Extracellular point mutations in FGFR2 result in elevated Erk1/2 activation and perturbation of neuronal differentiation

Annika C Schüller , Zamal Ahmed , John E Ladbury (1)

1 Department of Biochemistry & Molecular Biology

Two independent, gain-of-function point mutations (Ser252Trp and Pro253Arg) in the extracellular region of the fibroblast growth factor receptor 2 (FGFR2) 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 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 data show that the effects of both these extracellular mutations have unexpected intracellular phenotypes and cellular response. 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 activation. Although Erk1/2 activation is thought to transduce signals resulting in cell differentiation, this response was abrogated in the cells expressing the mutant receptors. Our data demonstrate that single extracellular point mutations in the FGFR2 have a profound effect on the intracellular signalling and ultimately on cell fate.

Mots clés: Life Sciences

Annika C Schüller, Zamal Ahmed, John E Ladbury. Extracellular point mutations in FGFR2 result in elevated Erk1/2 activation and perturbation of neuronal differentiation. Biochemical Journal, 2008, 410 (1), pp.205-211. ⟨10.1042/BJ20070859⟩. ⟨hal-00478837⟩