Fibroblast growth factor, but not activin, is a potentactivator of mitogen-activated protein kinase in Xenopusexplants.

Graves, Lee M.; Northrop, Jennifer L.; Potts, Brian C.; Krebs, Edwin G.; Kimelman, David

doi:10.1073/pnas.91.5.1662

Cited by 41 publications

(18 citation statements)

References 61 publications

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“…Embryos were injected with eFGF (5 pg/embryo) or FGFR1 act RNA (50 pg/embryo) either alone or with XLPTP-AS (70 ng/embryo). Whole embryonic lysates were prepared at stage 7 because this represents a period when endogenous MAP kinases are not activated (13,17,25). Since, phosphorylation of MAP kinase correlates with its activity, the phophorylation state of MAP kinase was assessed by Western blotting with anti-phosphoMAP kinase antibody.…”

Section: Resultsmentioning

confidence: 99%

Low-Molecular-Weight Protein Tyrosine Phosphatase Is a Positive Component of the Fibroblast Growth Factor Receptor Signaling Pathway

Park

Warner

Mood

et al. 2002

Molecular and Cellular Biology

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Low-molecular-weight protein tyrosine phosphatase (LMW-PTP) has been implicated in the regulation of cell growth and actin rearrangement mediated by several receptor tyrosine kinases, including platelet-derived growth factor and epidermal growth factor. Here we identify the Xenopus laevis homolog of LMW-PTP1 (XLPTP1) as an additional positive regulator in the fibroblast growth factor (FGF) signaling pathway during Xenopus development. XLPTP1 has an expression pattern that displays substantial overlap with FGF receptor 1 (FGFR1) during Xenopus development. Using morpholino antisense technology, we show that inhibition of endogenous XLPTP1 expression dramatically restricts anterior and posterior structure development and inhibits mesoderm formation. In ectodermal explants, loss of XLPTP1 expression dramatically blocks the induction of the early mesoderm gene, Xbrachyury (Xbra), by FGF and partially blocks Xbra induction by Activin. Moreover, FGF-induced activation of mitogen-activated protein (MAP) kinase is also inhibited by XLPTP1 morpholino antisense oligonucleotides; however, introduction of RNA encoding XLPTP1 is able to rescue morphological and biochemical effects of antisense inhibition. Inhibition of FGF-induced MAP kinase activity due to loss of XLPTP1 is also rescued by an active Ras, implying that XLPTP1 may act upstream of or parallel to Ras. Finally, XLPTP1 physically associates only with an activated FGFR1, and this interaction requires the presence of SNT1/FRS-2 (FGFR substrate 2). Although LMW-PTP1 has been shown to participate in other receptor systems, the data presented here also reveal XLPTP1 as a new and important component of the FGF signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Low-Molecular-Weight Protein Tyrosine Phosphatase Is a Positive Component of the Fibroblast Growth Factor Receptor Signaling Pathway

Park

Warner

Mood

et al. 2002

Molecular and Cellular Biology

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“…Xenopus explants treated with FGF activate MAPK and the downstream factor p90Rsk (17), and this activation is necessary for induction of mesoderm as shown by expression of mesodermal markers such as Xenopus brachyury (Xbra). In addition, expression of MAPK phosphatase can suppress FGF-induced mesoderm induction (18).…”

