MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb

Kawakami, Yasuhiko; Rodríguez-León, Joaquín; Koth, Christopher M.; Büscher, Dirk; Itoh, Tohru; Raya, Ángel; Ng, Jennifer K.; Esteban, Concepción Rodrı́guez; Takahashi, Shigeru; Henrique, Domingos; Schwarz, May; Asahara, Hiroshi; Belmonte, Juan Carlos Izpisúa

doi:10.1038/ncb989

Cited by 244 publications

(247 citation statements)

References 40 publications

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“…Third, using phosphorylated-ERK as an indicator of FGF signal activation, it has been shown that only cells in the distal mesenchyme of the limb bud are under the influence of FGF (Corson et al, 2003). This is confirmed by the expression patterns of Spry genes and Mkp3, which are transcriptionally regulated by FGF signaling (Eblaghie et al, 2003;Kawakami et al, 2003;Minowada et al, 1999). Consistent with our hypothesis, the expression pattern of Spry4 complements the observed cell death domain in normal limb buds (compare Fig.…”

Section: Fgfr1 Expressed In Lbm Is Essential For Cell Survivalmentioning

confidence: 65%

“…1E,F). To assess the impact on FGF signal reception, we assayed for the expression of genes regulated by FGFs, including sprouty (Spry) 2, Spry4 and Mkp3 (Dusp6 -Mouse Genome Informatics) (Eblaghie et al, 2003;Kawakami et al, 2003;Minowada et al, 1999). Their expression suggests that FGF signaling is markedly reduced, although not abolished, in the Tcre;Fgfr1 limb buds (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning

et al. 2005

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Previous studies have implicated fibroblast growth factor receptor 1(FGFR1) in limb development. However, the precise nature and complexity of its role have not been defined. Here, we dissect Fgfr1 function in mouse limb by conditional inactivation of Fgfr1 using two different Cre recombinase-expressing lines. Use of the T (brachyury)-cre line led to Fgfr1 inactivation in all limb bud mesenchyme (LBM) cells during limb initiation. This mutant reveals FGFR1 function in two phases of limb development. In a nascent limb bud, FGFR1 promotes the length of the proximodistal (PD) axis while restricting the dimensions of the other two axes. It also serves an unexpected role in limiting LBM cell number in this early phase. Later on during limb outgrowth, FGFR1 is essential for the expansion of skeletal precursor population by maintaining cell survival. Use of mice carrying the sonic hedgehogcre(Shhcre) allele led to Fgfr1 inactivation in posterior LBM cells. This mutant allows us to test the role of Fgfr1in gene expression regulation without disturbing limb bud growth. Our data show that during autopod patterning, FGFR1 influences digit number and identity, probably through cell-autonomous regulation of Shhexpression. Our study of these two Fgfr1 conditional mutants has elucidated the multiple roles of FGFR1 in limb bud establishment, growth and patterning.

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Section: Fgfr1 Expressed In Lbm Is Essential For Cell Survivalmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning

et al. 2005

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“…MKP-3 specifically binds to and inactivates ERK1 and 2, and recent studies indicate that this enzyme plays a pivotal role in regulating MAP kinase activity in response to fibroblast growth factor signaling during early development (6,41). MKPs exhibit distinct subcellular localization in mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

Both Nuclear-Cytoplasmic Shuttling of the Dual Specificity Phosphatase MKP-3 and Its Ability to Anchor MAP Kinase in the Cytoplasm Are Mediated by a Conserved Nuclear Export Signal

