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Molecular and Cellular Biology, June 2008, p. 4129-4141, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02117-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Fibroblast Growth Factor (FGF) Receptor 1 at Ser777 by p38 Mitogen-Activated Protein Kinase Regulates Translocation of Exogenous FGF1 to the Cytosol and Nucleus{triangledown}

Vigdis Sørensen,1,4,{dagger} Yan Zhen,1,4,{dagger} Malgorzata Zakrzewska,1,2,4 Ellen Margrethe Haugsten,1,4 Sébastien Wälchli,3 Trine Nilsen,1,4 Sjur Olsnes,1,4 and Antoni Wiedlocha1,4*

Centre for Cancer Biomedicine, Faculty Division Norwegian Radium Hospital, University of Oslo,1 Department of Immunology,3 Department of Biochemistry,4 Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway, and Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland2

Received 28 November 2007/ Returned for modification 2 January 2008/ Accepted 31 March 2008

Exogenous fibroblast growth factor 1 (FGF1) signals through activation of transmembrane FGF receptors (FGFRs) but may also regulate cellular processes after translocation to the cytosol and nucleus of target cells. Translocation of FGF1 occurs across the limiting membrane of intracellular vesicles and is a regulated process that depends on the C-terminal tail of the FGFR. Here, we report that translocation of FGF1 requires activity of the {alpha} isoform of p38 mitogen-activated protein kinase (MAPK). FGF1 translocation was inhibited after chemical inhibition of p38 MAPK or after small interfering RNA knockdown of p38{alpha}. Translocation was increased after stimulation of p38 MAPK with anisomycin, mannitol, or H2O2. The activity level of p38 MAPK was not found to affect endocytosis or intracellular sorting of FGF1/FGFR1. Instead, we found that p38 MAPK regulates FGF1 translocation by phosphorylation of FGFR1 at Ser777. The FGFR1 mutation S777A abolished FGF1 translocation, while phospho-mimetic mutations of Ser777 to Asp or Glu allowed translocation to take place and bypassed the requirement for active p38 MAPK. Ser777 in FGFR1 was directly phosphorylated by p38{alpha} in a cell-free system. These data demonstrate a crucial role for p38{alpha} MAPK in the regulated translocation of exogenous FGF1 into the cytosol/nucleus, and they reveal a specific role for p38{alpha} MAPK-mediated serine phosphorylation of FGFR1.

* Corresponding author. Mailing address: Department of Biochemistry, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway. Phone: 47 22934288. Fax: 47 22508692. E-mail: antoni.wiedlocha{at}rr-research.no

{triangledown} Published ahead of print on 14 April 2008.

{dagger} V.S. and Y.Z. contributed equally to this work.

Molecular and Cellular Biology, June 2008, p. 4129-4141, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02117-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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