NOTCH PROTEOLYSIS

Targeting the Notch Protease Interface

Coordinatore	UNIVERSITEIT MAASTRICHT    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	Netherlands [NL]
Totale costo	1˙200˙000 €
EC contributo	1˙200˙000 €
Programma	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)
Code Call	ERC-2007-StG
Funding Scheme	ERC-SG
Anno di inizio	2008
Periodo (anno-mese-giorno)	2008-09-01   -   2014-02-28

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITAIR MEDISCH CENTRUM UTRECHT  Organization address address: HEIDELBERGLAAN 100 city: UTRECHT postcode: 3584 CX contact info Titolo: Prof. Nome: Frank Cognome: Miedema Email: send email Telefono: -2503016 Fax: -2505412	NL (UTRECHT)	beneficiary	0.00
2	UNIVERSITEIT MAASTRICHT  Organization address address: Minderbroedersberg 4-6 city: MAASTRICHT postcode: 6200 MD contact info Titolo: Dr. Nome: Marc Antoine Gijsbert Gilles Cognome: Vooijs Email: send email Telefono: +31 43 3882912 Fax: +31 43 3884540	NL (MAASTRICHT)	hostInstitution	0.00
3	UNIVERSITEIT MAASTRICHT  Organization address address: Minderbroedersberg 4-6 city: MAASTRICHT postcode: 6200 MD contact info Titolo: Ms. Nome: Judith Cognome: Doomen Email: send email Telefono: +31 43 3881867 Fax: +31 43 388 1890	NL (MAASTRICHT)	hostInstitution	0.00

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 Obiettivo del progetto (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.'