Novel fibroblast growth factor receptor signalling pathways regulating neuronal differentiation.
| dc.contributor.advisor | Guthridge, Mark A. | en |
| dc.contributor.author | Kong, Yang | en |
| dc.contributor.school | School of Medicine | en |
| dc.date.issued | 2014 | en |
| dc.description.abstract | The fibroblast growth factors (FGFs) consist of a family of growth factors that regulate diverse (or pleiotropic) responses, such as cell survival, proliferation, differentiation, and migration in both development and adulthood. The FGFs exert their biological activities through the binding and activation of four structurally related FGF receptors (FGFR1-4). The activation of FGFRs leads to FGFR tyrosine phosphorylation and the recruitment of SH2/PTB-domain signalling proteins, which are essential for initiating the downstream signalling pathways. Although receptor tyrosine phosphorylation is known to be important for cellular responses mediated by FGFRs, the precise mechanisms by which the FGFRs regulate pleiotropic biological responses remain unclear. In addition to receptor tyrosine phosphorylation, previous work in the Cell Growth and Differentiation Laboratory has shown that the FGFR cytoplasmic domain is also phosphorylated on a specific serine residue, Serine 779(S779), which recruits and binds the 14-3-3 family of phosphoserine/threonine-binding adaptor/scaffold proteins. However the precise role of the receptor phosphoserine signalling event in regulating downstream pathways and biological events has remained unclear. Using PC12 pheochromocytoma cells and primary mouse bone marrow stromal cells (BMSCs) as models for growth factor-regulated neuronal differentiation, our study aimed to understand the biological roles of S779 in the cytoplasmic domain of the FGFRs in regulating neuronal differentiation mediated by FGFs. We have shown that S779 in the cytoplasmic domain of FGFR2 is phosphorylated in response to ligand stimulation in PC12 cells. Phosphorylation of S779 is required for inducing the maximal activation of the Ras/MAP kinase pathway but not for other FGFR phosphotyrosine pathways. Furthermore, we have shown that the maximal Ras/MAPK signalling promoted by S779 signalling is critical for PC12 cell neuronal differentiation in response to FGF9. We have further elucidated the functions of S779 of endogenous FGFR2 in BMSCs neuronal differentiation mediated by FGF2. Our results show that both Ras/MAP kinase and novel PKCs (nPKCs) signalling are important for the BMSCs neuronal differentiation. Further siRNA-mediated knockdown suggest the PKCε is required for BMSCs neuronal differentiation regulated by FGF2. Further studies from our laboratory have shown that in BMSCs FGF2 stimulation results in PKCε mediated S779 phosphorylation. Our results show that the increased phosphorylation of S779 is critical for the maximal Ras/MAP kinase signalling and neuronal differentiation mediated by FGF2 in BMSCs. Collectively, we show the S779 phosphorylation mediated by PKCε is critical for regulating the intracellular signalling events necessary for maximal Ras/MAP kinase signalling and neuronal differentiation mediated by FGFs. Our findings indicate that in addition to FGFR tyrosine phosphorylation, the phosphorylation of S779, a conserved serine residue in cytoplasmic domains of FGFR2, can quantitatively and selectively regulate Ras/MAP kinase signalling to mediate neuronal differentiation. | en |
| dc.description.dissertation | Thesis (M.Phil.) -- University of Adelaide, School of Medicine, 2014 | en |
| dc.identifier.uri | http://hdl.handle.net/2440/87309 | |
| dc.provenance | This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals | en |
| dc.subject | Fibroblast Growth Factor Receptor; ERK; signalling pathway; Serine Phosphorylation; neuronal differentiation | en |
| dc.title | Novel fibroblast growth factor receptor signalling pathways regulating neuronal differentiation. | en |
| dc.type | Thesis | en |
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