Novel regulatory themes in immune cell signal transduction: Physiological functions of death receptor endocytosis

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The objective of this proposal is to understand fundamental principals in the regulation and biology of receptor signal transduction. Recent evidence suggests that receptor signaling occurs not only at the plasma membrane, but also at specific endosomal compartments and receptor endocytosis is just beginning to emerge as a regulatory principle in receptor signal transduction. The proposed project explores novel regulatory themes in receptor signal transduction, by defining, for the first time, the role of death receptor endocytosis in a physiological context. To this end, novel and unique in vivo mouse model systems will be developed, in which the specific endocytosis rates of the death receptors Fas or TNFR1 will be genetically altered in a mouse knock-in approach. Based on in vitro findings, we hypothesize that defects in Fas- or TNFR1 receptor endocytosis will result in a shift from pro-apoptotic to pro-inflammatory signaling in mutant mice. By promoting the survival of ‘unwanted’, potentially dangerous cells, this may have severe pathological consequences and may lead to the development of autoimmunity and/or cancer. Thus our studies will not only provide important new insights into death receptor biology, but will also reveal the physiological relevance of receptor endocytosis and the subcellular trafficking of activated receptors in living organisms. Such knowledge is also critical for our understanding of immune disorders and cancer and may open up new prospects for potential new diagnostic and therapeutic applications.