Beyond the Identification of Transcribed Sequences:
Functional, Evolutionary and Expression Analysis
12th International Workshop
October 25-28, 2002
Washington, DC

List of Abstracts * Speakers * Organizers * Authors * Original Announcement

Regulated Alternative Splicing: A New Dimension of the Human Genome

Stefan Stamm
Institute of Biochemistry; Fahrstraße 17; 91054 Erlangen; Germany

The human genome project demonstrated that alternative splicing of gene is more the rule than the exception. Missplicing events are an important cause and indication of human disease. Changing alternative splicing patterns in response to an external stimulus seems to a physiological process performed by many cells. Organisms regulate alternative splice site selection by changing the concentration and activity of splicing regulatory proteins.

The SAM68 like molecules SLM-1 and SLM-2 provide good examples of how phosphorylation influences splice site selection. Both nuclear proteins are phosphorylated by tyrosine kinases, such as fyn, abl and sik. Mass-spec analysis identified three tyrosine phosphorylated residues in SLM-2. One of these tyrosines seems to regulate the intracellular localization of rSLM-2. Using yeast three hybrid and immunoprecipitation assays, we showed that phosphorylation influences the binding of several interacting proteins. Finally, in vivo splicing assays demonstrated that the regulation of the survival of motoneuron gene 2 (SMN2) by rSLM-1 is influenced by phosphorylation.

Tau exon 10 provides another example of phosphorylation dependent splice site selection. Tau is a microtubule-associated protein whose transcript undergoes regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and encodes a microtubule-binding domain. Mutations increasing the inclusion of exon 10 result in the production of tau protein which predominantly contains four microtubule-binding repeats and were shown to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Exon 10 usage is regulated by CDC2 like kinases CLK1, 2, 3 and 4 that phosphorylate serine-arginine rich proteins, which in turn regulate pre-mRNA splicing. Cotransfection experiments suggest that CLKs achieve this effect by releasing specific proteins from nuclear storage sites.

Our data showed that phosphorylation is a physiological mechanism to regulate splice site selection. Given the prevalence of alternative splicing, its regulation by external signals enhances the genetic information and offers a mechanism for adaptation according to cellular needs. Finally, our results could lead to new therapeutic approaches for spinal muscular atrophy and tauopathies.


Stamm, S. (2002) Signals and their transduction pathways regulating alternative splicing: a new dimension of the human genome. Hum. Mol. Genet., 11, in press.

Daoud, R., Mies, G., Smialowska, A., Oláh, L., Hossmann, K. and Stamm, S. (2002) Ischemia induces a translocation of the splicing factor tra2-beta1 and changes alternative splicing patterns in the brain. J. Neurosci., 22, 5889-5899.

Stoss, O., Olbrich, M., Hartmann, A.M., Konig, H., Memmott, J., Andreadis, A. and Stamm, S. (2001) The STAR/GSG family protein rSLM-2 regulates the selection of alternative splice sites. J Biol Chem, 276, 8665-8673.

Hartmann, A.M., Rujescu, D., Giannakouros, T., Nikolakaki, E., Goedert, M., Mandelkow, E.M., Gao, Q.S., Andreadis, A. and Stamm, S. (2001) Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors. Mol Cell Neurosci, 18, 80-90.

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