Functional interaction of phosphatase and tensin homologue (PTEN) with the E3 ligase NEDD4-1 during neuronal response to zinc Journal Article

Authors: Kwak, Y. D.; Wang, B.; Pan, W.; Xu, H.; Jiang, X.; Liao, F. F.
Article Title: Functional interaction of phosphatase and tensin homologue (PTEN) with the E3 ligase NEDD4-1 during neuronal response to zinc
Abstract: 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. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
Keywords: signal transduction; protein kinase b; controlled study; protein expression; unclassified drug; nonhuman; ubiquitin; neoplasm; neoplasms; proteins; animal cell; mouse; animal; metabolism; animals; mice; proteasome; proteasome endopeptidase complex; gene expression; biological model; models, biological; signaling; ubiquitin protein ligase; protein degradation; protein protein interaction; neurons; enzyme inhibitor; phosphorylation; phosphatidylinositol 3 kinase; mice, inbred c57bl; c57bl mouse; gene expression regulation; gene expression regulation, neoplastic; chemistry; regulatory mechanism; ubiquitination; enzyme inhibitors; nucleotide sequence; rat; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; blood brain barrier; 1-phosphatidylinositol 3-kinase; blood-brain barrier; pten phosphohydrolase; rats; feedback system; zinc; cell stimulation; nerve cell; endosomal sorting complexes required for transport; ubiquitin-protein ligases; pten protein, human; neuroblastomas; wortmannin; tumor suppressors; ligase; nerve degeneration; neurodegeneration; glycogen synthase kinase 3; e3 ligase; signaling pathways; degradation; phosphatidylinositol 3-kinase; nerve cell necrosis; cortical neurons; feed-back loop; functional interaction; key regulators; n2a cells; neuronal death; neuronal response; phosphatase and tensin homologues; protein level; reciprocal regulation; laws and legislation; phosphatases; ubiquitin protein ligase nedd4-1; zinc ion; escrt protein; nedd4 ubiquitin protein ligases; brain nerve cell
Journal Title: Journal of Biological Chemistry
Volume: 285
Issue: 13
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2010-03-26
Start Page: 9847
End Page: 9857
Language: English
DOI: 10.1074/jbc.M109.091637
PUBMED: 20100827
PROVIDER: scopus
PMCID: PMC2843233
Notes: --- - "Cited By (since 1996): 7" - "Export Date: 20 April 2011" - "CODEN: JBCHA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Xuejun Jiang
    107 Jiang
  2. Wei Pan
    4 Pan