EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2

	EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2
	Wu, YJ; Chen, ZJ; Ullrich, A
刊名	BIOLOGICAL CHEMISTRY
	2003
卷号	384 期号:8 页码:1215-1226
关键词	docking protein feedback regulation MAP kinase serine and threonine phosphorylation signal transduction tyrosine phosphorylation
通讯作者	Ullrich, A (reprint author), Max Planck Inst Biochem, Dept Mol Biol, D-82152 Martinsried, Germany.,
英文摘要	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.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	INSULIN-RECEPTOR SUBSTRATE-1 ; EPIDERMAL-GROWTH-FACTOR ; SHP-2 TYROSINE PHOSPHATASE ; PROTEIN-COUPLED RECEPTORS ; FACTOR-MEDIATED INTERACTION ; KINASE INTERACTION MOTIF ; DOCKING-PROTEIN ; PTP-SL ; PHOSPHORYLATION ; ACTIVATION
收录类别	SCI
语种	英语
WOS记录号	WOS:000184962700010
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/2337]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Wu, YJ,Chen, ZJ,Ullrich, A. EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2[J]. BIOLOGICAL CHEMISTRY,2003,384(8):1215-1226.
APA	Wu, YJ,Chen, ZJ,&Ullrich, A.(2003).EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2.BIOLOGICAL CHEMISTRY,384(8),1215-1226.
MLA	Wu, YJ,et al."EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2".BIOLOGICAL CHEMISTRY 384.8(2003):1215-1226.