REVIEWSR (serine/arginine-rich) proteins constitute a highly conserved family of RNA-binding proteins, which plays key roles in the execution and regulation of precursor-mRNA (pre-mRNA) splicing. By affecting splice site selection in a concentration-and phosphorylation-dependent fashion, SR proteins significantly contribute to the alternative splicing process, which they appear to modulate in a tissue-specific, developmentally-regulated and stress-responsive manner.The splicing of introns from the pre-mRNA is carried out by one of the largest molecular complexes of the cell, the spliceosome, which consists of five small nuclear ribonucleoproteins (snRNPs) and numerous additional proteins.1,2 Members of the SR protein family are non-snRNP spliceosomal factors that have been shown in animal systems to play vital roles in the most crucial and early steps of spliceosome assembly.3-6 These essential splicing factors share a multidomain structure typically characterized by the presence of one or two N-terminal RNA Recognition Motifs (RRMs) and a C-terminal reversibly phosphorylated arginine/serine-rich (RS) domain.3,7 Binding of SR proteins to the pre-mRNA is mediated by the RRM, which recognizes short and degenerate sequences such as exonic splicing enhancers or silencers (ESEs or ESSs, respectively). The RRM confers RNA-binding specificity and each ESE/ESS is thought