Lin, C.-C.; (2011) The role of Grb2 in FGFR2IIIc-mediated early signalling complexes. Doctoral thesis , UCL (University College London).

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Abstract

Receptor tyrosine kinases (RTKs) regulate cellular processes by undergoing autophosphorylation on their tyrosine residues upon ligand binding. Phosphotyrosine residues also provide binding sites for adaptor protein binding. Grb2 has been shown to play a role in RTK pathways by recruiting other signalling proteins. Previously we showed the direct binding of Grb2 SH3 domain to the last 15 residues of FGFR2 C-terminal tail. In the present study, it is demonstrated that the direct binding of full-length Grb2 to FGFR2 cytoplasmic domain is a 2:1 binding event. Importantly, the direct binding may induce an apparent FGFR2 conformational change and enhance the FGFR2 phosphorylation. It is also shown that the effect of Grb2 on FGFR2 phosphorylation is mediated by the Grb2 C-SH3 domain. In addition, both N-SH3 domain and SH2 domain of Grb2 may play a role in the enhancement of the C-SH3 domain-mediated FGFR2 phosphorylation by stabilising Grb2 polypeptide structure, thus increasing the binding affinity toward FGFR2. This study also shows Grb2 phosphorylation by FGFR2 mediated by the direct binding of Grb2 to the C-terminal of FGFR2. Three phosphorylation sites on Grb2 are identified; in vitro FGFR2 phosphorylation and ERK1/2 activation studies suggest that Grb2 phosphorylation may play a role in regulating FGFR2-mediated signalling pathway. Moreover, the interactions between Grb2 and SHP2, as well as FGFR2 and SHP2 have been characterised. It is also demonstrated that the binding of Grb2 to FGFR2 can prevent SHP2 binding to FGFR2, which is important in regulating FGFR2 activation. Finally, a model for the recruitment of FGFR2-Grb2-SHP2 signalling complex is proposed, in which Grb2 and SHP2 control FGFR2 early signalling complex formation. This study provides new insights into the role of Grb2 in the FGFR2-mediated signalling pathway.

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