Karlsson

Mathers

Dickinson

et al. 2004

Journal of Biological Chemistry

119

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MAP kinase phosphatase (MKP)-3 is a cytoplasmic dual specificity protein phosphatase that specifically binds to and inactivates the ERK1/2 MAP kinases in mammalian cells. However, the molecular basis of the cytoplasmic localization of MKP-3 or its physiological significance is unknown. We have used MKP-3-green fluorescent protein fusions in conjunction with leptomycin B to show that the cytoplasmic localization of MKP-3 is mediated by a chromosome region maintenance-1 (CRM1)-dependent nuclear export pathway. Furthermore, the nuclear translocation of MKP-3 seen in the presence of leptomycin B is mediated by an active process, indicating that MKP-3 shuttles between the nucleus and cytoplasm. The aminoterminal noncatalytic domain of MKP-3 is both necessary and sufficient for nuclear export of the phosphatase and contains a single functional leucine-rich nuclear export signal (NES). Even though this domain of the protein also mediates the binding of MKP-3 to MAP kinase, we show that mutations of the kinase interaction motif which abrogate ERK2 binding do not affect MKP-3 localization. Conversely, mutation of the NES does not affect either the binding or phosphatase activity of MKP-3 toward ERK2, indicating that the kinase interaction motif and NES function independently. Finally, we demonstrate that the ability of MKP-3 to cause the cytoplasmic retention of ERK2 requires both a functional kinase interaction motif and NES. We conclude that in addition to its established function in the regulated dephosphorylation and inactivation of MAP kinase, MKP-3 may also play a role in determining the subcellular localization of its substrate. Our results reinforce the idea that regulatory proteins such as MKP-3 may play a key role in the spatio-temporal regulation of MAP kinase activity.Dual specificity (Thr/Tyr) protein phosphatases play an important role in the regulation of signaling by mitogen-activated protein (MAP) 1 kinases in eukaryotic cells (1-3). These MAP kinase phosphatases (MKPs) act in direct opposition to the MAP kinase kinases (MKKs or MEKs) to dephosphorylate and inactivate the MAP kinase, thus regulating the duration and magnitude of activation and hence the biological outcome of signaling. Studies in Saccharomyces cerevisiae, Drosophila, and chicken embryos have also demonstrated that the expression of certain MKPs is induced in response to MAP kinase activation, indicating that they are components of negative feedback loops (4 -6). Furthermore, mathematical modeling of MAP kinase pathway dynamics emphasizes the role of MKPs in determining the timing and duration of MAP kinase activation in terms of bistable (switch-like) or monostable (proportional) response to agonists (7).There are 10 distinct MKPs in mammalian cells (3), and these enzymes feature a common structure comprising a carboxyl-terminal catalytic domain with sequence similarity to the prototypic VH1 dual specificity phosphatase of vaccinia virus (8) and an amino-terminal noncatalytic domain containing two short regions of homology with the cell ...

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“…The first clue as to a physiological function for DUSP6/MKP-3 came with the observation that it is expressed at many sites of fibroblast growth factor (FGF) signalling during early mouse development (Dickinson et al, 2002a). Subsequent studies in the developing limbs and nervous tissues in chicken embryos demonstrated that DUSP6/MKP-3 expression was mediated by FGFs as a component of a negative feedback control to regulate levels of activated ERK MAPK in these tissues (Eblaghie et al, 2003;Kawakami et al, 2003). There is currently some confusion as to which of the intracellular signalling pathways that lie downstream of the FGF-receptor is responsible for mediating DUSP6/MKP-3 expression, with evidence supporting a role for either ERK MAPK or PI3-kinase signalling in this process (Eblaghie et al, 2003;Kawakami et al, 2003;Tsang et al, 2004;Gomez et al, 2005;Smith et al, 2005).…”

Section: Mkps and The Regulation Of Immune Functionmentioning

confidence: 99%

Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases

2007

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The regulated dephosphorylation of mitogen-activated protein kinases (MAPKs) plays a key role in determining the magnitude and duration of kinase activation and hence the physiological outcome of signalling. In mammalian cells, an important component of this control is mediated by the differential expression and activities of a family of 10 dual-specificity (Thr/Tyr) MAPK phosphatases (MKPs). These enzymes share a common structure in which MAPK substrate recognition is determined by sequences within an amino-terminal non-catalytic domain whereas MAPK binding often leads to a conformational change within the C-terminal catalytic domain resulting in increased enzyme activity. MKPs can either recognize and inactivate a single class of MAP kinase, as in the specific inactivation of extracellular signal regulated kinase (ERK) by the cytoplasmic phosphatase DUSP6/MKP-3 or can regulate more than one MAPK pathway as illustrated by the ability of DUSP1/MKP-1 to dephosphorylate ERK, c-Jun amino-terminal kinase and p38 in the cell nucleus. These properties, coupled with transcriptional regulation of MKP expression in response to stimuli that activate MAPK signalling, suggest a complex negative regulatory network in which individual MAPK activities can be subject to negative feedback control, but also raise the possibility that signalling through multiple MAPK pathways may be integrated at the level of regulation by MKPs.

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MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb

Cited by 244 publications

References 40 publications

Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning

Conditional inactivation of Fgfr1 in mouse defines its role in limb bud establishment, outgrowth and digit patterning

Both Nuclear-Cytoplasmic Shuttling of the Dual Specificity Phosphatase MKP-3 and Its Ability to Anchor MAP Kinase in the Cytoplasm Are Mediated by a Conserved Nuclear Export Signal

Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases

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