Cell signalling and the control of pre-mRNA splicing

Abstract

Unlike transcription, where regulation is initiated most frequently by high-affinity, sequence-specific DNA-binding proteins, splicing regulation is frequently brought about by cooperative interactions between factors such as serine-arginine rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs), which have lower affinities and sequence specificities. HnRNP A1 represses variant exon-5 (v5) inclusion in human CD44 pre-mRNA in most tissues. In T cells that are activated by Ras signalling, SAM68, which is phosphorylated by extracellular signal-regulated kinase (ERK), interacts with v5 RNA in a way that interferes with the repressive activity of hnRNP A1, and enhances v5 inclusion in the final CD44 mRNA. Fas-mediated signalling regulates the alternative splicing of transcripts that encode apoptotic regulators. Alterations in the phosphorylation status of SR proteins probably lead to changes in alternative splicing of BCL-X pre-mRNAs. Additionally, Fas-mediated phosphorylation of TIA1 might modulate the alternative splicing of Fas pre-mRNA, thereby providing a positive autoregulatory loop to enhance Fas signalling. SRp38 functions as a splicing repressor when it is activated by dephosphorylation during M phase of the cell cycle and in response to heat shock. Splicing inhibition is brought about by an interaction between dephosphorylated SRp38, U1 small nuclear ribonucleoprotein particles (U1 snRNPs), and possibly other snRNPs. Ania-6–cyclin-dependent-kinase^p100 (CDK11^p100) provides a link between dopamine signalling and transcription-coupled splicing by phosphorylating SR proteins and the carboxy-terminal domain of the largest subunit of RNA polymerase II (RNAPII CTD). After depolarization of GH3 pituitary cells, the inclusion of the stress-axis-regulated (STREX) exon of the SLO pre-mRNA is repressed by the CaRRE (Ca²⁺/calmodulin-dependent protein kinase (CaMK)IV-responsive RNA element)-specific binding of an unidentified protein that is phosphorylated by CaMKIV.