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: 6.46). 02/2007; 134(1):167-76. DOI: 10.1242/dev.02701
Source: PubMed


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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    • "DUSP6/MKP-3 expression is growth factor inducible and this phosphatase plays a key role in the regulation of fibroblast growth factor (FGF) dependent ERK activation during early embryonic development [15] [16]. Despite early confusion as to which Ras effector pathway signals to the DUSP6/MKP-3 promoter, with both phosphatidylinositide 3-kinase (PI3K) and ERK signalling implicated in its regulation, it is now clear that DUSP6/MKP-3 is an ERK target gene and that it acts as a classical negative feedback regulator of ERK activity, both in a developmental context and in primary and cancer cell lines [16] [17] [18]. Furthermore, DUSP6/MKP-3 is one of a small group of genes that is consistently up regulated in response to elevated ERK signalling in cancer cells harbouring activating mutations in either Ras or Braf, where it is presumed to restrain oncogenic ERK signalling [19] [20] [21]. "
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    ABSTRACT: Dual-specificity MAP kinase (MAPK) phosphatases (MKPs or DUSPs) are well-established negative regulators of MAPK signalling in mammalian cells and tissues. By virtue of their differential subcellular localisation and ability to specifically recognise, dephosphorylate and inactivate different MAPK isoforms, they are key spatiotemporal regulators of pathway activity. Furthermore, as they are transcriptionally regulated as downstream targets of MAPK signalling they can either act as classical negative feedback regulators or mediate cross talk between distinct MAPK pathways. Because MAPKs and particularly Ras/ERK signalling are implicated in cancer initiation and development, the observation that MKPs are abnormally regulated in human tumours has been interpreted as evidence that these enzymes can either suppress or promote carcinogenesis. However, definitive evidence of such roles has been lacking. Here we review recent studies based on the use of mouse models, biochemical studies and clinical data that demonstrate key roles for MKPs in modulating the oncogenic potential of Ras/ERK signalling and also indicate that these enzymes may play a role in the response of tumours to certain anticancer drugs. Overall, this work reinforces the importance of negative regulatory mechanisms in modulating the activity of oncogenic MAPK signalling and indicates that MKPs may provide novel targets for therapeutic intervention in cancer.
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    • "Unlike the neighbouring cortical hem, a secondary organizer of the hippocampal primordium (Mangale et al. 2008), which displays strong expression for both Wnt and Bmp molecules (Grove et al. 1998), the EmT showed strong expression for Wnts but low levels of expression for members of the Bmp family. Fgfs showed restricted expression in the EmT but expression of Mkp3, a downstream negative regulator of Fgf signalling (Li et al. 2007), was more widespread. This compares to the restricted expression of Fgf8 in relation to the widespread expression domain of Mkp3 in the isthmus (Echevarria et al. 2005), a secondary organizer of the midbrain–hindbrain region (Martinez 2001). "
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    ABSTRACT: The mammalian eminentia thalami (EmT) (or thalamic eminence) is an embryonic forebrain structure of unknown function. Here, we examined the molecular and cellular properties of the mouse EmT. We first studied mRNA expression of signalling molecules and found that the EmT is a structure, rich in expression of secreted factors, with Wnts being the most abundantly detected. We then examined whether EmT tissue could induce cell fate changes when grafted ectopically. For this, we transplanted EmT tissue from a tau-GFP mouse to the ventral telencephalon of a wild type host, a telencephalic region where Wnt signalling is not normally active but which we showed in culture experiments is competent to respond to Wnts. We observed that the EmT was able to induce in adjacent ventral telencephalic cells ectopic expression of Lef1, a transcriptional activator and a target gene of the Wnt/β-catenin pathway. These Lef1-positive;GFP-negative cells expressed the telencephalic marker Foxg1 but not Ascl1, which is normally expressed by ventral telencephalic cells. These results suggest that the EmT has the capacity to activate Wnt/β-catenin signalling in the ventral telencephalon and to suppress ventral telencephalic gene expression. Altogether, our data support a role of the EmT as a signalling centre in the developing mouse forebrain.
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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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    ABSTRACT: Receptor tyrosine kinases (RTKs) signal through shared intracellular pathways yet mediate distinct outcomes across many cell types. To investigate the mechanisms underlying RTK specificity in craniofacial development, we performed RNA-seq to delineate the transcriptional response to platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling in mouse embryonic palatal mesenchyme cells. While the early gene expression profile induced by both growth factors is qualitatively similar, the late response is divergent. Comparing the effect of MEK (Mitogen/Extracellular signal-regulated kinase) and PI3K (phosphoinositide-3-kinase) inhibition, we find the FGF response is MEK-dependent while the PDGF response is PI3K-dependent. Further, FGF promotes proliferation but PDGF favors differentiation. Finally, we demonstrate overlapping domains of PDGF-PI3K signaling and osteoblast differentiation in the palate and increased osteogenesis in FGF mutants, indicating this differentiation circuit is conserved in vivo. Our results identify distinct responses to PDGF and FGF and provide insight into the mechanisms encoding RTK specificity.
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