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J. Biol. Chem., Vol. 283, Issue 3, 1223-1227, January 18, 2008

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Minireview

Regulation of Alternative Splicing by Reversible Protein Phosphorylation^*

From the Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky 40536-0509

The vast majority of human protein-coding genes are subject to alternative splicing, which allows the generation of more than one protein isoform from a single gene. Cells can change alternative splicing patterns in response to a signal, which creates protein variants with different biological properties. The selection of alternative splice sites is governed by the dynamic formation of protein complexes on the processed pre-mRNA. A unique set of these splicing regulatory proteins assembles on different pre-mRNAs, generating a "splicing" or "messenger ribonucleoprotein code" that determines exon recognition. By influencing protein/protein and protein/RNA interactions, reversible protein phosphorylation modulates the assembly of regulatory proteins on pre-mRNA and therefore contributes to the splicing code. Studies of the serine/arginine-rich protein class of regulators identified different kinases and protein phosphatase 1 as the molecules that control reversible phosphorylation, which controls not only splice site selection, but also the localization of serine/arginine-rich proteins and mRNA export. The involvement of protein phosphatase 1 explains why second messengers like cAMP and ceramide that control the activity of this phosphatase influence alternative splicing. The emerging mechanistic links between splicing regulatory proteins and known signal transduction pathways now allow in detail the understanding how cellular signals modulate gene expression by influencing alternative splicing. This knowledge can be applied to human diseases that are caused by the selection of wrong splice sites.

^* This minireview will be reprinted in the 2008 Minireview Compendium, which will be available in January, 2009. This work was supported by EURASNET, the Families of SMA, the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, and the German Cancer Aid. This is the fourth article of five in the Alternative Splicing Minireview Series.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, B283 Biomedical Biological Sciences Research Bldg., College of Medicine, University of Kentucky, 741 South Limestone, Lexington, KY 40536-0509. Fax: 859-323-1037; E-mail: stefan{at}stamms-lab.net.

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