Gondran P, Dautry F
Institut de Recherches sur le Cancer, CNRS UPR 9044 Génétique Moléculaire et Intégration des Fonctions Cellulaires, Villejuif, France.
Oncogene. 1999 Apr 22;18(16):2547-55. doi: 10.1038/sj.onc.1202598.
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 alpha (LTalpha) 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.
信号转导通路对转录的调控已有充分记载。此外，我们之前已表明src可调控前体mRNA加工。为研究src的哪些功能域参与淋巴毒素α（LTα）转录本的剪接和转运调控，我们使用了在催化、SH2和SH3结构域带有Y527F或E378G激活突变的src突变体。我们的结果表明，前体mRNA加工和转录的调控可相互独立发生。剪接和转运表型需要完整的酪氨酸激酶结构域，且二者对SH3结构域的缺失均不敏感。因此，这些表型不依赖于通过src的SH3结构域招募RNA结合蛋白（Sam 68、hnRNP K）。相比之下，SH2结构域的缺失对剪接无影响，但根据激活突变（Y527F或E378G），要么消除要么加剧转运表型。这些不同的反应与酪氨酸磷酸化蛋白模式的特定变化相关。因此，转录、剪接和mRNA转运的调控涉及src的不同效应子途径。此外，对转运表型的分析揭示了该蛋白的SH2结构域和催化结构域之间的相互作用。
