Journal
CELL CYCLE
Volume 12, Issue 19, Pages 3165-3174Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.26183
Keywords
signal transduction; post-translational modification; SUMO; Akt; PKB; alternative splicing; cell cycle
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Funding
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT) of Argentina
- Universidad de Buenos Aires, Argentina
- Fundacion Florencio Fiorini, Argentina
- L'Oreal-UNESCO-CONICET
- European Alternative Splicing Network (EURASNET)
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Akt/PKB is a key signaling molecule in higher eukaryotes and a crucial protein kinase in human health and disease. Phosphorylation, acetylation, and ubiquitylation have been reported as important regulatory post-translational modifications of this kinase. We describe here that Akt is modified by SUMO conjugation, and show that lysine residues 276 and 301 are the major SUMO attachment sites within this protein. We found that phosphorylation and SUMOylation of Akt appear as independent events. However, decreasing Akt SUMOylation levels severely affects the role of this kinase as a regulator of fibronectin and Bcl-x alternative splicing. Moreover, we observed that the Akt mutant (Akt E17K) found in several human tumors displays increased levels of SUMOylation and also an enhanced capacity to regulate fibronectin splicing patterns. This splicing regulatory activity is completely abolished by decreasing Akt E17K SUMO conjugation levels. Additionally, we found that SUMOylation controls Akt regulatory function at G/S transition during cell cycle progression. These findings reveal SUMO conjugation as a novel level of regulation for Akt activity, opening new areas of exploration related to the molecular mechanisms involved in the diverse cellular functions of this kinase.
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