Cel NOTCH signaling is a highly conserved short-range signaling pathway involved in virtually every aspect of embryonic development and controls homeostatic self-renewal in many adult tissues. Germ line mutations in the NOTCH pathway cause several hereditary diseases, and somatic mutations are found in cancer. NOTCH pathway activity is governed by ligand induced proteolytic cleavage of the receptor in the extracellular domain by a metalloprotease. This cleavage is required for the consecutive transmembrane cleavage by the γ-secretase complex leading to the release of the intracellular domain that mediates target gene activation. The precise mechanism that confers ligand regulated NOTCH proteolysis is unresolved but involves a ligand-induced conformational change. Virtually nothing is known on how conformational changes render the NOTCH receptor susceptible to proteolysis and which proteases are involved. Human cancer prone NOTCH1 receptor mutations are characterized by increased metalloprotease dependent cleavage and signaling activity. Here I hypothesize that these oncogenic mutations lead to exposure of buried scissile bonds that facilitate proteolysis. Since metalloprotease cleavage of NOTCH receptors is the regulatory event in NOTCH cascade activation, inhibition of this protease activity may find therapeutic application in diseases with deregulated NOTCH signaling such as cancer. Novel technologies and reagents are needed to gain further insight into the NOTCH-protease interface to accelerate drug target discovery and validate their use in pre-clinical models for cancer where deregulated protease activity plays crucial roles in disease progression. Dziedzina nauki natural sciencesbiological sciencesdevelopmental biologynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncology Słowa kluczowe activity based protein profiling antibodies cancer biology loss of function metalloprotease mouse models non-invasive imaging proteomics small molecules 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-SG-LS6 - ERC Starting Grant - Immunity and infection Zaproszenie do składania wniosków ERC-2007-StG Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-SG - ERC Starting Grant Instytucja przyjmująca UNIVERSITEIT MAASTRICHT Wkład UE € 902 835,79 Adres MINDERBROEDERSBERG 4 6200 MD Maastricht Niderlandy Zobacz na mapie Region Zuid-Nederland Limburg (NL) Zuid-Limburg Rodzaj działalności Higher or Secondary Education Establishments Kontakt administracyjny Judith Doomen (Ms.) Kierownik naukowy Marc Antoine Gijsbert Gilles Vooijs (Dr.) 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 UNIVERSITEIT MAASTRICHT Niderlandy Wkład UE € 902 835,79 Adres MINDERBROEDERSBERG 4 6200 MD Maastricht Zobacz na mapie Region Zuid-Nederland Limburg (NL) Zuid-Limburg Rodzaj działalności Higher or Secondary Education Establishments Kontakt administracyjny Judith Doomen (Ms.) Kierownik naukowy Marc Antoine Gijsbert Gilles Vooijs (Dr.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych UNIVERSITAIR MEDISCH CENTRUM UTRECHT Zakończenie uczestnictwa Niderlandy Wkład UE € 297 164,21 Adres HEIDELBERGLAAN 100 3584 CX Utrecht Zobacz na mapie Region West-Nederland Utrecht Utrecht Rodzaj działalności Higher or Secondary Education Establishments Kontakt administracyjny Frank Miedema (Prof.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych
