LINGO-1 Interacts with WNK1 to Regulate Nogo-induced Inhibition of Neurite Extension
LINGO-1 Interacts with WNK1 to Regulate Nogo-induced Inhibition of Neurite Extension
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DOI：
10.1074/jbc.m808751200
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发表时间：
2009-06-05
影响因子：
4.8
通讯作者：
He, Cheng
中科院分区：
文献类型：
--
作者：
Zhang, Zhaohuan;Xu, Xiaohui;He, Cheng
LINGO-1是三重受体复合物的一个组成部分，其作为响应于髓鞘相关抑制剂的细胞内信号传导的会聚介体，并导致生长锥的塌陷和神经突延伸的抑制。虽然LINGO-1的功能已被深入研究，但其下游信号转导仍然难以捉摸。在本研究中，LINGO-1和丝氨酸-苏氨酸激酶WNK 1之间的一个新的相互作用，通过酵母双杂交筛选确定。通过荧光共振能量转移和免疫共沉淀进一步验证了这种相互作用，并且这种相互作用通过Nogo 66处理而增强。形态学证据表明WNK 1和LINGO-1在皮层神经元中共定位。此外，通过RNA干扰抑制WNK 1表达或WNK 1-（123-510）的过表达减弱了Nogo 66诱导的对神经突延伸的抑制并抑制了RhoA的激活。此外，WNK 1被鉴定为与Rho-GDI 1相互作用，并且这种相互作用被Nogo 66处理减弱，进一步表明其对RhoA活化的调节作用。综上所述，我们的研究结果表明，WNK 1是一种新的信号分子，参与调节LINGO-1介导的抑制轴突延伸。
LINGO-1 is a component of the tripartite receptor complexes, which act as a convergent mediator of the intracellular signaling in response to myelin-associated inhibitors and lead to collapse of growth cone and inhibition of neurite extension. Although the function of LINGO-1 has been intensively studied, its downstream signaling remains elusive. In the present study, a novel interaction between LINGO-1 and a serine-threonine kinase WNK1 was identified by yeast two-hybrid screen. The interaction was further validated by fluorescence resonance energy transfer and co-immunoprecipitation, and this interaction was intensified by Nogo66 treatment. Morphological evidences showed that WNK1 and LINGO-1 were co-localized in cortical neurons. Furthermore, either suppressing WNK1 expression by RNA interference or overexpression of WNK1-(123-510) attenuated Nogo66-induced inhibition of neurite extension and inhibited the activation of RhoA. Moreover, WNK1 was identified to interact with Rho-GDI1, and this interaction was attenuated by Nogo66 treatment, further indicating its regulatory effect on RhoA activation. Taken together, our results suggest that WNK1 is a novel signaling molecule involved in regulation of LINGO-1 mediated inhibition of neurite extension.