Objectif MAL: an actin-regulated SRF transcriptional coactivatorRecent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology:¿ Actin as a transcriptional regulator¿ Actin as a signalling molecule¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin functionWe will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesmolecular biologystructural biology Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-AG-LS1 - ERC Advanced Grant - Molecular and Structural Biology and Biochemistry Appel à propositions ERC-2010-AdG_20100317 Voir d’autres projets de cet appel Régime de financement ERC-AG - ERC Advanced Grant Institution d’accueil THE FRANCIS CRICK INSTITUTE LIMITED Contribution de l’UE € 1 889 995,00 Adresse 1 MIDLAND ROAD NW1 1AT London Royaume-Uni Voir sur la carte Région London Inner London — West Camden and City of London Type d’activité Research Organisations Chercheur principal Richard Treisman (Dr.) Contact administratif Stéphane Maikovsky (Mr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (2) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire THE FRANCIS CRICK INSTITUTE LIMITED Royaume-Uni Contribution de l’UE € 1 889 995,00 Adresse 1 MIDLAND ROAD NW1 1AT London Voir sur la carte Région London Inner London — West Camden and City of London Type d’activité Research Organisations Chercheur principal Richard Treisman (Dr.) Contact administratif Stéphane Maikovsky (Mr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée CANCER RESEARCH UK LBG Participation terminée Royaume-Uni Contribution de l’UE Aucune donnée Adresse 2 Redman Place E20 1JQ LONDON Voir sur la carte Région London Inner London — West Camden and City of London Type d’activité Research Organisations Contact administratif Holly Elphinstone (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
