Centro de Biología Molecular "Severo Ochoa," CSIC and Universidad Autónoma de Madrid, Madrid, Spain.
PLoS Genet. 2013;9(12):e1003982. doi: 10.1371/journal.pgen.1003982. Epub 2013 Dec 12.
The regulation of Extracellular regulated kinase (Erk) activity is a key aspect of signalling by pathways activated by extracellular ligands acting through tyrosine kinase transmembrane receptors. In this process, participate proteins with kinase activity that phosphorylate and activate Erk, as well as different phosphatases that inactivate Erk by de-phosphorylation. The state of Erk phosphorylation affects not only its activity, but also its subcellular localization, defining the repertoire of Erk target proteins, and consequently, the cellular response to Erk. In this work, we characterise Tay bridge as a novel component of the EGFR/Erk signalling pathway. Tay bridge is a large nuclear protein with a domain of homology with human AUTS2, and was previously identified due to the neuronal phenotypes displayed by loss-of-function mutations. We show that Tay bridge antagonizes EGFR signalling in the Drosophila melanogaster wing disc and other tissues, and that the protein interacts with both Erk and Mkp3. We suggest that Tay bridge constitutes a novel element involved in the regulation of Erk activity, acting as a nuclear docking for Erk that retains this protein in an inactive form in the nucleus.
细胞外调节激酶（Erk）活性的调节是细胞外配体通过酪氨酸激酶跨膜受体激活的信号通路的信号传递的一个关键方面。在这个过程中，具有激酶活性的蛋白质参与磷酸化和激活 Erk，以及不同的磷酸酶通过去磷酸化使 Erk 失活。Erk 磷酸化的状态不仅影响其活性，还影响其亚细胞定位，决定 Erk 靶蛋白的种类，从而影响 Erk 对细胞的反应。在这项工作中，我们将 Tay bridge 鉴定为 EGFR/Erk 信号通路的一个新组成部分。Tay bridge 是一种大型核蛋白，与人类 AUTS2 具有同源结构域，并且由于功能丧失突变导致神经元表型而被先前鉴定出来。我们表明，Tay bridge 拮抗果蝇翅膀盘和其他组织中的 EGFR 信号，并且该蛋白与 Erk 和 Mkp3 相互作用。我们认为，Tay bridge 构成了参与 Erk 活性调节的新元件，作为 Erk 的核停泊蛋白，将该蛋白以非活性形式保留在核内。
