Stimulation of Rat-1 cells with lysophosphatidic acid (LPA) or epidermal growth factor (EGF) results in a biphasic, sustained activation of extracellular signal-regulated kinase 1 (ERK1). Pretreatment of Rat-1 cells with either cycloheximide or sodium orthovanadate had little effect on the early peak of ERK1 activity but potentiated the sustained phase. Cycloheximide also potentiated ERK1 activation in Rat-1 cells expressing ΔRaf-1:ER, an estradiol-regulated form of the oncogenic, human Raf-1. Since cycloheximide did not potentiate MEK activity but abrogated the expression of mitogen-activated protein kinase phosphatase (MKP-1) normally seen in response to EGF and LPA, we speculated that the level of MKP-1 expression may be an important regulator of ERK1 activity in Rat-1 cells. Inhibition of LPA-stimulated MEK and ERK activation with PD98059 and pertussis toxin, a selective inhibitor of Gi-protein-coupled signaling pathways, reduced LPA-stimulated MKP-1 expression by only 50%, suggesting the presence of additional MEK- and ERK-independent pathways for MKP-1 expression. Specific activation of the MEK/ERK pathway by ΔRaf-1:ER had little or no effect on MKP-1 expression, suggesting that activation of the Raf/MEK/ERK pathway is necessary but not sufficient for MKP-1 expression in Rat-1 cells. Activation of PKC played little part in growth factor-stimulated MKP-1 expression, but LPA- and EGF-induced MKP-1 expression was blocked by buffering [Ca2+]i, leading to a potentiation of the sustained phase of ERK1 activation without potentiating MEK activity. In Rat-1ΔRaf-1:ER cells, we observed a strong synergy of MKP-1 expression when cells were stimulated with estradiol in the presence of ionomycin, phorbol 12-myristate 13-acetate, or okadaic acid under conditions where these agents did not synergize for ERK activation. These results suggest that activation of the Raf/MEK/ERK pathway is insufficient to induce expression of MKP-1 but instead requires other signals, such as Ca2+, to fully reconstitute the response seen with growth factors. In this way, ERK-dependent and -independent signals may regulate MKP-1 expression, the magnitude of sustained ERK1 activity, and therefore gene expression. Stimulation of Rat-1 cells with lysophosphatidic acid (LPA) or epidermal growth factor (EGF) results in a biphasic, sustained activation of extracellular signal-regulated kinase 1 (ERK1). Pretreatment of Rat-1 cells with either cycloheximide or sodium orthovanadate had little effect on the early peak of ERK1 activity but potentiated the sustained phase. Cycloheximide also potentiated ERK1 activation in Rat-1 cells expressing ΔRaf-1:ER, an estradiol-regulated form of the oncogenic, human Raf-1. Since cycloheximide did not potentiate MEK activity but abrogated the expression of mitogen-activated protein kinase phosphatase (MKP-1) normally seen in response to EGF and LPA, we speculated that the level of MKP-1 expression may be an important regulator of ERK1 activity in Rat-1 cells. Inhibition of LPA-stimulated MEK and ERK activation with PD98059 and pertussis toxin, a selective inhibitor of Gi-protein-coupled signaling pathways, reduced LPA-stimulated MKP-1 expression by only 50%, suggesting the presence of additional MEK- and ERK-independent pathways for MKP-1 expression. Specific activation of the MEK/ERK pathway by ΔRaf-1:ER had little or no effect on MKP-1 expression, suggesting that activation of the Raf/MEK/ERK pathway is necessary but not sufficient for MKP-1 expression in Rat-1 cells. Activation of PKC played little part in growth factor-stimulated MKP-1 expression, but LPA- and EGF-induced MKP-1 expression was blocked by buffering [Ca2+]i, leading to a potentiation of the sustained phase of ERK1 activation without potentiating MEK activity. In Rat-1ΔRaf-1:ER cells, we observed a strong synergy of MKP-1 expression when cells were stimulated