Extracellular point mutations in FGFR2 result in elevated ERK1/2 activation and perturbation of neuronal differentiation

Annika C. Schüller, Zamal Ahmed, John E. Ladbury

    Research output: Contribution to journalArticlepeer-review

    13 Scopus citations

    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-signal-regulated 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.

    Original languageEnglish (US)
    Pages (from-to)205-211
    Number of pages7
    JournalBiochemical Journal
    Volume410
    Issue number1
    DOIs
    StatePublished - Feb 15 2008

    Keywords

    • Apert syndrome
    • Differentiation
    • Extracellular-signal-regulated kinase 1/2 (ERK1/2)
    • Fibroblast growth factor receptor 2 (FGFR2)
    • Green fluorescent protein (GFP)
    • PC12 cell

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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