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Title: The role of the protein tyrosine phosphatase SHP2 in T cell signalling
Author: Bailey, C. R. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2002
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The protein tyrosine phosphatase SHP2 regulates phosphotyrosine mediated signalling cascades by dephosphorylating specific phosphotyrosine residues on its protein substrates. It is regulated by tandem N terminal SH2 domains and tyrosine phosphorylation sites in the C terminus. Although the mechanism and targets of SHP2 have been extensively studied in the context of receptor tyrosine kinase and cytokine mediated signalling systems, its in vivo substrates and role in T cell antigen receptor (TCR) mediated signalling remain uncertain. The TCR complex possesses no intrinsic tyrosine kinase activity, yet its engagement by MHC-peptide complexes of stimulatory antibodies leads to an orchestrated sequence of signalling events initiated by the protein tyrosine kinases Lck and ZAP70 and leading ultimately to activation of the T cell, anergy, or death depending on the context and character of the engagement. It has previously been observed in this and other laboratories that SHP2 is recruited to the plasma membrane in association with an adaptor protein following TCR engagement, leading to the hypothesis that recruitment of SHP2 to the plasma membrane enables it to act on specific membrane associated substrates, and therefore play a role in determining the outcome of TCR engagement. In order to test this hypothesis, it was attempted to determine the identity of the adaptor protein to which SHP2 binds when recruited to the plasma membrane. A catalytically inactive (Cysteine to Serine) mutant form of SHP2 was also expressed in the Jurkat T cell line, a widely used model system for investigating TCR signalling. The effect of SHP2 on elements of the IL2 promoter, on signalling pathways distal to TCR engagement and on membrane associated phosphotyrosine containing protein complexes was investigated. Catalytically inactive SHP2 was found to inhibit the activity of the NFκB complex in Jurkat T cells, and to modulate the activity of its upstream activator, IκBα, implicating SHP2 in modulation of IL2 transcription following TCR engagement. Proteins which are targets of SHP2 regulated modulation of tyrosine phosphorylation at the plasma membrane following TCR engagement were also identified.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available