with estradiol in the presence of ionomycin, phorbol 12-myristate 13-acetate, or okadaic acid under conditions where these agents did not synergize for ERK activation. These results suggest that activation of the Raf/MEK/ERK pathway is insufficient to induce expression of MKP-1 but instead requires other signals, such as Ca2+, to fully reconstitute the response seen with growth factors. In this way, ERK-dependent and -independent signals may regulate MKP-1 expression, the magnitude of sustained ERK1 activity, and therefore gene expression. One of the major signal pathways responsible for regulating reentry into the cell cycle leads to activation of the extracellular signal-regulated kinases (ERKs) 1The abbreviations used are: ERK, extracellular signal-regulated kinase (also called mitogen-activated protein kinase or MAP kinase); BAPTA-AM, (1,2-bis(2)aminophenoxy)ethaneN,N,N′,N′-tetraacetic acid tetra(acetoxymethyl ester); EGF, epidermal growth factor; JNK, JUN N-terminal kinase; LPA, lysophosphatidic acid; MBP, myelin basic protein MEK, MAP kinase, or ERK kinase; MKP, MAP kinase phosphatase; PMA, phorbol 12-myristate 13-acetate; PAGE, polyacrylamide gel electrophoresis; PVDF, polyvinylidene difluoride; PBS, phosphate-buffered saline; β-E2, β-estradiol; PKC, protein kinase C; FBS, fetal bovine serum. 1The abbreviations used are: ERK, extracellular signal-regulated kinase (also called mitogen-activated protein kinase or MAP kinase); BAPTA-AM, (1,2-bis(2)aminophenoxy)ethaneN,N,N′,N′-tetraacetic acid tetra(acetoxymethyl ester); EGF, epidermal growth factor; JNK, JUN N-terminal kinase; LPA, lysophosphatidic acid; MBP, myelin basic protein MEK, MAP kinase, or ERK kinase; MKP, MAP kinase phosphatase; PMA, phorbol 12-myristate 13-acetate; PAGE, polyacrylamide gel electrophoresis; PVDF, polyvinylidene difluoride; PBS, phosphate-buffered saline; β-E2, β-estradiol; PKC, protein kinase C; FBS, fetal bovine serum. p44ERK1 and p42ERK2 (also called mitogen-activated protein kinases or MAP kinases) (1Cobb M.H. Hepler J.E. Cheng M. Robbins D. Semin. Cancer Biol. 1994; 5: 261-268PubMed Google Scholar, 2Johnson G.L. Vaillancourt R.R. Curr. Opin. Cell Biol. 1994; 6: 230-238Crossref PubMed Scopus (307) Google Scholar, 3Marshall C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4213) Google Scholar, 4Treisman R. Curr. Opin. 1994; PubMed Scopus Google activation of leads to the and activation of the protein kinase MEK, in the kinases by of and in the Robbins M.H. Cell. Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, C.J. Cell. Full Text PDF PubMed Scopus Google is to the and by the Google Scholar, C.J. 1994; PubMed Scopus Google Scholar, D. 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PubMed Scopus Google Scholar, C.J. Curr. Biol. 1994; Full Text Full Text PDF PubMed Scopus Google In this way, the ERK a signaling the and gene expression in the on the by this is by growth and to the of protein responsible for and kinase in the In the of ERK, and is of the on and PubMed Scopus Google and sustained ERK to be important for signaling PubMed Scopus Google Scholar, Biol. Full Text PDF PubMed Google Scholar, PubMed Scopus Google is the Cell. Biol. PubMed Google Scholar, Cell. Biol. PubMed Scopus Google Scholar, C.J. Curr. Biol. 1994; Full Text Full Text PDF PubMed Scopus Google a of protein that the and on ERK PubMed Scopus Google Scholar, Google Scholar, PubMed Scopus Google Scholar, Cell. Full Text PDF PubMed Scopus Google Scholar, R. D. R. Cell. Biol. PubMed Scopus Google of this is MAP kinase (MKP-1) is by human and or early by and PubMed Scopus Google Scholar, Google R. D. R. Cell. Biol. PubMed Scopus Google of MKP-1 activation of ERK Cell. Full Text PDF PubMed Scopus Google and cell cycle reentry D. 1994; PubMed Scopus Google Scholar, 1995; Google of cells with to expression of is to potentiate sustained ERK activation by in cells Cell. Full Text PDF PubMed Scopus Google Since MKP-1 to be in the a growth factor-stimulated activation and of ERK leading to MKP-1 expression, in in the and ERK, of the sustained phase of ERK activation Curr. Biol. 1994; Full Text Full Text PDF PubMed Scopus Google by the that in cells and cells MKP-1 is but may not be the phosphatase that ERK was that and an were responsible for of ERK Curr. 