期刊
BIOCHEMICAL JOURNAL
卷 412, 期 -, 页码 287-298出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20071512
关键词
dual-specificity phosphatase 6 (DUSP6); fibroblast growth factor (FGF); mitogen-activated protein kinase (MAPK); mitogen-activated protein kinase phosphatase-3 (MKP-3); phosphatase; transcription
资金
- Cancer Research UK Funding Source: Medline
- Medical Research Council [G0600234, G0200220, G113/18, G0301013(68304), G0301013] Funding Source: Medline
- MRC [G0301013, G0600234, G113/18] Funding Source: UKRI
- Medical Research Council [G0301013, G0600234, G113/18] Funding Source: researchfish
DUSP6 (dual-specificity phosphatase 6), also known as MKP-3 [MAPK (mitogen-activated protein kinase) phosphatase-3] specifically inactivates ERK1/2 (extracellular-signal-regulated kinase 1/2) in vitro and in vivo. DUSP6/MKP-3 is inducible by FGF (fibroblast growth factor) signalling and acts as a negative regulator of ERK activity in key and discrete signalling centres that direct outgrowth and patterning in early vertebrate embryos. However, the molecular mechanism by which FGFs, induce DUSP6/ MKP-3 expression and hence help to set ERK1/2 signalling levels is unknown. In the present study, we demonstrate, using pharmacological inhibitors and analysis of the murine DUSP6/ MKP-3 gene promoter, that the ERK pathway is critical for FGF-induced DUSP6/MKP-3 transcription. Furthermore, we show that this response is mediated by a conserved binding site for the Ets (E twenty-six) family of transcriptional regulators and that the Ets2 protein, a known target of ERK signalling, binds to the endogenous DUSP6/MKP-3 promoter. Finally, the murine DUSP6/MKP-3 promoter coupled to EGFP (enhanced green fluorescent protein) recapitulates the specific pattern of endogenous DUSP6/MKP-3 mRNA expression in the chicken neural plate, where its activity depends on FGFR (FGF receptor) and MAPK signalling and an intact Ets-binding site. These findings identify a conserved Ets-factor-dependent mechanism by which ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling.
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