Serine 707 of APPL1 is Critical for the Synaptic NMDA Receptor-Mediated Akt Phosphorylation Signaling Pathway.
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.
Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Jiejie
J
Wang
Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Wen
W
Lu
The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
Lin
L
Chen
Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
Ping
P
Zhang
Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
Tingting
T
Qian
Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Wei
W
Cao
Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China. luojianhong@zju.edu.cn.
Jianhong
J
Luo
D015761:4-Aminopyridine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D018756:GABA Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D026902:Potassium Channel Blockers; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D015761:4-Aminopyridine; D051058:Oncogene Protein v-akt; D001640:Bicuculline
APPL1; Akt; NMDA receptors; Neuroprotection; PSD95