Fibroblast growth factor receptor 2 phosphorylation on serine 779 couples to 14-3-3 and regulates cell survival and proliferation.
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 remain unclear. We now identify a new mechanism by which FGFR2 is able to regulate intracellular signaling and cellular responses. We show that FGFR2 is phosphorylated on serine 779 (S779) in response to FGF2. S779, which lies adjacent to the phospholipase Cgamma 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 phosphatidylinositol 3-kinase and Ras/mitogen-activated protein kinase pathways. Furthermore, S779 signaling is essential for promoting cell survival and proliferation in both Ba/F3 cells and BALB/c 3T3 fibroblasts. This new mode of FGFR2 phosphoserine signaling via the 14-3-3 proteins may provide an increased repertoire of signaling 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.
Lonic
Ana
A
Division of Human Immunology, Institute of Medical and Veterinary Science, Frome Rd. Adelaide, South Australia, Australia.
Barry
Emma F
EF
Quach
Cindy
C
Kobe
Bostjan
B
Saunders
Neil
N
Guthridge
Mark A
MA
D048948:14-3-3 Proteins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D041702:BALB 3T3 Cells; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction
D048948:14-3-3 Proteins; D018076:DNA, Complementary; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D012694:Serine; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D011493:Protein Kinase C