p to 38,000 possible alternative transcripts.5 Pre-mRNA splicing allows increased protein diversity and cellular complexity between species and also provides the plasticity for one cell to alter its protein complement dynamically in response to cellular stress or developmental cues. As one would expect, the mechanisms of pre-mRNA splicing are tightly regulated to maintain cellular and tissue homeostasis, and errors in splicing underlie a host of genetic diseases and can contribute to cancer development and progression. In fact, it is estimated that 22% of disease causing mutations affect splicing6. Although there are many dozens of splicing factors, many of which are serine arginine -rich, ostensibly their functions in splicing are regulated by several serine/threonine kinases. These kinases share a general preference for phosphorylating SR-rich proteins and collectively are referred to as SR protein specific kinases, or simply splicing kinases. Therefore, it is perhaps not surprising to note that during evolution there appears to be a concomitant increase in the diversity and number of isoforms of these kinases. This Aglafoline chemical information occurs in lockstep with increasing gene complexity in terms of alternative splicing between single-cell eukaryotes like S. cerevisiae, which encode very few intron-containing genes and a single bona fide SR-protein kinase Sky1, to complex metazoans like humans, whose genome encodes many intron containing genes and multiple paralogs of at least 3 classes of splicing kinases. In humans, the 3 classes of splicing kinases include the serinearginine protein kinases, the CDC-like kinases 279 www.tandfonline.com Nucleus , and the pre-mRNA processing factor 4 kinase. Each class of splicing kinase has a distinct cellular localization, which may be based in part on their different roles in splicing regulation. One of the first splicing kinases to be described in the literature is the SRSF protein kinase 1, which was identified by Gui et al. in 
1994 when the authors purified and cloned a cell cycle regulated kinase which was responsible for redistribution of SR proteins from a nuclear speckle localization in interphase cells, to a more ubiquitous nucleoplasm localization in mitotic cells.10,11 SRPK2 and SRPK3 were later identified based on sequence homology with SRPK1.12,13 SRPK2, much like SRPK1, was shown to regulate splicing through SR protein phosphorylation12 while SRPK3 was identified for its role in normal muscle growth and homeostasis.13 CDC-like kinase 1 was identified as a splicing kinase in 1996 when a yeast 2 hybrid screen using Clk/sty kinase as bait identified 5 SR proteins as binding partners.14 The authors went on to show that one of the interacting SR proteins, ASF/SF2, was phosphorylated within its RS domain by Clk/sty, and that overexpression of Clk/sty, much like SRPK1, caused a redistribution of SR proteins from nuclear speckles, to a ubiquitous nucleoplasm localization.14 Pre-mRNA processing factor 4 kinase, a lesser-known splicing kinase, was first linked to splicing in 1991 when a temperature sensitive library of Schizosaccharomyces pombe mutants were screened for splicing defects.15 At the restrictive temperature, yeast carrying a temperature sensitive mutation in prp4 accumulated un-spliced pre-mRNA. Subsequent characterization of the prp4 gene revealed that the splicing factor encoded by the gene contained the characteristic sequence that defines a serine/threonine protein kinase, making prp4 the PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19840930 first kina
