Small Molecule-Induced Cytosolic Activation of Protein Kinase Akt Rescues Ischemia-Elicited Neuronal Death
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Author
Mondal, Subhanjan
Nagata, Eiichiro
Takizawa, Shunya
Hou, Qingming
Shanmugasundaram, Kumaran
Prasad, Amit
Tung, Joe K.
Tejeda, Alexander O.
Man, Hengye
Rigby, Alan C.
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https://doi.org/10.1073/pnas.1202810109Metadata
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Jo, Hakryul, Subhanjan Mondal, Dewar Tan, Eiichiro Nagata, Shunya Takizawa, Alok K. Sharma, Qingming Hou, et al. 2012. "Small Molecule-Induced Cytosolic Activation of Protein Kinase Akt Rescues Ischemia-Elicited Neuronal Death." Proceedings of the National Academy of Sciences 106 (9): 10581–10586. doi:10.1073/pnas.1202810109.Abstract
Elevating Akt activation is an obvious clinical strategy to prevent progressive neuronal death in neurological diseases. However, this endeavor has been hindered because of the lack of specific Akt activators. Here, from a cell-based high-throughput chemical genetic screening, we identified a small molecule SC79 that inhibits Akt membrane translocation, but paradoxically activates Akt in the cytosol. SC79 specifically binds to the PH domain of Akt. SC79-bound Akt adopts a conformation favorable for phosphorylation by upstream protein kinases. In a hippocampal neuronal culture system and a mouse model for ischemic stroke, the cytosolic activation of Akt by SC79 is sufficient to recapitulate the primary cellular function of Akt signaling, resulting in augmented neuronal survival. Thus, SC79 is a unique specific Akt activator that may be used to enhance Akt activity in various physiological and pathological conditions.Other Sources
http://www.ncbi.nlm.nih.gov/pubmed/22689977Terms of Use
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