The request for funding from the ANR via the MRSEI programme aims to support the preparation of an European Doctoral Network “MSCA Doctoral Network - Joint Doctorates” of the Horizon Europe work Programme. The title of the project is: European Language Awareness (EuLaWa). Motivated by the goal to promote and contribute to the sustainable development of plurilingualism, an essential component of European citizenship in a multilingual and multicultural Europe, the EuLaWa network is based on the collaboration of university lecturers and researchers specializing in German Linguistics and Romance Linguistics including a contrastive dimension, and involving 6 European languages that belong to 3 language families: German, Danish, French, Italian, Polish and Czech. As an official language in several European countries and a working language of the European institutions, German will be the lingua franca of the network. The aim of the project is to train a pool of highly qualified young graduates with solid and directly exploitable skills in various future-oriented professional areas characterized by many requirements of plurilingual competences, in particular the sectors of digital technologies, business communication in multinational groups, translation, tourism and plurilingual education. At the interface between academic research and technological innovation, the network is based on an internal scientific structure with four main, closely correlated scientific poles: "Communication in a multilingual society in the digital age: practices, discourses, stereotypes", "Language policy and European citizenship", "Information systems and specialized communication: lexicography and translation", "Foreign language teaching/learning and plurilingual education". Specific interdisciplinary and intersectoral research activities will lead to the development of new digital tools related to European societal evolution and migration flows such as the creation of new dictionary resources and specialized multilingual terminological glossaries adapted to business needs, the development of innovative pedagogical resources to support the learning and teaching of foreign languages, and the improvement of current mono- and bilingual digital dictionaries aimed at eliminating widely-held gender stereotypes. In this way, the EuLaWa network will not only strengthen France's role as a driving force for European joint research at university level, which is unprecedented in this field, but also the EU's innovation potential through the synergy implemented between different academic and non-academic partners. The network currently includes 8 European universities, including one in Switzerland, and 13 associated non-academic partners, bringing together at this stage multinational companies, translation agencies, publishing companies and research organizations. Innovative, intersectoral and international, the EuLaWa network will offer participants exceptional mobility in the 9 countries currently covered: Germany, Denmark, Spain, France, Italy, Luxembourg, Poland, the Czech Republic and Switzerland, for short data collection missions and/or consultations of specialists or for a longer period of secondment. It provides for the training of 15 PhD candidates financed by MCSA funds and one additional PhD candidate financed by Swiss funds (SERI), within the framework of thesis co-supervisions (‘cotuelles’). The ANR MRSEI grant is essential to consolidate the consortium and to organize a number of workshops in 2023 in order to improve the excellence of the proposed research and training doctoral programme.

The majority of hormones and neurotransmitters communicate information to cells via G protein-coupled receptors (GPCRs). The large number of biological functions they control also makes these membrane receptors one of the most prominent families of pharmacological targets in biomedicine. GPCRs exhibit complex signaling behaviors. Indeed, a single receptor can activate both G protein-dependent and G protein-independent pathways. The latter result from the coupling of the receptor to a major family of signaling proteins, arrestins. Although arrestin-dependent signaling is a major component of GPCR functioning, we are just beginning to grasp its mechanistic bases, even for the best-studied GPCRs. The current model of GPCR:arrestin interaction, the so-called phospho-barcode model, states that, upon activation by their ligand, GPCRs get phosphorylated at different sites on their C-terminal domain, and this impacts on the way arrestin interacts with these regions, in turn affecting its conformation and, ultimately, the intracellular signal arrestin triggers. However, the experimental demonstrations of this mode of functioning are still scarce. Interestingly, the GPCR C-terminal domains appear to present all the structural, dynamic and functional characteristics of intrinsically disorder regions (IDRs), a family of proteins whose specific role in fundamental signaling and regulation processes started to be revealed very recently. In GPCteR, we propose an analysis of the molecular mechanisms underlying arrestin:GPCR interaction, and hence arrestin-dependent signaling, using a combination of state-of-the-art biophysical methods, namely solution-state Nuclear Magnetic Resonance, Small Angle Neutron or X-ray Scattering and fluorescence spectroscopy. These methods will be applied to a full range of model systems of increasing complexity composed of isolated GPCR C-terminal peptides, purified arrestins, and kinases and full-length receptors assembled into membrane-mimicking systems. Three different GPCR systems, the ghrelin, the vasopressin V2 and the B2-adrenergic receptors will be used as models. Besides the fact that these receptors are representative of the two different classes of arrestin binders, they are also important pharmaceutical targets due to their major role in fundamental physiological and patho-physiological processes. We expect these studies to illuminate the structural and dynamic keys required for the interaction of GPCRs with arrestins and, as such, to help us understand how G protein-independent signaling proceeds. This is not of academic interest only as our studies will likely provide also essential information to guide the rational design of peptide mimetics that could interfere with this interaction and thus be used as selective drugs and/or pharmacological tools to only affect receptor:arrestin interaction, to modulate specific signaling cascades, and therefore to impact on a limited set of all the biological effects controlled by GPCRs.