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Disassembly of signalling protein complexes in T cell plasma membrane domains


Signalling via cell surface receptors is a key element of cell regulation. The physiological response of the cell touch external stimuli is determined by multimolecular complexes at the plasma membrane that allow for the interaction of signalling enzymes with their respective substrates. Despite extensive knowledge of proteins that compose these complexes, very little is understood about the structure and dynamics of signalling assemblies. Here, the well-characterised system of T cell activation via the T cell receptor (TCR) is used to study complexes of signalling enzymes and adaptors that form around activated TCR in sub domains of the T lymphocyte plasma membrane. Complex formation is nucleated by the Tran membrane adaptor protein LAT and induces the activation of multiple signalling enzymes, which catalyse downstream reactions leading to the physiological responses of the activated T cell. Subsequently, the complexes disintegrate in order to attenuate the signalling. This study addresses the mechanisms of T cell signalling complex disassembly using biochemical analysis of native signalling assemblies purified by a novel immunoisolation procedure. In particular, it aims to elucidate the role of proteins involved ¡n the negative regulation of T cell signalling noncomplex disintegration. Somatic mutants of the well-characterized leukaemia T cell line Junket and the powerful method of RNA interference will be employed to analyse complex disassembly in cells deficient in negative regulatory proteins. An important candidate for a role in complex disassembly is the tyrosine phosphate SHP-1, which dephosphorylates critical tyrosine residues of other signalling proteins. Using a cell-free assay, it is planned to identify cryptozoic factors that are potentially involved in the disintegration of T cell signalling complexes followed by elucidation of their specific function in this process. The understanding of the dynamics of T cell#

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