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

• DOI: 10.1073/pnas.1011665108
• Publication Date: 2011-06-14T18:03:48Z
• Authors: Revati Wani; Jiang Qian; Leimiao Yin; Erika Bechtold; S. Bruce King; Leslie B. Poole; Eunok Paek; Allen W. Tsang; Cristina M. Furdui
• Keywords: Platelet-Derived Growth Factor; 0301 basic medicine; 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

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.