Regulation of Akt Activity by SUMO Conjugation

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

Buenos Aires

Simposio; Molecular mechanisms in cell signaling and gene expression; 2013

Sociedad Argentina de Investigacion en Bioquimica y Biologia Molecular

Our laboratory studies the regulation of pre-mRNA alternative splicing by signal transduction pathways. We have reported that Akt activation regulates the activity of two splicing factors of the SR protein family (SRSF1 and SRSF7), altering different steps along mRNA metabolism: alternative splicing and translation. We also revealed Akt as an SR protein kinase capable of phosphorylating these SR proteins. We found that the SR protein SRSF1 enhances SUMO conjugation to several target proteins, including Akt. Here, the further explored this unexpected post-translational modification of Akt. By site directed mutagenesis we mapped SUMO conjugation sites within Akt. We found that Akt SUMOylation is required for its regulatory role on fibronectin and Bcl-x altrnative splicing. Consistent with the pro-survival and pro-proliferative role of this kinase, we showed that its SUMOylation favors the production of fibronectin mRNA isoforms characteristic of highly proliferative tissues and tumors, as well as of anti-apoptotic Bcl-x mRNA isoforms. We also found that SUMOylation of Akt controls its function as a regulator of cell cycle progression. These findings reveal a novel level of regulation for Akt function, opening new areas of exploration related to the molecular mechanisms determining that the activation of a single kinase can lead to a vast diversity of cellular responses.