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Extracellular point mutations in FGFR2 result in elevated ERK1/2 activation and perturbation of neuronal differentiation
- Source :
- Biochemical Journal. 410:205-211
- Publication Year :
- 2008
- Publisher :
- Portland Press Ltd., 2008.
-
Abstract
- Two independent gain-of-function point mutations (S252W and P253R) in the extracellular region of the FGFR2 (fibroblast growth factor receptor 2) increase the binding affinity for the growth factor. The effect of this enhanced growth factor binding by these mutants is expected to be an increase in activation of regular signalling pathways from FGFR2 as a result of more receptors being engaged by ligand at any given time. Using PC12 (pheochromocytoma) cells as a model cell system we investigated the effect of these mutations on protein phosphorylation including the receptor, the activation of downstream signalling pathways and cell differentiation. Our results show that the effects of both of these extracellular mutations have unexpected intracellular phenotypes and cellular responses. Receptor phosphorylation was altered in both the ligand-stimulated and unstimulated states. The mutants also resulted in differential phosphorylation of a number of intracellular proteins. Both mutations resulted in enhanced ERK1/2 (extracellular-signalregulated kinase1/2) activation. Although ERK1/2 activation is believed to transduce signals resulting in cell differentiation, this response was abrogated in the cells expressing the mutant receptors. The results of the present study demonstrate that single extracellular point mutations in the FGFR2 have a profound effect on intracellular signalling and ultimately on cell fate.
- Subjects :
- Fibroblast Growth Factor 9
medicine.medical_treatment
Cellular differentiation
Biology
PC12 Cells
Biochemistry
03 medical and health sciences
0302 clinical medicine
medicine
Extracellular
Animals
Point Mutation
Cell Lineage
Protein phosphorylation
Phosphorylation
Receptor, Fibroblast Growth Factor, Type 2
Receptor
Molecular Biology
030304 developmental biology
Mitogen-Activated Protein Kinase 1
Neurons
0303 health sciences
Mitogen-Activated Protein Kinase 3
Fibroblast growth factor receptor 2
Growth factor
Cell Differentiation
Cell Biology
Molecular biology
Rats
Cell biology
Enzyme Activation
030217 neurology & neurosurgery
Intracellular
Signal Transduction
Subjects
Details
- ISSN :
- 14708728 and 02646021
- Volume :
- 410
- Database :
- OpenAIRE
- Journal :
- Biochemical Journal
- Accession number :
- edsair.doi.dedup.....834a0d288f31ba3e0d2c05dd96e0758d