Objective 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. Fields of science natural sciencesbiological sciencesdevelopmental biologynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncology Keywords activity based protein profiling antibodies cancer biology loss of function metalloprotease mouse models non-invasive imaging proteomics small molecules 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) Topic(s) ERC-SG-LS6 - ERC Starting Grant - Immunity and infection Call for proposal ERC-2007-StG See other projects for this call Funding Scheme ERC-SG - ERC Starting Grant Host institution UNIVERSITEIT MAASTRICHT EU contribution € 902 835,79 Address MINDERBROEDERSBERG 4 6200 MD Maastricht Netherlands See on map Region Zuid-Nederland Limburg (NL) Zuid-Limburg Activity type Higher or Secondary Education Establishments Administrative Contact Judith Doomen (Ms.) Principal investigator Marc Antoine Gijsbert Gilles Vooijs (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all UNIVERSITEIT MAASTRICHT Netherlands EU contribution € 902 835,79 Address MINDERBROEDERSBERG 4 6200 MD Maastricht See on map Region Zuid-Nederland Limburg (NL) Zuid-Limburg Activity type Higher or Secondary Education Establishments Administrative Contact Judith Doomen (Ms.) Principal investigator Marc Antoine Gijsbert Gilles Vooijs (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data UNIVERSITAIR MEDISCH CENTRUM UTRECHT Participation ended Netherlands EU contribution € 297 164,21 Address HEIDELBERGLAAN 100 3584 CX Utrecht See on map Region West-Nederland Utrecht Utrecht Activity type Higher or Secondary Education Establishments Administrative Contact Frank Miedema (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data