Projet ANR-06-BLAN-0093 – ProLipFas : Molecular mechanisms underlying protein-lipid interactions : regulation of modes and magnitude of the death receptor Fas signaling
Programme : Programme blanc (BLANC) 2006
Année de financement : 2006
Coordinateur du projet : CNRS DELEGATION REGIONALE COTE D'AZUR (CNRS DELEGATION REGIONALE COTE D'AZUR)
Partenaires : Centre national de la recherche scientifique
Montant : 280000.0 euros
Date de début : 2006
Durée : 36 mois
Résumé : The role of the Fas/CD95 receptor in cell death signalling has been intensively studied and is indisputable. However, during the years it becomes apparent that this receptor transmits also nonapoptotic signals leading to cell survival, proliferation or cellular mobility. Interestingly, these signals, in contrast to the death signals, are not inhibited in a tumoral context but are even exacerbated therefore allowing a propagation of signals favourable to the survival and the diffusion of cancerous cells. The main objective of this project is to understand the molecular nature and the diverging pathways of these various signals in order not only to restore or promote the Fas-dependant death signals but also to inhibit the survival/proliferation pathways abnormally exacerbated in the tumoral cell.  Most of the elucidated mechanisms reported for the Fas signaling pathways are dedicated to the role of protein-protein interactions. Indeed only a very small portion of existing reports have dealt with the molecular mechanisms governing protein-lipid interactions in the functions of Fas, even though such interactions are inevitable. Fas, as a transmembrane protein, is surrounded by membrane lipids, which are heterogeneous in nature and there is mounting evidence supporting the importance of association of Fas to specific membrane domains (rafts), as well as the roles of bioreactive lipids, particularly sphingolipids and glycolipids, in the functions of Fas signaling. Therefore, it is undeniable that in order to really understand the mechanisms regulating the modes of actions of Fas, be it in the cell death or non-cell death context, the molecular mechanisms underlying the interaction between the Fas and lipids that it encounters throughout the course of its signal transduction must be thoroughly investigated. The fact that the understanding of the molecular mechanisms of the protein-lipid interactions in Fas signaling lags behind that of protein-protein interaction may have been, in part, due to the lack of less laborious methods in lipid studies, molecular tools, and lipid databases, when compared to the protein counterparts. Nevertheless, improvements in those areas have been continually made and thus making the studies of protein-lipid interactions more and more widely achievable.  The overall goal of this proposed research project (Pro Lip Fas) is to understand the molecular mechanisms underlying the roles of protein-lipid interactions in the regulation of types, specificity, and magnitude of Fas signaling.The proposed studies will be focused upon: A. Fas palmitoylation as the bifurcation switch for Fas-mediated cell death and non-cell death signals.  B. The interaction between Fas and glycosphingolipids (GSL) it encounters in the intracellular transport compartments during the course of its death/non-death signal transduction. C. The interaction between Fas and the phosphoinositide signaling lipids in the transduction of Fas signaling, with specific interest on phosphatidylinositol-4,5-bisphosphate (PIP2)