Negative feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter
Résumé
DUSP6 (dual-specificity phosphatase 6) also known as MKP-3 (mitogen-activated protein kinase [MAPK] phosphatase -3) specifically inactivates ERK1/2 in vitro and in vivo. DUSP6/MKP-3 is inducible by fibroblast growth factor (FGF) 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 signaling levels is unknown. Here 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 E-twenty-six-specific sequence (Ets) 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 recapitulates the specific pattern of endogenous DUSP6/MKP-3 mRNA expression in the chicken neural plate, where its activity depends on FGFR 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.
Origine : Fichiers produits par l'(les) auteur(s)
Loading...