EGFR and FGFR Signaling through FRS2 Is Subject to Negative Feedback Control by ERK1/2
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Y. Wu
Abstract
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 carboxyterminal 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 ligandstimulated negative regulatory feedback loop in which activated ERK1/2 phosphorylates FRS2 on serine/threonine residues thereby downregulating its tyrosine phosphorylation. Our findings support a broader role of FRS2 in EGFRcontrolled signaling pathways in A-431 cells and provide insight into a molecular mechanism for ligandstimulated feedback regulation with FRS2 as a central regulatory switch point.
Copyright © 2003 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
- Molecular and Functional Interdependence of the Urokinase-Type Plasminogen Activator System with Integrins
- Differential Haemoglobin Gene Expression in the Crustacean Daphnia magna Exposed to Different Oxygen Partial Pressures
- Cloning and Characterization of the Promoter Region of the Mouse Frizzled-Related Protein 4 Gene
- The Bloom's Syndrome Helicase Interacts Directly with the Human DNA Mismatch Repair Protein hMSH6
- Assignment of Disulphide Bridges in Par j 2.0101, a Major Allergen of Parietaria judaica Pollen
- Determination of the NMR Structure of Gln25-Ribonuclease T1
- The Molecular Chaperone, α-Crystallin, Protects against Loss of Antigenicity and Activity of Esterase Caused by Sugars, Sugar Phosphate and a Steroid
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- Trans-Sialidase-Like Sequences from Trypanosoma congolense Conserve Most of the Critical Active Site Residues Found in Other Trans-Sialidases
- EGFR and FGFR Signaling through FRS2 Is Subject to Negative Feedback Control by ERK1/2
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