An understanding of cellular signalling from a systems-based approach has to be robust to assess 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 processes or disease states cannot be obtained. Two single, proximal point mutations (S252W and P253R) in the extracellular region of FGFR2 (fibroblast growth factor receptor 2) prolong growth factor engagement resulting in dramatically different intracellular phenotypes. Following ligand stimulation, the wild-type receptor undergoes rapid endocytosis into lysosomes, whereas SWFGFR2 (the S252W FGFR2 point mutation) and PRFGFR2 (the P253R FGFR2 point mutation) remain on the cell membrane for an extended period of time, modifying protein recruitment and elevating downstream ERK (extracellular-signal-regulated kinase) phosphorylation. FLIM (fluorescent lifetime imaging microscopy) reveals that direct interaction of FRS2 (FGFR substrate 2) with wild-type receptor occurs primarily at the vesicular membrane, whereas 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 the present study these profound intracellular phenotypes resulting from extracellular receptor modification reveal a new level of complexity which will challenge a systems biology interpretation.
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Research Article|
June 12 2008
Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling
Zamal Ahmed;
Zamal Ahmed
*Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
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Annika C. Schüller;
Annika C. Schüller
*Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
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Klaus Suhling;
Klaus Suhling
†Department of Physics, Kings College London, The Strand, London WC2R 2LS, U.K.
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Carolyn Tregidgo;
Carolyn Tregidgo
†Department of Physics, Kings College London, The Strand, London WC2R 2LS, U.K.
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John E. Ladbury
John E. Ladbury
1
*Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K.
1To whom correspondence should be addressed (email j.ladbury@biochem.ucl.ac.uk).
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Publisher: Portland Press Ltd
Received:
November 26 2007
Revision Received:
March 19 2008
Accepted:
March 28 2008
Accepted Manuscript online:
March 28 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 413 (1): 37–49.
Article history
Received:
November 26 2007
Revision Received:
March 19 2008
Accepted:
March 28 2008
Accepted Manuscript online:
March 28 2008
Citation
Zamal Ahmed, Annika C. Schüller, Klaus Suhling, Carolyn Tregidgo, John E. Ladbury; Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling. Biochem J 1 July 2008; 413 (1): 37–49. doi: https://doi.org/10.1042/BJ20071594
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