Schller, A.C.; (2007) Protein recruitment to receptor tyrosine kinase-mediated early signalling complexes. Doctoral thesis , University of London.

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Abstract

Receptor tyrosine kinase (RTK) signalling regulates the activation of numerous cellular processes in response to various external stimuli. Spatio-temporal regulation of protein recruitment to activated tyrosine kinase receptors is important for the generation of specific cellular responses to various external stimuli. The involvement of the signalling proteins She, FRS2, Grb2 and Sos and the formation of distinct signalling complexes downstream of three RTKs (TrkA, EGFR, FGFR) was assessed to analyse their role in maintaining signalling specificity. All four signalling proteins played a role in TrkA, EGFR and FGFR signalling, but their recruitment to and involvement in signalling complexes varied depending on the stimulus. The observations indicated that formation of unique multiprotein assemblies provides a mechanism for different receptors to elicit specific signals despite employing the same signalling proteins. Detailed analysis of She recruitment to the FGFR2 revealed co-localisation and co-precipitation with the receptor but no direct interaction. This finding provided additional insight into how the availability of binding sites on different receptors regulates the recruitment of individual proteins to receptor-specific signalling complexes. Secondly, the effects of mutations in the FGFR2 extracellular region on protein recruitment to the receptor and its overall signalling specificity were investigated. Two substitution mutations in the FGFR2, which cause Apert syndrome, result in increased affinity of FGFR2 for FGF. Detailed analysis of the FGFR2 itself and signalling from it in the presence of these mutations indicated that they also result in altered receptor glycosylation, phosphorylation and glycosaminoglycans dependency as well as enhanced Erkl/2 activation. Additionally, recruitment and phosphorylation of She were altered in cells expressing the Apert syndrome mutations. The effects of the mutations on the FGFR2 and the signalling complex formed profoundly altered FGFR2-induced signals and cellular responses. These findings highlight the importance of retaining the integrity of protein recruitment and signalling complex formation to achieve signalling specificity.

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