{alpha}-Syntrophin regulates ARMS localization at the neuromuscular junction and enhances EphA4 signaling in an ARMS-dependent manner.
{alpha}-Syntrophin regulates ARMS localization at the neuromuscular junction and enhances EphA4 signaling in an ARMS-dependent manner.
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DOI：
10.1083/jcb.200412008
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发表时间：
2005-06-06
影响因子：
7.8
通讯作者：
Ip, Nancy Y
中科院分区：
文献类型：
--
作者：
Luo, Shuo;Chen, Yu;Lai, Kwok-On;Arevalo, Juan Carlos;Froehner, Stanley C;Adams, Marvin E;Chao, Moses V;Ip, Nancy Y
EphA 4信号转导最近被认为参与了突触形成和可塑性的调节。在这项研究中，我们表明，锚蛋白重复丰富的跨膜（ARMS;也被称为激酶D相互作用底物的220 kD），肝配蛋白和神经营养因子受体的底物，在发育中的肌肉中表达，并集中在神经肌肉接头（NMJ）。使用酵母双杂交筛选，我们鉴定出PDZ（PSD-95、Dlg、ZO-1）结构域蛋白α-syntrophin是肌肉中与ARMS相互作用的蛋白。α-syntrophin的过表达以PDZ结构域依赖的方式诱导ARMS聚集。ARMS的共表达增强了EphA 4信号传导，这通过α-促突触素的存在而进一步增强。此外，在通过RNA干扰阻断ARMS和α-syntrophin表达后，ephrin-A1诱导的EphA 4酪氨酸磷酸化在C2 C12肌管中减少。最后，α-促突触素缺失小鼠表现出ARMS和EphA 4在NMJ的定位被破坏，肌肉中ARMS的表达减少。总之，我们的研究结果表明，ARMS可能发挥重要的作用，通过突触营养蛋白介导的受体酪氨酸激酶，如EphA 4的本地化调节突触后信号转导。
EphA4 signaling has recently been implicated in the regulation of synapse formation and plasticity. In this study, we show that ankyrin repeat-rich membrane spanning (ARMS; also known as a kinase D–interacting substrate of 220 kD), a substrate for ephrin and neurotrophin receptors, was expressed in developing muscle and was concentrated at the neuromuscular junction (NMJ). Using yeast two-hybrid screening, we identified a PDZ (PSD-95, Dlg, ZO-1) domain protein, α-syntrophin, as an ARMS-interacting protein in muscle. Overexpression of α-syntrophin induced ARMS clustering in a PDZ domain–dependent manner. Coexpression of ARMS enhanced EphA4 signaling, which was further augmented by the presence of α-syntrophin. Moreover, the ephrin-A1–induced tyrosine phosphorylation of EphA4 was reduced in C2C12 myotubes after the blockade of ARMS and α-syntrophin expression by RNA interference. Finally, α-syntrophin–null mice exhibited a disrupted localization of ARMS and EphA4 at the NMJ and a reduced expression of ARMS in muscle. Altogether, our findings suggest that ARMS may play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EphA4.