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Sci. Signal., 12 February 2013
Vol. 6, Issue 262, p. ra11
[DOI: 10.1126/scisignal.2003087]

RESEARCH ARTICLES

ERK-Mediated Phosphorylation of Fibroblast Growth Factor Receptor 1 on Ser777 Inhibits Signaling

Malgorzata Zakrzewska1,2,3, Ellen Margrethe Haugsten1,2, Beata Nadratowska-Wesolowska1,2, Angela Oppelt1,2, Barbara Hausott4, Yixin Jin1,2, Jacek Otlewski3, Jørgen Wesche1,2, and Antoni Wiedlocha1,2*

1 Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0310 Oslo, Norway.
2 Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0310 Oslo, Norway.
3 Faculty of Biotechnology, University of Wroclaw, Tamka 2, 50-137 Wroclaw, Poland.
4 Division of Neuroanatomy, Innsbruck Medical University, Muellerstrasse 59, 6020 Innsbruck, Austria.

Abstract: Fibroblast growth factor 1 (FGF1) controls cellular activities through the activation of specific cell-surface FGF receptors (FGFRs). Transphosphorylation of tyrosine residues in the kinase domain of FGFRs leads to activation of intracellular signaling cascades, including those mediated by mitogen-activated protein kinases (MAPKs). FGFRs also contain a serine-rich C-terminal tail. We identified a regulatory mechanism of FGFR signaling involving phosphorylation of Ser777 in the C-terminal region of FGFR1 by the MAPKs extracellular signal–regulated kinase 1 (ERK1) and ERK2. Prevention of the phosphorylation of Ser777 in FGFR1 or mutation of Ser777 to alanine enhanced FGF-stimulated receptor tyrosine phosphorylation and increased cell proliferation, cell migration, and axonal growth. A form of FGFR1 with a phosphomimetic mutation at Ser777 exhibited reduced signaling. Activation of MAPKs by other receptor tyrosine kinases also resulted in phosphorylation of Ser777 in FGFR1, thereby enabling crosstalk regulation of FGFR activity by other signaling pathways. Our data reveal a negative feedback mechanism that controls FGF signaling and thereby protects the cell from excessive activation of FGFR.

* To whom correspondence should be addressed. E-mail: Antoni.Wiedlocha{at}rr-research.no

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).

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