omain, with dual specificity, and an N-terminal RS domain, which allows their interaction with the SR proteins. CLKs colocalize with SR proteins in nuclear speckles, and their overexpression leads to hyperphosphorylation of SR proteins and induces speckles disassembly. Several studies reported the ability of CLKs to influence get (S)-(-)-Blebbistatin splicing events by regulating the subnuclear localization of SR proteins. In particular, the release of SR proteins from nuclear speckles induced by CLKs overexpression has been reported to modulate splicing of the E1A reporter minigene and of the exon 10 of the TAU gene, whose aberrant regulation has been implicated in several neurodegenerative diseases. Recently 
it has been shown that CLKs also modulate the activity of splicing factors not related to the SR-protein family, such as SPF45. CLK-mediated phosphorylation of SPF45 interferes with its proteasomal degradation and enhances exon 6 inclusion of FAS by promoting binding of this splicing factor to the FAS pre-mRNA. The nuclear localization of CLKs is one of the major differences between them and SRPKs, which are instead mainly cytosolic. Because of their different localization, CLKs and SRPKs can cooperate in regulating SR proteins subcellular localization. Indeed, it has been shown that SRPK1 interacts with SRSF1 and phosphorylates the Nterminal part of its RS domain, a posttranslational modification that is essential for its assembly into nuclear speckles, whereas CLKs phosphorylate the C-terminal part of its RS domain, thereby causing release of SRSF1 from the speckles. Moreover, SRPKs and CLKs have also distinct substrate specificity, as SRPKs preferentially phosphorylate Ser-Arg sites, while CLKs have a broader specificity and can phosphorylate also Ser-Lys or Ser-Pro sites. Therefore, even if apparently redundant, the coordinated activity of SRPKs and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19818716 CLKs is crucial for correct splicing regulation. This was well illustrated by Nowak and colleagues, whose work highlighted how SR-proteins phosphorylation induced by these two families of kinases may differently control a single splicing event. The vascular endothelial growth factor A gene, a key regulator of angiogenesis, produces several isoforms by alternative splice-site selection in the terminal exon 8: proximal splice-site selection results in proangiogenic VEGFxxx isoforms, whereas distal splicesite selection results in antiangiogenic isoforms VEGFxxxb. Different growth factors inversely influence these splicing events by inducing in both cases phosphorylation of SR proteins. However, IGF-1 and TNF- induced production of VEGFxxx through activation of SRPKs, whereas TGF-1 enhanced VEGFxxxb production by activating CLKs. 5 6. Signaling-Activated Splicing Factor Kinases AS represents a crucial step in the regulation of gene expression in eukaryotic cells. Therefore, its regulation needs to be finely integrated in the complex network of regulative mechanisms that allows the cell to modulate gene expression in response to the different physiological and pathological stimuli that are received from both the internal and external environment. In support of this notion, activation of signal transduction pathways has been shown to modulate AS in a large number of situations. However, while in some cases the mechanism has been described, in other cases the transacting factors mediating the response are unknown. Here we will review signaling-activated kinases that can modulate AS by directly phosphorylating spl
