action of both cis-acting RNA sequence elements and trans-acting RNA binding proteins, such as Ser/Arg rich proteins, heterogeneous nuclear ribonucleoproteins, and splicing factors belonging to other RBP families. In addition, AS is also regulated by mechanisms acting both co- and posttranscriptionally, through epigenetic SB-590885 biological activity modifications of the chromatin, regulation of the RNA polymerase II 2 transcription rate, and posttranslational modifications of both spliceosome components and auxiliary splicing factors, among which reversible phosphorylation acts as a major player. International Journal of Cell Biology. This SR protein acts as a specific splicing activator in its RS-phosphorylated form, whereas dephosphorylation converts it into a potent splicing repressor. Notably, dephosphorylation of SRSF10 occurs during the M phase of the cell cycle or under stress condition, when general inhibition of splicing occurs. In particular, it was demonstrated that, under normal conditions, phosphorylated SRSF10 is a sequence-specific splicing activator, which promotes U1 and U2 snRNP assembly on target pre-mRNAs endowed with SRSF10-dependent exonic splicing enhancer sequences. Conversely, under stressful cellular conditions, as during heat shock, SRSF10 is rapidly dephosphorylated by PP1, while other SR proteins are maintained in phosphorylated state by SR protein kinases . Interestingly, during the stress response all SR proteins are similarly dephosphorylated by PP1. However, they are rapidly rephosphorylated by SRPKs, while SRSF10, which is a poor substrate for SRPKs, remains dephosphorylated. Under this condition, SRSF10 can still interact with the U1 snRNP, but in this case the interaction impairs its ability to recognize the 5 splice site, thus resulting in splicing inhibition. Phosphorylation of the RS domain can also dictate SR protein subcellular localization, by affecting both their intranuclear localization and their nucleocytoplasmic shuttling. In interphase cells, SR proteins are enriched in interchromatin granules called nuclear speckles, which are enriched in factors involved in pre-mRNA processing and RNA transport. The recruitment of SR proteins to nascent pre-mRNAs from these sites of storage is regulated by their phosphorylation; indeed, it has been shown that phosphorylation of the RS domain is a prerequisite for their recruitment to transcription sites in vivo. This modification plays also an important role in the regulation of nucleocytoplasmic shuttling of SR proteins. For instance, phosphorylation 
of SR proteins in the cytoplasm is required for their nuclear import. On the other hand, dephosphorylation of the RS domain is essential for their translocation to the cytoplasm during mRNP maturation . Interestingly, dephosphorylation of SRSF1 and SRSF7 enhances their interaction with the export receptor TAP, thereby favoring also the export of their target mRNAs. Furthermore, SRSF1 translational activity is increased by dephosphorylation of its RS domain . Phosphorylation has therefore a great impact also on the splicing unrelated functions in which many SR proteins are involved. Ser/Thr phosphorylation represents an important regulative process not only for SR proteins but also for hnRNPs and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19818408 other splicing factors. For instance, hnRNP A1 is phosphorylated by the mitogen-activated protein kinase p38 in response to stress conditions, thus causing its cytoplasmic translocation and consequent modulation of hnRNP A1-sensitive AS event