Li C, Scott DA, Hatch E, Tian X, Mansour SL.. Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development 134: 167-176

Department of Human Genetics, University of Utah, 15 N 2030 E RM 2100, Salt Lake City, UT 84112-5330, USA.
Development (Impact Factor: 6.27). 02/2007; 134(1):167-76. DOI: 10.1242/dev.02701
Source: PubMed

ABSTRACT Mitogen-activated protein kinase (MAPK) pathways are major mediators of extracellular signals that are transduced to the nucleus. MAPK signaling is attenuated at several levels, and one class of dual-specificity phosphatases, the MAPK phosphatases (MKPs), inhibit MAPK signaling by dephosphorylating activated MAPKs. Several of the MKPs are themselves induced by the signaling pathways they regulate, forming negative feedback loops that attenuate the signals. We show here that in mouse embryos, Fibroblast growth factor receptors (FGFRs) are required for transcription of Dusp6, which encodes MKP3, an extracellular signal-regulated kinase (ERK)-specific MKP. Targeted inactivation of Dusp6 increases levels of phosphorylated ERK, as well as the pERK target, Erm, and transcripts initiated from the Dusp6 promoter itself. Finally, the Dusp6 mutant allele causes variably penetrant, dominant postnatal lethality, skeletal dwarfism, coronal craniosynostosis and hearing loss; phenotypes that are also characteristic of mutations that activate FGFRs inappropriately. Taken together, these results show that DUSP6 serves in vivo as a negative feedback regulator of FGFR signaling and suggest that mutations in DUSP6 or related genes are candidates for causing or modifying unexplained cases of FGFR-like syndromes.

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Available from: Suzanne L Mansour, Jan 07, 2014
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    • "The top results for genes enriched following FGF treatment are sets associated with modulation of signaling, such as protein kinases and GTPase regulators, which may function as activators of Ras to promote MEK/ERK signaling. Transcriptional feedback regulation of RTK signaling is well established, particularly the role of DUSPs providing negative feedback for MAPK signaling (Amit et al., 2007; Li et al., 2007; Owens and Keyse, 2007). Indeed, many DUSPs (MAPK phosphatases) are induced in response to both PDGF and FGF treatment at 1 hr (Figure 1—figure supplement 1D), but FGF alone induces the expression of kinases and GTPase regulators at 4 hr, suggesting a distinct role for the FGF response in regulating MEK/ERK activity. "
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    • "miRNA326 0.0002 1.58 times Maintenance and survival of striatal precursor pool TGM7 [16] [17] miRNA181c 0.0029 1.50 times Switch for lineage-to-self-renewal and telomerase expression PTPN11, PTPN22, DUSP6, PBX3, IRF8, and ZEB2 [18] [19] [20] [21] "
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    • "miRNA326 0.0002 1.58 times Maintenance and survival of striatal precursor pool TGM7 [16] [17] miRNA181c 0.0029 1.50 times Switch for lineage-to-self-renewal and telomerase expression PTPN11, PTPN22, DUSP6, PBX3, IRF8, and ZEB2 [18] [19] [20] [21] "
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