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A functional proteomics approach to extracellular redox signalling

Objective

Biological redox reactions have been identified as control mechanisms for all aspects of cellular life. Extracellular redox signals contribute to cellular communication, including host-tumour and host-pathogen interactions.

Recent evidence suggests that disulfide bonds in extracellular domains of cell surface receptors have the potential to act as redox-operated switches for protein function. However, target proteins of extracellular redox activity are mostly unknown and the impact of specific cell surface redox changes on cellular interactions and signal transduction remains to be studied.

We propose to identify and functionally analyze redox-regulated surface proteins involved in cellular communication. We will focus on redox signals involved in the activation of primary T cells and in the growth of transformed T cells. Both processes are stimulated by the thiol-disulfide oxidoreductase thioredoxin-1, which is either secreted by dendritic cells in response to antigen-specific recognition of T cells or by T cells themselves as a result of transformation.

The extracellular activities of thioredoxin are known to depend on its redox activity. It is not yet understood how redox changes on the cell surface effect increased sensitivity to particular growth factors and cytokines. In order to identify thioredoxin-regulated proteins on T cells we will apply novel strategies of functional proteomics, including mechanism-based trapping with mutant thioredoxin-1.

Thioredoxin-based signals and their disruption will be analyzed in a DC-T cell coculture system. We are also pioneering techniques to track redox changes by flow cytometry and thereby aim at correlating in vivo events with specific redox signals. We expect to obtain fundamental insight into the emerging field of extracellular redox signalling.

Call for proposal

FP6-2002-MOBILITY-8
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Coordinator

DEUTSCHES KREBSFORSCHUNGSZENTRUM
Address
Im Neuenheimer Feld 280
Heidelberg
Germany