Regulation of Akt/PKB by SUMO conjugation

RISSO, GUILLERMO; PELISCH, FEDERICO; POZZI, BERTA; BLAUSTEIN MATIAS; COLMAN LERNER, ALEJANDRO; SREBROW, ANABELLA

Bariloche

Simposio; Second South American Spring Symposium in Signal Transduction and Molecular Medicine (SISTAM2012).; 2012

Our laboratory has been studying the regulation of fibronectin pre-mRNA alternative splicing by signal transduction pathways triggered by cell-cell and cell-ECM interactions. We reported that the activation of a signaling cascade involving Akt/PKB regulates the activity of at least two splicing factors of the SR protein family, SRSF1 and SRSF7 (a.k.a SF2/ASF and 9G8), simultaneously altering both nuclear and cytoplasm steps along mRNA metabolism: alternative splicing and translation. Moreover, we revealed Akt as an SR protein kinase capable of phosphorylating these two SR proteins.  Recently, we found that the SR protein SRSF1, apart from its multiple mRNA-related tasks, enhances SUMO conjugation to a variety of target proteins both in vitro and in living cells. Among the different SUMO conjugation substrates regulated by SRSF1, we uncovered Akt/PKB.  Based on these results we proposed to further explore this unexpected post-translational modification of Akt, as well as a putative regulatory feedback loop within the Pi3K/Akt/SR protein axis. We mapped SUMO conjugation sites on Akt1 and generated a SUMOylation-defective Akt1 mutant to study the cellular and physio-pathological relevance of SUMO conjugation to Akt. So far, we found that several of the known Akt cellular functions are impaired by the lack of SUMOylation of this kinase while others remain unaltered, suggesting that this post-translational modification could represent a novel regulatory step for Akt activity.