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Full Text PDF PubMed Google In cells were stimulated and in and results with were for by were or with a is in Stimulation of Rat-1 cells with in a in ERK1 activity, a phase level for to Pretreatment of cells with cycloheximide for by with had no effect on the magnitude of peak ERK1 activity or the of but did potentiate the sustained phase of ERK1 activity 1 the magnitude of LPA-stimulated ERK1 activity, as a of the response was in cells but in the the and was results were when EGF was the 1 with cycloheximide had a effect on ERK1 activity 1 also the effect of cycloheximide on ERK1 activation by ΔRaf-1:ER M.H. M. Cell. Biol. PubMed Scopus Google in the cell Activation of ΔRaf-1:ER by results in the activation of MEK and ERK in these cells, the other pathways by of ΔRaf-1:ER to ERK1 was potentiated by with cycloheximide These results suggest that a protein as a regulator of sustained ERK1 activity, stimulated by a kinase, a or the form of the human effect was not to with a that only the of ERK1 and in the that ERK1 and were in a sustained in the presence of cycloheximide 1 with a that only and that cycloheximide did not or LPA-stimulated MEK activation under these conditions 1 These results that cycloheximide effect the level of ERK, not MEK, by the of ERK1 and Since these for we were in were in response to growth in these cells. the expression of MKP-1 in response to LPA, EGF, and in Rat-1 cells by cell with an to the of human Biol. Full Text Full Text PDF PubMed Scopus Google MKP-1 and Biol. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, 1995; Google but not M. R. M. Biol. 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Biol. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, Biol. 1994; Full Text PDF PubMed Google or J.E. 1995; PubMed Scopus Google other of the of we the that may also to the of ERK activity in these cells. additional for MKP-1 or a phosphatase a in the sustained phase of ERK1 we the effect of sodium an inhibitor of MKP-1 PubMed Scopus Google of Rat-1 cells with sodium orthovanadate in activation of ERK1 in a and ERK1 activation by sodium orthovanadate an of and was that observed with LPA, In of sodium orthovanadate in ERK1 activation to a as that seen with to the effect of sodium orthovanadate on growth factor-stimulated ERK1 we used to Rat-1 cells to the of In the presence of sodium we were to a potentiation of the sustained phase of ERK1 activation in response to as seen with cycloheximide the magnitude of LPA-stimulated ERK activity, as a of the response was in cells but in sodium the the and was Activation of ERK1 by this of orthovanadate was and and was therefore that the potentiation seen with sodium orthovanadate was results were when we the effect of sodium orthovanadate on the EGF and and the of sodium orthovanadate used did not LPA-stimulated expression of MKP-1 the potentiation we observed was not to of protein these results is that the magnitude of sustained ERK1 activity in Rat-1 cells is by expression of a growth to signaling pathways responsible for MKP-1 expression in response to the ERK is a and EGF signaling pathways that may be regulate gene expression. Pretreatment of Rat-1 cells with the MEK inhibitor PD98059 Biol. 1995; Full Text Full Text PDF PubMed Scopus Google in a of LPA- or ERK activation such that ERK activity was by or PD98059 Pretreatment of Rat-1 cells with PD98059 in of of LPA- and MKP-1 suggesting that MKP-1 is