Negative Feedback Regulation of FGF Signaling Levels by Pyst1/MKP3 in Chick Embryos

Eblaghie, Maxwell C.; Lunn, J. Simon; Dickinson, Robin J.; Münsterberg, Andrea; Sanz‐Ezquerro, Juan José; Farrell, Elizabeth R.; Mathers, Joanne; Keyse, Stephen M.; Storey, Kate G.; Tickle, Cheryll

doi:10.1016/s0960-9822(03)00381-6

Cited by 159 publications

(181 citation statements)

References 54 publications

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“…More specifically, Fgf3 and Fgf8 have pronounced expression in the pharyngeal endoderm and ectoderm, and embryos injected with antisense morpholinos directed against the transcripts of these two genes fail to form pharyngeal cartilages (David et al, 2002;Walshe and Mason, 2003). Other studies have also noted that the mature pharyngeal arches are a prominent site of expression of members of the FGF synexpression group, including the transcriptional effectors pea3 and erm, as well as inhibitors of FGF signaling, such as Pyst1 (MKP3) and sprouty 2 (Munchberg et al, 1999;Chambers and Mason, 2000;Chotteau-Lelievre et al, 2001;Eblaghie et al, 2003;Walshe and Mason, 2003).…”

Section: Resultsmentioning

confidence: 99%

The emergence of ectomesenchyme

Blentic

Tandon

Payton

et al. 2008

Developmental Dynamics

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Section: Resultsmentioning

confidence: 99%

The emergence of ectomesenchyme

Blentic

Tandon

Payton

et al. 2008

Developmental Dynamics

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“…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%

“…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: 94%

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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“…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%

“…To dissect the sequence requirements for this localization, we have expressed MKP-3 as an amino-terminal GFP fusion protein. This protein is fully active and able to dephosphorylate ERK2 when expressed in mammalian cells, indicating that MKP-3 is not folded abnormally when expressed as a fusion to GFP (6). Unlike GFP alone, which is distributed between the nucleus and the cytoplasm, MKP-3-GFP is predominantly cytoplasmic when expressed in both HeLa and NIH3T3 cells (Fig.…”

Section: Both Endogenous Mkp-3 and Mkp-3-gfp Are Cytoplasmicmentioning

confidence: 91%

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

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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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Negative Feedback Regulation of FGF Signaling Levels by Pyst1/MKP3 in Chick Embryos

Cited by 159 publications

References 54 publications

The emergence of ectomesenchyme

The emergence of ectomesenchyme

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

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