Detailseite
Projekt
Interfering with protein interaction of phosphoinositide-3-kinase gamma and of store-operated calcium channels
Antragsteller
Professor Dr. Michael Schaefer
Fachliche Zuordnung
Pharmakologie
Förderung
Förderung von 2007 bis 2014
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 29078704
The regulated interaction of soluble or endomembrane-bound proteins with plasma membrane proteins is a common phenomenon in outside-in and inside-out signalling in immune cells and contributes to pathophysiological states in inflammation and allergy. By docking to the active forms of Gßy and Ras, phosphoinositide 3-kinase y is controlled by chemokines acting on G-protein-coupled receptors and by antigen recognition by IgE-loaded Fes receptors, triggering directional migration, oxidative burst or degranulation responses. Protein-protein interaction interfaces on the p101 and p87 adapter proteins of phosphoinositide 3-kinase y that are required for this signalling have revealed unanticipated properties and are characterized in more detail and subjected to displacement screening with small molecules. Coincident with PISKy activation, phospholipase C-mediated [Ca2+]i signalling is triggered, whose delayed and longlasting component or ongoing oscillatory activity critically depends on a Ca2+ store refilling mechanism acting in an inside-out manner. The reversible association of STIM1, an endoplasmic reticulum Ca2+ sensor protein, with Orai1, a plasma membrane-located Ca2+-channel provide a molecular machine for Ca2+ releaseactivated Ca2+ influx (ICRAC) to refill Ca2+ stores and to maintain the Ca2+ signalling network in a responsive state. Using stably transfected cell lines and small molecule screening, we are targeting this pathway. In addition, we have identified a group of Orai1-interacting proteins, ORIP1 and ORIP2, whose functions are so far unknown. These complexes may represent additional targets for modulation of immunological responses by pharmacological interference.
DFG-Verfahren
Forschungsgruppen