activation of the we not of LPA- or MKP-1 expression by PD98059 ERK1 was suggesting that additional pathways also used by and EGF to regulate MKP-1 expression. is by the that in the MKP-1 expression was by PD98059 and of PKC little in growth factor-stimulated MKP-1 expression in Rat-1 cells. of Rat-1 cells were in the presence of 1 or for were stimulated for 1 with EGF or Rat-1 cells were with PD98059 for with or for 1 cell were by and for MKP-1 expression with as under In Rat-1 cells, ERK1 by a major and sustained is by a pertussis protein and and a and may PKC and PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, Biol. 1994; Full Text PDF PubMed Google Scholar, R. 1994; PubMed Scopus Google Pretreatment of Rat-1 cells with pertussis of LPA-stimulated MKP-1 the pertussis of peak ERK1 activation and of the sustained response PubMed Scopus Google These results with the PD98059 with a pathway of ERK1 activation a in MKP-1 expression by we not the that the for MKP-1 expression was of that for ERK activation. this we Rat-1 cells expressing Activation of in Rat-1 cells results in a sustained in ERK1 activity of magnitude to that observed with the peak of the response is by results observed in cells expressing we observed activation of ERK1 to the as that with LPA, of ΔRaf-1:ER in a in MKP-1 expression with that observed with or when stimulated for to that sustained activation of the ERK may be necessary but is not sufficient to induce of cells with pertussis LPA-stimulated MKP-1 expression activation of ΔRaf-1:ER with the effect of pertussis on MKP-1 expression that the response to was fully these ΔRaf-1:ER activation little MKP-1 but fully for the of or signal pathways, was or These results suggest that of the pathways by in Rat-1 cells, the ERK is sufficient to for and synergize with LPA-stimulated signals to reconstitute MKP-1 expression. 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Full Text Full Text PDF PubMed Scopus Google and suggest that the major signal by that MKP-1 in with is with little for of the an to the of MKP-1 expression, of ERK activation. we observed results when was for Since is to the of the without the these results that the synergy ΔRaf-1:ER and PMA, ionomycin, or okadaic acid is to of the kinase and activation of the ERK magnitude and of ERK activation to be a in cell signaling C.J. Cell. 1995; 80: 179-185Abstract Full Text PDF PubMed Scopus (4213) Google Scholar, PubMed Scopus Google Scholar, Biol. Full Text PDF PubMed Google Scholar, PubMed Scopus Google Scholar, C.J. Curr. Biol. 1994; Full Text Full Text PDF PubMed Scopus Google the and R. Curr. Opin. 1994; PubMed Scopus Google Scholar, R. 1994; PubMed Scopus Google of the is by such as in response to and These to a for of ERK activity in activation and of ERK results in expression of in ERK Curr. 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PubMed Scopus Google Scholar, D. 1994; Google as as of these signals the response is also MEK/ERK and we a synergy ΔRaf-1:ER and is important to that under these conditions we not synergy for ERK suggesting that the signals not to the ERK of and PKC signals is by the that of but not of PKC MKP-1 expression by growth and the synergy ΔRaf-1:ER and signals in pertussis cells. that is the major signal by for regulating MKP-1 expression. this in the of expression of MKP-1 Rat-1 cells and cells Biol. Full Text Full Text PDF PubMed Scopus Google the of was not in cells, was that of PKC MKP-1 expression, results and PKC suggest little for PKC in the to growth Biol. Full Text Full Text PDF PubMed Scopus Google and this for the pathway and other signals by pathways for MKP-1 expression the that MKP-1 may be the for ERK-independent One such is the that buffering to MKP-1 expression sustained ERK activity. may that strong by the pathway ERK in a Biol. 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