Serine 707 of APPL1 is Critical for the Synaptic NMDA Receptor-Mediated Akt Phosphorylation Signaling Pathway
Serine 707 of APPL1 is Critical for the Synaptic NMDA Receptor-Mediated Akt Phosphorylation Signaling Pathway
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APPL1 的丝氨酸 707 对于突触 NMDA 受体介导的 Akt 磷酸化信号通路至关重要
DOI：
10.1007/s12264-016-0042-9
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发表时间：
2016-08-01
影响因子：
5.6
通讯作者：
Luo, Jianhong
中科院分区：
文献类型：
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作者：
Wang, Jiejie;Lu, Wen;Luo, Jianhong
越来越多的证据表明，N-甲基-d-天冬氨酸受体（NMDARs）的突触激活对神经元具有神经保护作用。我们的前期研究表明APPL1（adaptor protein containing pleckstrin homology domain，phosphotyrosine-binding domain，and leucine zipper motif）通过与NMDAR-PSD95（postsynaptic density protein 95）复合物偶联介导了PI3K-Akt信号通路的突触活性依赖性激活。然而，这一过程背后的分子机制仍然是未知的。在本研究中，我们研究了APPL1与PSD 95的相互作用，使用共免疫细胞化学染色和蛋白质印迹。我们发现PSD95的PDZ 2结构域是APPL1的结合伴侣。此外，我们确定了APPL1的丝氨酸707，一个预测的磷酸化位点内的PDZ结合基序在C-末端，作为关键的APPL1的结合到PSD 95，以及激活Akt信号通路在突触活动。这表明APPL1的丝氨酸707是一个潜在的磷酸化位点，可能参与调节依赖于突触NMDAR活性的神经保护性Akt信号通路。
Accumulating evidence indicates that the synaptic activation ofN-methyl-d-aspartate receptors (NMDARs) has a neuroprotective effect on neurons. Our previous study demonstrated that APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif) mediates the synaptic activity-dependent activation of PI3K-Akt signalingviacoupling this pathway with NMDAR-PSD95 (postsynaptic density protein 95) complexes. However, the molecular mechanism underlying this process is still unknown. In the present study, we investigated the interaction of APPL1 with PSD95 using co-immunocytochemical staining and western blotting. We found that the PDZ2 domain of PSD95 is a binding partner of APPL1. Furthermore, we identified serine 707 of APPL1, a predicted phosphorylation site within the PDZ-binding motif at the C-terminus, as critical for the binding of APPL1 to PSD95, as well as for activation of the Akt signaling pathway during synaptic activity. This suggests that serine 707 of APPL1 is a potential phosphorylation site and may be involved in regulating the neuroprotective Akt signaling pathway that depends on synaptic NMDAR activity.