title: ERK-mediated phosphorylation of fibroblast growth factor receptor 1 on Ser777 inhibits signaling.
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 Ser(777) in the C-terminal region of FGFR1 by the MAPKs extracellular signal-regulated kinase 1 (ERK1) and ERK2. Prevention of the phosphorylation of Ser(777) in FGFR1 or mutation of Ser(777) 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 Ser(777) exhibited reduced signaling. Activation of MAPKs by other receptor tyrosine kinases also resulted in phosphorylation of Ser(777) 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.
authors: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0310 Oslo, Norway.
authors: Malgorzata
authors: M
authors: Zakrzewska
authors: Ellen Margrethe
authors: EM
authors: Haugsten
authors: Beata
authors: B
authors: Nadratowska-Wesolowska
authors: Angela
authors: A
authors: Oppelt
authors: Barbara
authors: B
authors: Hausott
authors: Yixin
authors: Y
authors: Jin
authors: Jacek
authors: J
authors: Otlewski
authors: Jørgen
authors: J
authors: Wesche
authors: Antoni
authors: A
authors: Wiedlocha
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D012694:Serine; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases