EGFR and FGFR Signaling through FRS2 Is Subject to Negative Feedback Control by ERK1/2
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| 024 | 7 | 0 | |a 10.1515/BC.2003.134 |2 doi |
| 035 | |a (NATIONALLICENCE)gruyter-10.1515/BC.2003.134 | ||
| 245 | 0 | 0 | |a EGFR and FGFR Signaling through FRS2 Is Subject to Negative Feedback Control by ERK1/2 |h [Elektronische Daten] |c [Y. Wu, Z. Chen, A. Ullrich] |
| 520 | 3 | |a 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. | |
| 540 | |a Copyright © 2003 by Walter de Gruyter GmbH & Co. KG | ||
| 690 | 7 | |a Biochemistry |2 nationallicence | |
| 690 | 7 | |a Molecular biology |2 nationallicence | |
| 690 | 7 | |a Cellular biology |2 nationallicence | |
| 700 | 1 | |a Wu |D Y. |4 aut | |
| 700 | 1 | |a Chen |D Z. |4 aut | |
| 700 | 1 | |a Ullrich |D A. |4 aut | |
| 773 | 0 | |t Biological Chemistry |d Walter de Gruyter |g 384/8(2003-08-20), 1215-1226 |x 1431-6730 |q 384:8<1215 |1 2003 |2 384 |o bchm | |
| 856 | 4 | 0 | |u https://doi.org/10.1515/BC.2003.134 |q text/html |z Onlinezugriff via DOI |
| 908 | |D 1 |a research article |2 jats | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1515/BC.2003.134 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Wu |D Y. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Chen |D Z. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Ullrich |D A. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Biological Chemistry |d Walter de Gruyter |g 384/8(2003-08-20), 1215-1226 |x 1431-6730 |q 384:8<1215 |1 2003 |2 384 |o bchm | ||
| 900 | 7 | |b CC0 |u http://creativecommons.org/publicdomain/zero/1.0 |2 nationallicence | |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-gruyter | ||