Post-Translational Modifications Influence the Splicing Machinery and Vice Versa

RISSO, GUILLERMO; MAMMI, PABLO; POZZI, BERTA; SREBROW ANABELLA

Rosario

Conferencia; L REUNION ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIONES EN BIOQUIMICA Y BIOLOGIA MOLECULAR; 2014

SAIB

Our laboratory has focused on 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 Pi3K-Akt signaling axis regulates the activity of two splicing factors of the SR protein family, SRSF1 and SRSF7, simultaneously altering alternative splicing and translation. We also revealed Akt as an SR protein kinase capable of phosphorylating these two factors. More recently, we described that SRSF1, apart from its multiple mRNA-related tasks, enhances SUMO conjugation to a variety of proteins, among them we uncovered Akt as a SUMO substrate. Phosphorylation and SUMOylation of Akt appear as independent events. However, several functions of this kinase are impaired by its lack of SUMOylation. In agreement with the pro-survival role of Akt, we found that its SUMOylation is relevant for G1/S transition along cell cycle progression and for the regulation of alternative splicing leading to the production of mRNA isoforms associated with cell proliferation and survival. These findings reveal SUMO conjugation as a novel level of regulation for Akt, a crucial signaling molecule in human health and disease. We propose that this posttranslational modification does not regulate Akt activation, but it might regulate its subcellular localization and interaction with downstream targets.