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 (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences developmental biology
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
ERC-2007-StG
See other projects for this call
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Host institution
6200 MD Maastricht
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.