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Cell Cycle. 2013 Oct 1;12(19):3165-74. doi: 10.4161/cc.26183. Epub 2013 Aug 27.

Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle.

Author information

1
Instituto de Fisiología, Biología Molecular y Neurociencias-Consejo Nacional de Investigaciones Científicas y Técnicas; Departamento de Fisiología, Biología Molecular y Celular; Facultad de Ciencias Exactas y Naturales-Universidad de Buenos Aires; Buenos Aires, Argentina.

Abstract

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 G₁/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.

KEYWORDS:

Akt/PKB; SUMO; alternative splicing; cell cycle; post-translational modification; signal transduction

PMID:
24013425
PMCID:
PMC3865012
DOI:
10.4161/cc.26183
[Indexed for MEDLINE]
Free PMC Article

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