Functional interaction of phosphatase and tensin homologue (PTEN) with the E3 ligase NEDD4-1 during neuronal response to zinc.
The contribution of zinc-mediated neuronal death in the process of both acute and chronic neurodegeneration has been increasingly appreciated. Phosphatase and tensin homologue, deleted on chromosome 10 (PTEN), the major tumor suppressor and key regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, plays a critical role in neuronal death in response to various insults. NEDD4-1-mediated PTEN ubiquitination and subsequent degradation via the ubiquitin proteosomal system have recently been demonstrated to be the important regulatory mechanism for PTEN in several cancer types. We now demonstrate that PTEN is also the key mediator of the PI3K/Akt pathway in the neuronal response to zinc insult. We used primary cortical neurons and neuroblastoma N2a cells to show that zinc treatment results in a reduction of the PTEN protein level in parallel with increased NEDD4-1 gene/protein expression. The reduced PTEN level is associated with an activated PI3K pathway as determined by elevated phosphorylation of both Akt and GSK-3 as well as by the attenuating effect of a specific PI3K inhibitor (wortmannin). The reduction of PTEN can be attributed to increased protein degradation via the ubiquitin proteosomal system, as we show NEDD4-1 to be the major E3 ligase responsible for PTEN ubiquitination in neurons. Moreover, PTEN and NEDD4-1 appear to be able to counter-regulate each other to mediate the neuronal response to zinc. This reciprocal regulation requires the PI3K signaling pathway, suggesting a feedback loop mechanism. This study demonstrates that NEDD4-1-mediated PTEN ubiquitination is crucial in the regulation of PI3K/Akt signaling by PTEN during the neuronal response to zinc, which may represent a common mechanism in neurodegeneration.
Kwak
Young-Don
YD
Neurodegenerative Disease Program, Burnham Institute for Medical Research, La Jolla, California 92037.
Wang
Bin
B
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
Pan
Wei
W
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065.
Xu
Huaxi
H
Neurodegenerative Disease Program, Burnham Institute for Medical Research, La Jolla, California 92037.
Jiang
Xuejun
X
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065.
Liao
Francesca-Fang
FF
Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163. Electronic address: fliao@uthsc.edu.
D000818:Animals; D001812:Blood-Brain Barrier; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000075702:Nedd4 Ubiquitin Protein Ligases; D009369:Neoplasms / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
D056827:Endosomal Sorting Complexes Required for Transport; D004791:Enzyme Inhibitors; D025801:Ubiquitin; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D046988:Proteasome Endopeptidase Complex; D015032:Zinc