Cel Wnts are signaling proteins that act both at short and long range in developing tissues. Several proteins, such as Wntless, are specifically devoted to Wnt secretion, indicating that Wnts may follow a distinct secretory route. Moreover, Wnts carry two lipid modifications, which are likely to interfere with diffusion in the extracellular space. Much of our work will focus on the trafficking of Wingless (the main Drosophila Wnt), which forms a concentration gradient in wing imaginal discs. To chart the route taken by Wingless from the ER to responding cells, we will devise techniques (e.g. BirA-dependent in vivo biotinylation) to pulse label endogenously expressed Wingless in the secretory pathway and at the cell surface. Wingless routing will also be investigated in conditions that alter Evi/Wntless trafficking. We will capitalize on our observation that Wingless and Wntless are present on exosomes in conditioned medium. These exosomes will be purified and characterized by mass spectrometry and the resulting information will be used to devise rigorous functional assays. Similar approaches will be used to identify and characterize proteins that associate with soluble Wingless, which is also present in conditioned medium. Our proposed approaches will also enable us to assess, for the first time, the function of exosomes in an intact animal. Once secreted, Wingless and associated proteins spread in the extracellular space while remaining associated with the epithelial surface. We will use single molecule imaging in a reconstituted system along with mathematical modeling to test the hypothesis that the glypican-Wnt interaction is sufficiently strong to ensure surface retention while allowing diffusion in two dimensions. Finally we will use biochemical approaches and molecular genetics in Drosophila and mice to investigate the mode of action of Notum, a glypican-modifying enzyme that could be relevant to the progression of Wnt signaling dependent cancers. Dziedzina nauki natural sciencesbiological sciencesmolecular biologymolecular geneticsnatural sciencesbiological sciencescell biologymedical and health sciencesclinical medicineoncologynatural scienceschemical sciencesanalytical chemistrymass spectrometrynatural sciencesmathematicsapplied mathematicsmathematical model Program(-y) 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) Temat(-y) ERC-AG-LS3 - ERC Advanced Grant - Cellular and Developmental Biology Zaproszenie do składania wniosków ERC-2011-ADG_20110310 Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-AG - ERC Advanced Grant Instytucja przyjmująca THE FRANCIS CRICK INSTITUTE LIMITED Wkład UE € 1 938 845,57 Adres 1 MIDLAND ROAD NW1 1AT London Zjednoczone Królestwo Zobacz na mapie Region London Inner London — West Camden and City of London Rodzaj działalności Research Organisations Kierownik naukowy Jean-Paul B.B. Vincent (Dr.) Kontakt administracyjny Stéphane Maikovsky (Mr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych Beneficjenci (2) Sortuj alfabetycznie Sortuj według wkładu UE Rozwiń wszystko Zwiń wszystko THE FRANCIS CRICK INSTITUTE LIMITED Zjednoczone Królestwo Wkład UE € 1 938 845,57 Adres 1 MIDLAND ROAD NW1 1AT London Zobacz na mapie Region London Inner London — West Camden and City of London Rodzaj działalności Research Organisations Kierownik naukowy Jean-Paul B.B. Vincent (Dr.) Kontakt administracyjny Stéphane Maikovsky (Mr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych MEDICAL RESEARCH COUNCIL Zjednoczone Królestwo Wkład UE Brak danych Adres 20 Park Crescent W1B 1AL LONDON Zobacz na mapie Rodzaj działalności Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments) Kontakt administracyjny David Jones (Mr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych
