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Regulation of mRNA splicing and transport by the tyrosine kinase activity of src

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Abstract

The regulation of transcription by signal transduction pathways is well documented. In addition, we have previously shown that src can regulate pre-mRNA processing. To investigate which functional domains of src are involved in the regulation of splicing and transport of Lymphotoxin α (LTα) transcripts, we have used src mutants in the catalytic, SH2 and SH3 domains in association with the Y527F or the E378G activating mutation. Our results establish that the regulation of pre-mRNA processing and transcription can occur independently of each other. The splicing and transport phenotypes require an intact tyrosine kinase domain and both are insensitive to the deletion of the SH3 domain. Therefore these phenotypes do not depend upon the recruitment through the SH3 domain of src of RNA binding proteins (Sam 68, hnRNP K). By contrast, deletions in the SH2 domain have no effect on splicing but either abolish or exacerbate the transport phenotype depending upon the activating mutation (Y527F or E378G). These divergent responses are associated with specific changes in the pattern of tyrosine phosphorylated proteins. Thus, the regulation of transcription, splicing and mRNA transport implicate different effector pathways of src. Furthermore, analysis of the transport phenotype reveals the interplay between the SH2 and catalytic domain of the protein.

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Acknowledgements

We thank H Neel for his contributions to the initial phase of this study, D Weil for comments and J Brugge for providing src mutants. This work was supported by the Ligue Departementale contre le Cancer du Val de Marne.

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  1. Laboratory of Medical Oncology and Medical Chemistry, University of Liège, Belgium

    Pierre Gondran & François Dautry

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  1. Pierre Gondran
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  2. François Dautry
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Gondran, P., Dautry, F. Regulation of mRNA splicing and transport by the tyrosine kinase activity of src. Oncogene 18, 2547–2555 (1999). https://doi.org/10.1038/sj.onc.1202598

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