Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer

Abstract

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.

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

“…Dynamic phosphorylation and dephosphorylation of splicing factors regulate spliceosome assembly and selection of splice sites (for review, see Naro and Sette 2013). For example, region-specific phosphorylation of serine-arginine rich proteins is well-known to regulate splicing factor localization and spliceosome assembly (for review, see Zhou and Fu 2013).…”

Regulation of translation by upstream translation initiation codons of surfactant protein A1 splice variants

“…It is well known that splice variant ratios are regulated by external stimuli through cell signaling pathways in pathological conditions, such as cancer (61). Moreover, such interplay between genetic complexity and signaling events has been demonstrated in other systems as well (57,63).…”

Proteomics of tissue factor silencing in cardiomyocytic cells reveals a new role for this coagulation factor in splicing machinery control

“…A wide variety of interactions have been described between 470 components of the RNA processing machinery and traditional signalling molecules: for example, 471 hnRNP K protein contains multiple modules that bind kinases while recruiting chromatin, 472 transcription, splicing and translation factors [65]. We focused our analysis to kinases such as the 473 mitogen-activated protein kinase and PI3-kinase/Akt pathways because they are related TF 474 signalling, and we have not analysed the full spectrum of kinases and phosphatases (reviewed in 475 [66]) involved in the post-traslational modifications of the spliceosomal components and 476 accessory splicing factors which significantly contribute to their activity. Regulation of splicing 477 factors by Akt is not heretical [67]; activated Akt has been involved in directly modulating 478 serine/arginine-rich proteins (SR proteins) [68]; more recently, hnRNP L has been recently 479 identified as a direct substrate of Akt, thus influencing the alternative splicing of caspase-9 [69], 480 and down-regulation of splicing factors has been also observed in U373 glioma cells after Akt 481 silencing [70].…”