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

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, phosphotyrosinebinding 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.

Amyloid precursor protein and endosomal‐lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease

“…Knockdown of APPL1 expression, such as APP–βCTF or rab5 knockdown, in fibroblasts of patients with DS fully corrects the endosomopathy (20), including elevated nuclear translocation of p65/RelA and activation of NF‐kB signaling that are mediated by rab5 endosomes (55). Additional roles for APPL1 that are potentially relevant to AD include cellular signaling via insulin (55, 56), Akt (57), phosphoinositides (58), epidermal growth factor, and tropomoysin receptor kinase (Trk)A and TrkB receptors (59, 60). Of note, APPL1 localizes prominently to dendritic spines and synapses (61, 62), mediates the synaptic activity–dependent activation of PI3K‐Akt signaling by coupling this pathway to NMDA receptor–PSD95 complexes (57), and activates the phosphatidylinositol 3,4,5 trisphosphate pathway in response to long‐term potentiation (LTP) induction (63).…”

“…Additional roles for APPL1 that are potentially relevant to AD include cellular signaling via insulin (55, 56), Akt (57), phosphoinositides (58), epidermal growth factor, and tropomoysin receptor kinase (Trk)A and TrkB receptors (59, 60). Of note, APPL1 localizes prominently to dendritic spines and synapses (61, 62), mediates the synaptic activity–dependent activation of PI3K‐Akt signaling by coupling this pathway to NMDA receptor–PSD95 complexes (57), and activates the phosphatidylinositol 3,4,5 trisphosphate pathway in response to long‐term potentiation (LTP) induction (63). In the brains of patients with AD, but not in those of controls, APPL1 colocalizes with glutamate receptor 2 and ubiquitin in nonplaque dystrophic dendrites (61).…”

Primary Blast-Induced Changes in Akt and GSK3β Phosphorylation in Rat Hippocampus

“…However, its phosphorylation levels are altered in both neurons and glial cells during cellular stress, brain inflammation, and various forms of brain injury ( 30 – 33 ). In order for Akt to exert its functions, it must be activated through phosphorylation at both threonine-308 and serine-473 positions via its upstream kinase phosphatidylinositol 3-kinase (PI3K) in response to various growth and survival factors such as insulin-like growth factor ( 34 ) or to the activation of synaptic N -methyl- d -aspartate (NMDA) receptors ( 35 , 36 ). Upon phosphorylation, Akt is translocated to the cell membrane to modulate its downstream effectors including glycogen synthase kinase-3β (GSK 3β ), which plays an important role in regulating neurodegeneration during disease and injury ( 37 ).…”

Molecular Mechanisms of Curcumin Renoprotection in Experimental Acute Renal Injury

“…Furthermore, as a crucial element of protein trafficking and cell signaling, APPL1 can mediate the Akt signaling pathway to augment various pathophysiological processes (Tan et al, 2016 ; Wang et al, 2016 ). Thus, based on our APPL1 and phosphorylated Akt results, we investigated whether the APPL1/Akt signaling pathway mediated the effect of curcumin on IR-induced AKI.…”