Protein kinases that phosphorylate splicing factors: Roles in cancer development, progression and possible therapeutic options.

Disturbed alternative splicing is a common feature of human tumors. Splicing factors that control alternative splicing are phosphorylated by multiple kinases, including these that specifically add phosphoryl groups to serine-arginine rich proteins (e.g. SR-protein kinases, cdc2-like kinases, topoisomerase 1), and protein kinases that govern key cellular signaling pathways (i.e. AKT). Phosphorylation of splicing factors regulates their subcellular localization and interactions with target transcripts and protein partners, and thus significantly contributes the final result of splicing reactions. In this review we aim to summarize the current knowledge on the role of splicing kinases in cancer. Published studies and recently released data of The Cancer Genome Atlas demonstrate that expressions and activities of splicing kinases are commonly disturbed in cancers. Aberrant functioning of splicing kinases results in changed alternative splicing of tumor suppressors (e.g. p53) and regulators of cell signaling (e.g. MAPKs), apoptosis (e.g. MCL), and angiogenesis (VEGF). Splicing kinases act in complicated regulatory networks in which they mutually affect each other's activity to provide tight control of cellular signaling. Dysregulation of these regulatory networks contributes to oncogenic transformation, uncontrolled proliferation, enhanced migration and invasion. Furthermore, the activities of splicing kinases significantly contribute to cellular responses to genotoxic stress. In conclusion, published data provide strong evidence that splicing kinases emerge as important regulators of key processes governing malignant transformation, progression, and response to therapeutic treatments, suggesting their potential as clinically relevant targets.