Concerted regulation of alternative splicing and translation by extracellular

MATÍAS BLAUSTEIN; FEDERICO PELISCH; LEANDRO QUADRANA; ANABELLA SREBROW

Pinamar, Argentina

Congreso; Reunión Anual de la Sociedad Argentina de Investigaciones Bioquímicas - SAIB; 2005

Alternative pre-mRNA splicing is the most important source of protein diversity in vertebrates. Regulation of this process by extracellular cues represents a key event in the control of gene expression. We used the fibronectin (FN) gene as a model to study the linkage between the cellular microenvironment and the splicing machinery. We found that growth factors up-regulate the inclusion of the FN EDA alternative exon via PI 3-kinase. We also found that growth factors alter translation of reporter mRNAs containing a FN EDA exonic splicing enhancer. The effects at both splicing and translation levels are mediated by AKT and inhibited by knocking-down specific Serine/Arginine-rich (SR) splicing factors. Finally, we demonstrated that AKT phosphorylates SR proteins in vitro and that its over-expression elicits opposite effects to those evoked by the previously described SR protein kinases Clk/Sty and SRPK on SR protein localization and alternative splicing. These results show how SR protein activity is modified in response to extracellular cues leading to a concerted regulation of splicing and translation.