Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling

Zamal Ahmed , Annika C Schuller , Klaus Suhling , Carolyn Tregidgo , John E Ladbury (1)

1 Department of Biochemistry & Molecular Biology

An understanding of cellular signalling from a systems-based approach has to be robust to the effects of point mutations in component proteins. Outcomes of these perturbations should be predictable in terms of downstream response otherwise a holistic interpretation of biological process or disease states cannot be obtained. Two single, proximal point mutations (S252W and P253R) in the extracellular region of FGFR2 prolong growth factor engagement resulting in dramatically different intracellular phenotypes. Following ligand stimulation the wild type receptor undergoes rapid endocytosis into lysosomes, whereas SWFGFR2 and PRFGFR2 remain on the cell membrane for extended period of time, modifying protein recruitment and elevating downstream ERK phosphorylation. FLIM reveals that direct interaction of FRS2 with wild type receptor occurs primarily at the vesicular membrane while the interaction with the P253R receptor occurs exclusively at the plasma membrane. These observations suggest that the altered FRS2 recruitment by the mutant receptors results in an abnormal cellular signalling mechanism. In this study these profound intracellular phenotypes resulting from extracellular modification reveal a new level of complexity which will challenge a systems biology interpretation.

Mots clés: Life Sciences

Zamal Ahmed, Annika C Schuller, Klaus Suhling, Carolyn Tregidgo, John E Ladbury. Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling. Biochemical Journal, 2008, 413 (1), pp.37-49. ⟨10.1042/BJ20071594⟩. ⟨hal-00478922⟩