Connecting the speckles: Splicing kinases and their role in tumorigenesis and treatment response

Abstract

Abbreviations: SR, serine arginine; SRPK, serine arginine protein kinase; CLK, CDC-like kinase; PRP4K, pre-mRNA processing factor 4 kinase; snRNP, small nuclear ribonucleic protein. Alternative pre-mRNA splicing in higher eukaryotes enhances transcriptome complexity and proteome diversity. Its regulation is mediated by a complex RNA-protein network that is essential for the maintenance of cellular and tissue homeostasis. Disruptions to this regulatory network underlie a host of human diseases and contribute to cancer development and progression. The splicing kinases are an important family of pre-mRNA splicing regulators, , which includes the CDC-like kinases (CLKs), the SRSF protein kinases (SRPKs) and pre-mRNA splicing 4 kinase (PRP4K/PRPF4B). These splicing kinases regulate pre-mRNA splicing via phosphorylation of spliceosomal components and serine- arginine (SR) proteins, affecting both their nuclear localization within nuclear speckle domains as well as their nucleocytoplasmic shuttling. Here we summarize the emerging evidence that splicing kinases are dysregulated in cancer and play important roles in both tumorigenesis as well as therapeutic response to radiation and chemotherapy.