MCB Accepts, published online ahead of print on 10 March 2008

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Mol. Cell. Biol. doi:10.1128/MCB.01837-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

FGFR2 phosphorylation on Serine 779 couples to 14-3-3 and regulates cell survival and proliferation

Ana Lonic, Emma F. Barry, Cindy Quach, Bostjan Kobe, Neil Saunders, and Mark A. Guthridge^*

Cell Growth and Differentiation Laboratory, Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science; and the Department of Medicine, University of Adelaide; School of Molecular and Microbial Sciences and Institute for Molecular Bioscience, Queensland

^* To whom correspondence should be addressed. Email: mark.guthridge{at}imvs.sa.gov.au.

The fibroblast growth factors (FGFs) exert their diverse (or pleiotropic) biological responses through the binding and activation of specific cell surface receptors (FGFRs). While FGFRs are known to initiate intracellular signaling through receptor tyrosine phosphorylation, the precise mechanisms by which the FGFRs regulate pleiotropic biological responses remains unclear. We now identify a new mechanism by which FGFR2 is able to regulate intracellular signalling and cellular responses. We show that FGFR2 is phosphorylated on serine 779 (S779) in response to FGF2. S779, which lies adjacent to the PLC binding site at Y766, provides a docking site for the 14-3-3 phosphoserine-binding proteins and is essential for the full activation of the PI 3-kinase and Ras/MAP kinase pathways. Furthermore, S779 signalling is essential for promoting cell survival and proliferation in both Ba/F3 cells and Balb/c 3T3 fibroblasts. This new mode of FGFR2 phosphoserine signalling via the 14-3-3 proteins may provide an increased repertoire of signalling outputs to allow the regulation of pleiotropic biological responses. In this regard, we have identified conserved putative phosphotyrosine/phosphoserine motifs in the cytoplasmic domains of diverse cell surface receptors suggesting that they may perform important functional roles beyond the FGFRs.

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