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Cell signalling and the control of pre-mRNA splicing

Nature Reviews Molecular Cell Biology volume 5, pages 727–738 (2004)Cite this article

Key Points

  • 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-kinasep100 (CDK11p100) 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.

Abstract

The transcripts of most metazoan protein-coding genes are alternatively spliced, but the mechanisms that are involved in the control of splicing are not well understood. Recent evidence supports the potential of both extra- and intracellular signalling to the splicing machinery as a means of regulating gene expression, and indicates that this form of gene control is widespread and mechanistically complex. However, important questions about these pathways need to be answered before this method of post-transcriptional regulation can be fully appreciated.

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Figure 1: Regulation of variant exon-5 (v5) splicing in human CD44 pre-mRNA.
Figure 2: Fas-mediated signalling regulates the alternative splicing of transcripts that encode apoptotic regulators.
Figure 3: Splicing repression by dSRp38 during M phase or in response to heat shock.
Figure 4: Interaction between Ania-6 and CDK11p110 provides a link between dopamine signalling and transcription-coupled splicing.
Figure 5: Alternative splicing regulation of the STREX exon of the SLO pre-mRNA.

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Acknowledgements

We are grateful to members of the Manley laboratory for their helpful comments, and to Inna Boluk for help with preparation of the manuscript. Work from the authors' laboratory was supported by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Biological Sciences, Columbia University, New York, 10027, New York, USA

    Chanseok Shin & James L. Manley

Authors
  1. Chanseok Shin
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  2. James L. Manley
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Corresponding author

Correspondence to James L. Manley.

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Competing interests

The authors declare no competing financial interests.

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DATABASES

Entrez

Ania-6

KCNMA1

SwissProt

ASF/SF2

BCL-X

CaMKIV

CDK11

CRK7

NIPP1

PTB

SAM68

SRp38

TIA1

U2AF

FURTHER INFORMATION

James L. Manley's laboratory

Glossary

EXONIC SPLICING ENHANCER

(ESE). A sequence that recruits serine-arginine rich (SR) proteins and related factors to pre-mRNA where they promote both constitutive and regulated splicing by interacting with each other, as well as with other factors including snRNP-associated RS-domain-containing proteins. Different ESEs are recognized by specific subsets of SR proteins.

SRPK

The first identified serine-arginine rich (SR)-protein kinase, which phosphorylates Ser residues in the RS domain of SR proteins. The kinase is predominantly localized in the cytoplasm of interphase cells, and shows increased kinase activity during mitosis. In mammals, the SRPK family consists of SRPK1 and SRPK2.

CLK/STY

A member of the CLK/STY-kinase family, which comprises dual-specificity kinases that can potentially phosphorylate Ser/Thr and Tyr residues. Targets include SR proteins, and the kinase itself is extensively autophosphorylated. The mammalian CLK/STY family consists of at least four kinases, CLK/STY, CLK2, CLK3 and CLK4.

EXONIC SPLICING SILENCER

(ESS). A sequence that recruits splicing-repressor proteins such as hnRNP A1. This protein inhibits the formation or stabilization of the snRNP–pre-mRNA complex. Repressor proteins can function directly by binding to SR proteins, or by blocking the binding of SR proteins to downstream ESEs. They can also inhibit the activity of the ESE complex, thereby preventing the use of adjacent 3′ splice sites.

KH-TYPE RNA-BINDING MOTIF

This K-homology (KH) motif, which was originally identified in the human hnRNP K protein, is important for RNA binding and probably binds RNA directly. Several proteins that contain KH-type RNA-binding motifs, including SAM68, are thought to function in signalling pathways, and are members of the signal transduction and activation of RNA (STAR) family.

CERAMIDE

The backbone molecule of sphingolipid, which is a component of membrane lipids. It is generated either by hydrolysis of more complex sphingolipids or by de novo synthesis, and recently has been shown to function as a regulator of the stress response and death-receptor-mediated apoptosis.

CYCLIN-DEPENDENT KINASE

(CDK). A protein kinase that is active only when it is in a complex with a regulatory cyclin protein. CDK–cyclin complexes phosphorylate specific target proteins to trigger different stages of the cell cycle, or different aspects of the RNA polymerase II transcription cycle.

NUCLEAR SPECKLE

An irregularly shaped nuclear organelle that can be visualized by immunofluorescence microscopy using anti-splicing-factor antibodies. Usually, approximately 25–50 speckles are present in the interphase mammalian nucleus, and they are thought to constitute storage/assembly sites for certain splicing factors.

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Shin, C., Manley, J. Cell signalling and the control of pre-mRNA splicing. Nat Rev Mol Cell Biol 5, 727–738 (2004). https://doi.org/10.1038/nrm1467

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  • DOI: https://doi.org/10.1038/nrm1467

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