Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN.
The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid and protein phosphatase. We report here that PTEN physically associates with the NR1 and NR2B subunits of NMDA receptors (NMDARs) in rat hippocampus. Downregulating the protein expression of PTEN inhibits the function of extrasynaptic NMDARs and decreases NMDAR surface expression, suggesting a crucial role for endogenous PTEN in the modulation of NMDAR-mediated neuronal function. Reducing PTEN expression also enhances Akt/Bad phosphorylation in hippocampal neurons. Importantly, suppressing lipid and protein phosphatase activity of PTEN, respectively, activates Akt and inhibits extrasynaptic NMDAR activity and thereby protects against ischemic neuronal death in vitro and in vivo. Thus, our study reveals a dual neuroprotective mechanism by which Akt/Bad and extrasynaptic NMDARs are regulated via downregulation of two distinct PTEN phosphatase activities and present the possibility of PTEN as a potential therapeutic target for stroke treatment.
Ning
Ke
K
Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network, Toronto, Canada M5T 2S8.
Pei
Lin
L
Liao
Mingxia
M
Liu
Baosong
B
Zhang
Yunzhou
Y
Jiang
Wen
W
Mielke
John G
JG
Li
Lei
L
Chen
Yonghong
Y
El-Hayek
Youssef H
YH
Fehlings
Michael G
MG
Zhang
Xia
X
Liu
Fang
F
Eubanks
James
J
Wan
Qi
Q
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D046911:Macromolecular Substances; D008297:Male; D009474:Neurons / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051025:bcl-Associated Death Protein
C494821:Bad protein, rat; D002352:Carrier Proteins; D046911:Macromolecular Substances; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D051025:bcl-Associated Death Protein; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat