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Critical cysteines in Akt1 regulate its activity and proteasomal degradation: implications for neurodegenerative diseases

Ahmad, Faraz and Nidadavolu, Prakash and Durgadoss, Lalitha and Ravindranath, Vijayalakshmi (2014) Critical cysteines in Akt1 regulate its activity and proteasomal degradation: implications for neurodegenerative diseases. In: FREE RADICAL BIOLOGY AND MEDICINE, 74 . pp. 118-128.

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Impaired Akt1 signaling is observed in neurodegenerative diseases, including Parkinson's disease (PD). In PD models oxidative modification of Akt1 leads to its dephosphorylation and consequent loss of its kinase activity. To explore the underlying mechanism we exposed Neuro2A cells to cadmium, a pan inhibitor of protein thiol disulfide oxidoreductases, including glutaredoxin 1 (Grx1), or downregulated Grx1, which led to dephosphorylation of Akt1, loss of its kinase activity, and also decreased Akt1 protein levels. Mutation of cysteines to serines at 296 and 310 in Akt1 did not affect its basal kinase activity but abolished cadmium- and Grx1 downregulation-induced reduction in Akt1 kinase activity, indicating their critical role in redox modulation of Akt1 function and turnover. Cadmium-induced decrease in phosphorylated Akt1 correlated with increased association of wild-type (WT) Akt1 with PP2A, which was absent in the C296-310S Akt1 mutant and was also abolished by N-acetylcysteine treatment. Further, increased proteasomal degradation of Akt1 by cadmium was not seen in the C296-310S Akt1 mutant, indicating that oxidation of cysteine residues facilitates degradation of WT Akt1. Moreover, preventing oxidative modification of Akt1 cysteines 296 and 310 by mutating them to serines increased the cell survival effects of Akt1. Thus, in neurodegenerative states such as PD, maintaining the thiol status of cysteines 296 and 310 in Akt1 would be critical for Akt1 kinase activity and for preventing its degradation by proteasomes. Preventing downregulation of Akt signaling not only has long-range consequences for cell survival but could also affect the multiple roles that Ala plays, including in the Akt-mTOR signaling cascade. (C) 2014 Elsevier Inc. All rights reserved.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the ELSEVIER SCIENCE INC, 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
Department/Centre: Division of Biological Sciences > Centre for Neuroscience
Date Deposited: 10 Oct 2014 06:33
Last Modified: 10 Oct 2014 06:33
URI: http://eprints.iisc.ac.in/id/eprint/49966

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