Journal
BIOLOGICAL CHEMISTRY
Volume 384, Issue 8, Pages 1215-1226Publisher
WALTER DE GRUYTER GMBH
DOI: 10.1515/BC.2003.134
Keywords
docking protein; feedback regulation; MAP kinase; serine and threonine phosphorylation; signal transduction; tyrosine phosphorylation
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Fibroblast growth factor (FGF) receptor substrate 2 (FRS2) is a membraneanchored docking protein that has been shown to play an important role in linking FGF, nerve growth factor (NGF) and glial cellderived neurotrophic factor (GDNF) receptors with the Ras/mitogenactivated 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 SDSPAGE 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.
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