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Sci. Signal., 12 February 2013
Vol. 6, Issue 262, p. ra11
Limiting Growth Factor Signaling
Binding of fibroblast growth factors (FGFs) to receptor tyrosine kinases in the FGFR family triggers activation of these receptors through phosphorylation of tyrosine residues, thereby initiating signaling that stimulates cell proliferation and differentiation in various developmental processes, such as axonal growth. Zakrzewska et al. investigated the effect of phosphorylation of serine residues in FGFR1 on receptor activity. FGF-dependent activation of the mitogen-activated protein kinases ERK1 and ERK2 (ERK1/2) resulted in phosphorylation of Ser777 in the C-terminal region of the receptor, and this phosphorylation event was associated with decreased activation of FGFR1 and attenuated signaling. Dorsal root ganglion neurons expressing a S777A mutant FGFR1 exhibited enhanced and sustained receptor activation and extended longer axons than those expressing the wild-type receptor. In addition, previous stimulation of cells with epidermal growth factor, a ligand for a distinct receptor tyrosine kinase, resulted in the ERK1/2-mediated serine phosphorylation of FGFR1 and a reduction in subsequent FGF-dependent signaling. Together, these data suggest that an ERK-dependent mechanism initiated by activation of FGFR1 or other growth factor receptors prevents excessive FGFR1 signaling.
Citation: M. Zakrzewska, E. M. Haugsten, B. Nadratowska-Wesolowska, A. Oppelt, B. Hausott, Y. Jin, J. Otlewski, J. Wesche, A. Wiedlocha, ERK-Mediated Phosphorylation of Fibroblast Growth Factor Receptor 1 on Ser777 Inhibits Signaling. Sci. Signal.6, ra11 (2013).
Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer.
F. Malchers, F. Dietlein, J. Schottle, X. Lu, L. Nogova, K. Albus, L. Fernandez-Cuesta, J. M. Heuckmann, O. Gautschi, J. Diebold, et al. (2014)
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