From the role of SRSF1 as a regulator of the SUMO conjugation pathway to the involvement of SUMO conjugation in splicing regulation

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

TRIESTE

Simposio; ICGEB 2nd Post-EURASNET Symposium; 2013

EURASNET- ICGEB

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 (aka PKB) regulates the activity of at least two splicing factors of the SR protein family, SRSF1 and SRSF7, simultaneously altering alternative splicing and translation. Moreover, we revealed Akt as an SR protein kinase capable of phosphorylating these two SR proteins. Few years ago, we described that SRSF1, apart from its multiple mRNA-related tasks, enhances SUMO conjugation to a variety of target proteins both in vitro and in living cells. These results led us to propose a putative regulatory connection between SUMO conjugation and splicing. Among the different SUMO conjugation substrates regulated by SRSF1, we uncovered Akt and decided to deeply analyze this unexpected post-translational modification of a key signaling molecule in higher eukaryotes and a crucial protein kinase in human health and disease. We found that whereas phosphorylation and SUMOylation of Akt appear as independent events, several of the known cellular functions of Akt are impaired by its lack of SUMOylation. In particular and in agreement with the pro-survival role of this kinase, we found that its SUMOylation is not only relevant for the G1/S transition along cell cycle progression but also for the production of different mRNA splice variants that are associated with cell proliferation and survival. To further explore the aforementioned hypothesis, we are currently studying the functional role of SUMO conjugation on spliceosome assembly/disassembly cycle and other aspects of the splicing process.