Obiettivo The contribution of clathrin-independent endocytosis to the cellular entry of signaling receptors, cell adhesion factors, and other cell surface molecules is well documented. However, how this process is initiated is still unknown. We have recently found that a cellular lectin, galectin-3 (Gal3), entered cells via morphologically distinct tubular structures, so-called clathrin-independent carriers (CLICs); Gal3 endocytosis was required for the uptake of the CLIC cargo CD44, a cell adhesion/migration factor; CD44 and Gal3 uptake required glycosphingolipids (GSLs); Gal3 induced tubular membrane invaginations in a GSL-dependent manner. Based on these findings we propose the groundbreaking hypothesis that Gal3 is an adaptor that clusters cargo proteins carrying defined carbohydrate modifications together with specific GSLs into nanoscale membrane environments whose mechanical properties drive the clathrin-independent formation of endocytic pits. In this program, we will first establish the compositional topology of endocytic galectin processes (Aim 1). The adaptor hypothesis will then be tested using innovative chemical biology tools (Aim 2). Quantitative models of cargo clustering and membrane shape changes will be developed on the basis of biophysical measurements and coarse grain simulations (Aim 3). Intravital imaging of endocytosis and cell migration in mice will finally explore how the functional link between galectins and GSLs contributes to wound healing in the colon (Aim 4). The molecular functions of galectins and GSLs in endocytosis — major unresolved questions in cellular membrane biology — will thereby be established, providing details from atomic arrangements via multi-molecular complexes and meso-scaled membrane domains to in vivo physiology. I am confident that this program will lead to the discovery of a new clathrin-independent endocytic mechanism by which different types of cargo are sorted to and internalized from specific membrane domains. Campo scientifico agricultural sciencesagriculture, forestry, and fisheriesagriculturegrains and oilseedsnatural sciencesmathematicspure mathematicstopologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencescell biologynatural sciencesbiological sciencesbiochemistrybiomoleculescarbohydrates Programma(i) 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) Argomento(i) ERC-AG-LS3 - ERC Advanced Grant - Cellular and Developmental Biology Invito a presentare proposte ERC-2013-ADG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-AG - ERC Advanced Grant Istituzione ospitante INSTITUT CURIE Contributo UE € 1 924 454,00 Indirizzo RUE D ULM 26 75231 Paris Francia Mostra sulla mappa Regione Ile-de-France Ile-de-France Paris Tipo di attività Research Organisations Ricercatore principale Ludger Johannes (Mr.) Contatto amministrativo Sylvie Le Coidic (Mrs.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato Beneficiari (2) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto INSTITUT CURIE Francia Contributo UE € 1 924 454,00 Indirizzo RUE D ULM 26 75231 Paris Mostra sulla mappa Regione Ile-de-France Ile-de-France Paris Tipo di attività Research Organisations Ricercatore principale Ludger Johannes (Mr.) Contatto amministrativo Sylvie Le Coidic (Mrs.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato UNIVERSITY OF NEW SOUTH WALES Australia Contributo UE € 345 600,00 Indirizzo ANZAC PARADE 2052 Sydney Mostra sulla mappa Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Roslyn Mccann (Ms.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
