Isoform-specific regulation of Akt by PDGF-induced reactive oxygen species

Platelet-Derived Growth Factor 0301 basic medicine 0303 health sciences Base Sequence Phospholipase C gamma Molecular Sequence Data Cell Line 3. Good health Mice 03 medical and health sciences Mutagenesis, Site-Directed NIH 3T3 Cells Animals Humans Protein Isoforms Amino Acid Sequence Reactive Oxygen Species Oxidation-Reduction Proto-Oncogene Proteins c-akt DNA Primers Signal Transduction
DOI: 10.1073/pnas.1011665108 Publication Date: 2011-06-14T18:03:48Z
ABSTRACT
Isoform-specific signaling of Akt, a major signaling hub and a prominent therapeutic target, remained poorly defined until recently. Subcellular distribution, tissue-specific expression, substrate specificity, and posttranslational modifications are believed to underlie isoform-specific signaling of Akt. The studies reported here show inhibition of Akt2 activity under physiologically relevant conditions of oxidation created by PDGF-induced reactive oxygen species. Combined MS and functional assays identified Cys124 located in the linker region between the N-terminal pleckstrin homology domain and the catalytic kinase domain as one of the unique regulatory redox sites in Akt2 with functional consequence on PDGF-stimulated glucose uptake. A model is proposed describing the consequence of increased endogenous oxidation induced by extracellular cues such as PDGF on Akt2 activity.
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