IPAD

"Intramembrane Proteases, their Inactive cognates, and Disease"

Coordinatore	FUNDACAO CALOUSTE GULBENKIAN    more  Organization address address: AVENIDA DE BERNA 45A city: LISBOA postcode: 1000 contact info Titolo: Mr. Nome: Jose Mario Cognome: Leite Email: send email Telefono: 351214000000 Fax: 351214000000
Nazionalità Coordinatore	Portugal [PT]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2013-CIG
Funding Scheme	MC-CIG
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-01-01   -   2017-12-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	FUNDACAO CALOUSTE GULBENKIAN  Organization address address: AVENIDA DE BERNA 45A city: LISBOA postcode: 1000 contact info Titolo: Mr. Nome: Jose Mario Cognome: Leite Email: send email Telefono: 351214000000 Fax: 351214000000	PT (LISBOA)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'The ability to release signals from the cell surface is dependent on the correct functioning of the secretory pathway. This proposal focuses on trafficking regulation and quality control within the secretory pathway by members of the rhomboid superfamily, and members of the Signal Peptide Peptidase-Like family (SPPL). The metalloprotease TACE (TNF alpha converting enzyme) is an important sheddase for cell surface proteins, including the proinflammatory cytokine TNF (tumour necrosis factor), and ligands of the epidermal growth factor receptor. Crucially, TACE activity is highly regulated by diverse physiological and pathological stimuli, but little is known about the mechanism of regulation. Recently I have shown that iRhoms, endoplasmic reticulum (ER)-localized catalytically inactive homologs of rhomboid proteases, are essential TACE regulators. iRhoms act as trafficking factors: they bind to TACE in the ER and control its trafficking into the Golgi apparatus, wherein TACE undergoes an essential activation step (prodomain removal). Because of this TACE activation defect, mice null for iRhom2 have profound inflammatory defects (caused by a failure to shed TNF). iRhom1 mice die a few weeks after birth because of a range of defects, whereas iRhom double knockout (DKO) mice, which completely lack TACE activity, die during mid embryogenesis. The fact that the DKO phenotype is worse than the TACE knockout implies the existence of novel clients. This program, which has a strong biomedical focus, will examine iRhom regulation in response to stimuli to address whether iRhoms are the illusive ‘sensors’ for TACE-activating stimuli. It will also identify novel clients implied by the severe iRhom DKO phenotype. Combining mouse knockouts, disease models and biochemistry, we will also examine the role of the rhomboid-like protein UBAC2, in aspects of ER quality control. Finally, we will examine the physiological and mechanistic roles of members of the SPPL family.'