Calpains-Mediated PTEN Cleavage in Excitotoxic Neuronal Death


Authors: Minghui Jessica Chen, Piang Chin Benjamin Soo,Meng Shyan Choy, Zhao Feng Peng, Heung-Chin Cheng, and Nam Sang Cheung
Page Range: 13-28
Published in: Journal of Biochemistry and Molecular Biology in the Post Genomic Era, 1#1 (2011)
ISSN: 2156-5732

Table of Contents


The tumor suppressor PTEN (phosphatase and tensin homolog deleted from chromosome 10) has been implicated in the pathogenesis of numerous neurodegenerative diseases, and is particularly noted for its inhibition of the pro-survival PI3K-Akt pathway. Excitotoxicity due to over-stimulation of ionotropic glutamate receptors in neurons are known to contribute to neurodegenerative diseases such as Alzheimer’s disease and ischemic stroke. Previously we have demonstrated that the proteasomal inhibitor, lactacystin, induced cleavage of PTEN to a truncated 50kDa fragment which accumulates to the detergent-insoluble membrane fraction of the neuronal cells. Herein, we report that overstimulation of the ionotropic glutamate receptors with excess NMDA while causing induction of calpains activation in cultured cortical neurons results in the formation of a novel truncated PTEN fragment of molecular weight <50kDa. In vitro cleavage assay further confirmed that calpains-mediated cleavage is responsible for the expression of <50kDa, while the 50kDa PTEN fragment observed in latacystin-mediated neuronal death is held accountable by caspase-3 activation. Both truncated PTEN fragments preferentially partition to the detergent-insoluble fraction of neuronal cells. The fragments did not react with the phospho-specific PTEN antibody targeting the C-terminal regulatory serine and threonine residues, suggesting that the cleavage sites are localised at the C-terminal tail or the cleavage enhances dephosphorylation of these C-terminal regulatory sites. Future investigation to define the function and regulation of calpain- and caspase 3-generated truncated PTEN fragment will shed light on the role of PTEN in proteasome inhibition- and excitotoxicity-induced neuronal death in neurological diseases. Classification Terms: Section: Neurophysiology; Neuropharmacology; other forms of Intercellular Communication.

Keywords: PTEN, Truncation, Calpains, Caspase-3.

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