Section: Discussionmentioning

confidence: 99%

Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation

Yao

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

281

217

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The extracellular signal-regulated kinase (ERK) is a component of the mitogen-activated protein kinase cascade. Exon 2 of erk2 was deleted by homologous recombination and resulted in embryonic lethality at embryonic day 6.5. erk2 mutant embryos did not form mesoderm and showed increased apoptosis but comparable levels of BrdUrd incorporation, indicating a defect in differentiation. erk2 null embryonic stem (ES) cells exhibited reduced total ERK activity upon serum stimulation, augmented ERK1 phosphorylation, and decreased downstream p90Rsk phosphorylation and activity; yet ES cell proliferation was unaffected. Mutant ES cells were capable of forming mesoderm; however, treatment of mutant ES cells with the mitogen-activated protein kinase kinase inhibitor PD184352 decreased total ERK activity and expression of the mesodermal marker brachyury, suggesting that ERK1 can compensate for ERK2 in vitro. Normal embryos at embryonic day 6.5 expressed activated ERK1͞2 in the extraembryonic ectoderm, whereas erk2 mutant embryos had no detectable activated ERK1͞2 in this region, suggesting that activated ERK1 was not expressed, and therefore cannot compensate for loss of ERK2 in vivo. These data indicate that ERK2 plays an essential role in mesoderm differentiation during embryonic development.T he extracellular signal-regulated kinase (ERK) mitogenactivated protein kinase (MAPK) cascade is a key signaling pathway controlling cell proliferation, differentiation, and apoptosis. Two members of this pathway, ERK1 and ERK2, share an overall 75% identity at the amino acid level and up to 90% identity at the C terminus (1), present the same in vitro substrate specificity, and are ubiquitously expressed. The classic MAPK cascade involves sequential activation of the serine͞threonine kinase Raf, the dual-specificity MAPK kinase (MEK) and the MAPK ERK upon stimulation by growth factors, serum, or phorbol esters. Activated ERK phosphorylates numerous substrates on (S͞T) P sites in different cellular compartments (reviewed in ref.2), leading to increased nucleotide synthesis, activated transcription and translation, and enhanced cell cycle progression (reviewed in refs. 3 and 4). It has been shown that the duration and strength of ERK activation can gate cells to antagonistic fates such as proliferation or differentiation (5), cell cycle entry or G 1 arrest (6), and apoptosis or survival (7,8). Thus, the ERK pathway must be tightly controlled to ensure proper outcome of such integrated biological responses.The identification of the exclusive MEK1͞ERK1 scaffold protein MEK Partner 1 (MP1) indicates that ERK1 and ERK2 likely have different roles (9). This view is supported by genetic ablation studies in mice. erk1-deficient mice are viable and fertile, but have defective thymocyte maturation (10). These mice also have enhanced long-term memory and are able to up-regulate ERK2 signaling in response to glutamate (11). These results suggest that ERK2 cannot compensate for all of the functions mediated by ERK1. ERK2 itself may also possess d...

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“…Activation of FGFR by binding of ligands stimulates a multitude of downstream signaling cascades (Graves et al 1994;Seger & Krebs 1995;Triesman 1996). A main pathway is a protein kinase transduction pathway, which includes Ras, Raf, mitogen-activated protein (MAP) kinase kinase (MEK) and extracellular signal-regulated kinase/MAP kinase (ERK).…”

Section: Introductionmentioning

confidence: 99%

Role of the FGF and MEK signaling pathway in the ascidian embryo

2001

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In the ascidian embryo, a fibroblast growth factor (FGF)-like signal from presumptive endoderm blastomeres between the 32-cell and early 64-cell stages induces the formation of notochord and mesenchyme cells. However, it has not been known whether endogenous FGF signaling is involved in the process. Here it is shown that 64-cell embryos exhibit a marked increase in endogenous extracellular signal-regulated kinase (ERK/MAPK) activity. The increase in ERK activity was reduced by treatment with an FGF receptor 1 inhibitor, SU5402, and a MEK (ERK kinase/MAPKK) inhibitor, U0126. Both drugs blocked the formation of notochord and mesenchyme when embryos were treated at the 32-cell stage, but not at the 2-or 110-cell stages. The dominant-negative form of Ras also suppressed notochord and mesenchyme formation. Both inhibitors suppressed induction by exogenous basic FGF. These results suggest that the FGF signaling cascade is indeed necessary for the formation of notochord and mesenchyme cells during ascidian embryogenesis. It is also shown that FGF signaling is required for formation of the secondary notochord, secondary muscle and neural tissues, and at least ERK activity is necessary for the formation of trunk lateral cells and posterior endoderm. Therefore, FGF and MEK signaling are required for the formation of various tissues in the ascidian embryo.

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Fibroblast growth factor, but not activin, is a potentactivator of mitogen-activated protein kinase in Xenopusexplants.

Abstract: Isolated explants from the animal hemisphere of Xenopus embryos were incubated with Xenopus basic fibroblast growth factor (XbFGF) or human activin A. XbFGF incubation resulted in the rapid activation of mitogen-activated protein kinase (MAPK) and ribosomal S6 protein kinase

Cited by 41 publications

References 61 publications

Low-Molecular-Weight Protein Tyrosine Phosphatase Is a Positive Component of the Fibroblast Growth Factor Receptor Signaling Pathway

Low-Molecular-Weight Protein Tyrosine Phosphatase Is a Positive Component of the Fibroblast Growth Factor Receptor Signaling Pathway

Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation

Role of the FGF and MEK signaling pathway in the ascidian embryo

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