Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer

Alternative splicing (AS) is one of the key processes involved in the regulation of gene expression in eukaryotic cells. AS catalyzes the removal of intronic sequences and the joining of selected exons, thus ensuring the correct processing of the primary transcript into the mature mRNA. The combinatorial nature of AS allows a great expansion of the genome coding potential, as multiple splice-variants encoding for different proteins may arise from a single gene. Splicing is mediated by a large macromolecular complex, the spliceosome, whose activity needs a fine regulation exerted by cis-acting RNA sequence elements and trans-acting RNA binding proteins (RBP). The activity of both core spliceosomal components and accessory splicing factors is modulated by their reversible phosphorylation. The kinases and phosphatases involved in these posttranslational modifications significantly contribute to AS regulation and to its integration in the complex regulative network that controls gene expression in eukaryotic cells. Herein, we will review the major canonical and noncanonical splicing factor kinases and phosphatases, focusing on those whose activity has been implicated in the aberrant splicing events that characterize neoplastic transformation. 1. Introduction In eukaryotic cells, the expression of each gene is finely tuned by a complex network of regulative processes affecting all steps of transcript maturation, from nuclear transcription to cytosolic export and utilization of the mRNA. A crucial step in this regulative network is represented by pre-mRNA splicing, the molecular process that mediates the removal of intronic sequences and the joining of exons. What makes splicing an outstanding player in controlling gene expression is its flexibility, which allows a remarkable increase of the coding potential of the genome through alternative selection of exons. Indeed, alternative splicing (AS) allows each gene to encode for several coding and noncoding mRNA variants, which often display different activities and/or patterns of expression. AS is, therefore, one of the principal mechanisms underlying the well-known discrepancy between increasing organismal complexity and content of genes contained in the genome [1]. In line with its central contribution to genome complexity, it is estimated that up to 90% of human multiexon genes undergo AS [2], and the importance of this regulative mechanism for both developmentally regulated and pathological cellular processes is now well recognized (reviewed in [3]). The splicing process is carried out by the spliceosome, a