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| Going out on a limb: FGF8 signaling and MKP3
Fibroblast growth factor 8 (FGF8) regulates mesenchymal MAP kinase phosphatase 3 (Mkp3) expression. MKP3 then functions via the PI(3)K pathway to antagonize the MAPK/ERK signaling cascade, thus acting as an apoptotic regulator in the developing vertebrate limb. MAPK phosphatase 3 (MKP3) is a dual-specificity phosphatase that antagonizes MAPK/ERK thereby regulating apoptosis and proliferation of cells. Belmonte et al. have investigated the role of MKP3 in fibroblast growth factor 8 (FGF8) signaling during limb/fin development in chick, mouse and zebrafish.
The authors characterized an FGF8 regulated synexpression group (a set of genes expressed in a spatio-temporal manner correlating with the presence of the ligand of interest). In the developing limb bud, Mkp3 exhibited a high level of expression in the mesenchyme similar to that of FGF8. Implantation of a bead soaked in FGF8 into the flank tissue of a developing chick embryo, resulted in the rapid induction of Mkp3 expression ahead of other FGF8 synexpression group members. These results suggest that FGF8 is able to induce expression of Mkp3 and establish that Mkp3 is one of the earliest known targets of FGF8 signaling. FGF signals are known to activate the MAP kinase (MAPK) and phosphotidylinositol 3 kinase (PI(3)K) pathways. Pharmacological inhibition of the PI(3)K pathway in cells containing a reporter construct incorporating upstream regulatory sequences of the Mkp3 promoter, halved reporter activity. Furthermore, a constitutively active mutant form of Akt could substitute for FGF8, resulting in upregulation of reporter activity even in the presence of a PI(3)K inhibitor. Thus, FGF8 induces the expression of Mkp3 via activation of the PI(3)K/Akt pathway. Antibodies directed against phosphorylated ERK (pERK) detected the highest ERK activity in tissue lacking Mkp3 expression, such as the apical ectodermal ridge (AER). Phosphorylated Akt (pAkt) was not present in the AER, but high in the mesenchyme, similar to MKP3 but opposite to pERK, consistent with a role for MKP3 in regulating mesenchymal ERK phosphorylation. Injection of Mkp3 siRNA to downregulate MKP3 activity resulted in a marked increase in ERK phosphorylation and consequently, to cell death in the developing limb mesenchyme. This, combined with PI(3)K/Akt's known anti-apoptotic role, indicates that MKP3 may regulate apoptosis in the mesenchyme. Although it cannot be excluded that pathways other than FGF8 may be involved in the expression of Mkp3, these results reveal that Mkp3 expression is regulated by FGF8 signaling. MKP3 functions via the PI(3)K/Akt pathway, antagonizing the MAPK/ERK signaling cascade through the dephosphorylation of ERK, thus mediating FGF8 proliferative and anti-apoptotic signaling. Brenda Riley, Assistant Editor
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