Laurence, Arian Dominic John; (2003) Investigation of serine kinase signalling networks in T lymphocytes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of the work that constitutes the present PhD thesis was to elucidate the intracellular serine/threonine (S/T) kinase dependant signalling pathways downstream of the T cell receptor in human T lymphocytes. S/T kinases are known to play key roles in mediating growth, survival and differentiation in response to antigenic stimulation of T cells. The T cell receptor exerts its function through a complex web of tyrosine kinases and regulatory adaptor proteins that culminate in the activation of phosphatidyl-inositol and small G protein dependent S/T kinases. The variety of S/T kinases and high proportion of proteins that are phosphorylated at their S/T residues have paradoxically made the search for protein substrates for these kinases notoriously difficult. It is of fundamental importance for understanding cellular regulation to discover new cell-specific downstream targets and ultimate effectors of these pathways. We herein describe a successful strategy to identify new, cell specific, effectors of S/T kinases in signalling cascade. We utilised the properties of an antiserum, raised against a sequence phosphorylated on a serine residue, to cross-react with several phosphorylated proteins that have a similar structure at the site of phosphorylation. Using this antiserum together with proteomics analysis we were able to purify and characterise new targets of antigen receptor initiated signalling in T-lymphocytes. This approach led us to unearth two haematopoietic proteins, namely proIL-16 and SLY, neither having been described previously as a target for T cell receptor regulation. The use of proteomics coupled to sera detecting specific phosphorylation has proved a powerful tool to discover downstream effectors of TcR activation. The versatility of the technique should prove invaluable in fingerprinting other cell types, or comparing subpopulations of lymphocytes.

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