作用是由MuSK的胞外结构域介导的，这提示存在一种跨膜中间体。除了rapsyn的结构作用外，我们还证明它是MuSK信号传导早期步骤（AChR磷酸化）所必需的。这种信号传导需要MuSK的激酶结构域，但不需要其胞外结构域。因此，MuSK可能以多种方式与rapsyn相互作用，在聚集蛋白诱导的分化过程中发挥结构和信号传导作用。
