Abstract
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.
Highlights
The Epidermal Growth Factor Receptor (EGFR) signalling pathway is a conserved module that plays multiple roles during development and tissue homeostasis in eukaryotic organisms [1,2,3]
Extracellular regulated kinases (Erk) mediate signalling by pathways activated by tyrosine kinase transmembrane receptors
Tay bridge has a domain of homology with human AUTS2, and was previously identified due to the neuronal phenotypes displayed by loss-of-function mutations
Summary
The Epidermal Growth Factor Receptor (EGFR) signalling pathway is a conserved module that plays multiple roles during development and tissue homeostasis in eukaryotic organisms [1,2,3]. The best-characterized functions of the pathway involve the EGFR downstream proteins Sos, Ras, Raf, Mek and Erk, the MAPK that is encoded by rolled in Drosophila melanogaster [4]. The activity of these core components is required in multiple developmental contexts, influencing cell proliferation, migration, apoptosis, epithelial integrity and cell fate acquisition [1,5]. Upon activation by Mek, the Erk serine/threonine kinase is transported into the nucleus, where it can phosphorylate specific transcription factors, regulating their activity and gene expression. Erk is de-phosphorylated and inactivated by dual-specificity phosphatases, which promote Erk accumulation in an inactive state in the cytoplasm [2,9]
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