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Serine 707 of APPL1 is Critical for the Synaptic NMDA Receptor-Mediated Akt Phosphorylation Signaling Pathway

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Abstract

Accumulating evidence indicates that the synaptic activation of N-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 signaling via coupling 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.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (91232303, 81221003, and 81561168).

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Authors and Affiliations

  1. Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Jiejie Wang, Wen Lu, Wei Cao & Jianhong Luo

  2. The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China

    Lin Chen

  3. Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

    Ping Zhang & Tingting Qian

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  1. Jiejie Wang
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  2. Wen Lu
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  3. Lin Chen
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  4. Ping Zhang
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  6. Wei Cao
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  7. Jianhong Luo
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Correspondence to Jianhong Luo.

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Wang, J., Lu, W., Chen, L. et al. Serine 707 of APPL1 is Critical for the Synaptic NMDA Receptor-Mediated Akt Phosphorylation Signaling Pathway. Neurosci. Bull. 32, 323–330 (2016). https://doi.org/10.1007/s12264-016-0042-9

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  • DOI: https://doi.org/10.1007/s12264-016-0042-9

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