EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2.
Fibroblast growth factor (FGF) receptor substrate 2 (FRS2) is a membrane-anchored docking protein that has been shown to play an important role in linking FGF, nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF) receptors with the Ras/mitogen-activated protein (MAP) kinase signaling cascade. Here we provide evidence that FRS2 ... can also play a role in epidermal growth factor (EGF) signaling. Upon EGF stimulation, FRS2 mediates enhanced MAPK activity and undergoes phosphorylation on tyrosine as well as serine/threonine residues. This involves the direct interaction of the FRS2 PTB domain with the EGFR and results in a significantly altered mobility of FRS2 in SDS-PAGE which is also observed in FGF stimulated cells. This migration shift of FRS2 is completely abrogated by U0126, a specific MAPK kinase 1 (MEK1) inhibitor, suggesting that ERK1/2 acts as serine/threonine kinase upstream of FRS2. Indeed, we show that the central portion of FRS2 constitutively associates with ERK1/2, whereas the FRS2 carboxy-terminal region serves as substrate for ERK2 phosphorylation in response to EGF and FGF stimulation. Notably, tyrosine phosphorylation of FRS2 is enhanced when ERK1/2 activation is inhibited after both EGF and FGF stimulation. These results indicate a ligand-stimulated negative regulatory feedback loop in which activated ERK1/2 phosphorylates FRS2 on serine/threonine residues thereby down-regulating its tyrosine phosphorylation. Our findings support a broader role of FRS2 in EGFR-controlled signaling pathways in A-431 cells and provide insight into a molecular mechanism for ligand-stimulated feedback regulation with FRS2 as a central regulatory switch point.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, COS Cells, Cell Line, Tumor, ErbB Receptors, Feedback, Physiological, Humans, Membrane Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Phosphoproteins, Phosphorylation, Protein Binding, Receptors, Fibroblast Growth Factor, Receptors, G-Protein-Coupled, Serine, Signal Transduction, Threonine, Tyrosine
Adaptor Proteins, Signal Transducing, Animals, COS Cells, Cell Line, Tumor, ErbB Receptors, Feedback, Physiological, Humans, Membrane Proteins, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Phosphoproteins, Phosphorylation, Protein Binding, Receptors, Fibroblast Growth Factor, Receptors, G-Protein-Coupled, Serine, Signal Transduction, Threonine, Tyrosine
Biol. Chem.
Date: Aug. 01, 2003
PubMed ID: 12974390
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