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."
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 sciencesbiological sciencesdevelopmental biology
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensors
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
You need to log in or register to use this function
We are sorry... an unexpected error occurred during execution.
You need to be authenticated. Your session might have expired.
Thank you for your feedback. You will soon receive an email to confirm the submission. If you have selected to be notified about the reporting status, you will also be contacted when the reporting status will change.
Call for proposal
FP7-PEOPLE-2013-CIG
See other projects for this call
Coordinator
1067-001 LISBOA
Portugal