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Research ArticleCELLULAR AND MOLECULAR

Extracellular Signal-Regulated Kinases and G Protein-Coupled Receptors in Megakaryocytic Human Erythroleukemia Cells: Selective Activation, Differential Regulation, and Dissociation from Mitogenesis

Hung Wu, Huang-Wei Shen, Tin-Feng Wu, Lawrence F. Brass and Kuo-Chun Sung
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 339-345; DOI: https://doi.org/10.1124/jpet.300.1.339
Hung Wu
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Huang-Wei Shen
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Tin-Feng Wu
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Lawrence F. Brass
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Kuo-Chun Sung
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Abstract

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are a group of kinases that play an important role in proliferation and differentiation. In megakaryocyte-like human erythroleukemia (HEL) cells, ERK2 was found to be predominantly expressed and strongly activated by prostaglandin (PG) E2, thrombin, and epinephrine. On the other hand, adenosine, ADP, ATP, and UTP did not significantly increase ERK1/2 phosphorylation. However, of the agonists tested, only ADP was able to stimulate thymidine uptake. Pretreatment with pertussis toxin abolished the PGE2 response but had less of an effect on thrombin. PGE2- and thrombin-induced ERK1/2 activation was mimicked by 4-β-phorbol-12-myristate-13-acetate and ionomycin and blocked by mitogen-activated protein kinase kinase inhibitor 1,4 diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene but displayed differential sensitivity to protein kinase C inhibitor bisindolylmaleimide I and Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid. Analogs of cAMP or agents that stimulate cAMP production were either weak or ineffective activators. Further studies indicate that the effect of thrombin was blocked by the phosphoinositide 3-kinase inhibitor wortmannin but not by agents inhibiting tyrosine kinase activity. On the contrary, herbimycin, but not wortmannin, attenuated the effect of PGE2. Collectively, these results indicate that ERK1/2 are selectively activated by G protein-coupled receptors and not functionally associated with proliferation in HEL cells. ERK1/2 activation in response to PGE2 and thrombin is mediated by distinctive types of G proteins and is differentially regulated by multiple pathways, including calcium mobilization, protein kinase C, phosphoinositide 3-kinase, and tyrosine kinases.

Footnotes

  • This work was supported in part by a grant from the National Science Council in Taiwan (NSC-86-2314-B-041-010). Portions of this work have been reported in abstract form (Southeast Asian-Western Pacific Regional Meeting of Pharmacologists, Nov 1–5, 1999).

  • Abbreviations

    ERK
    extracellular signal-regulated kinases
    MAPK
    mitogen-activated protein kinase
    HEL
    erythroleukemia
    BAPTA/AM
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid/acetoxymethyl ester
    U0126
    1,4 diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene
    PG
    prostaglandin
    ANOVA
    analysis of variance
    PMA
    4-β-phorbol-12-myristate-13-acetate
    [Ca2+]i
    cytosolic free Ca2+concentration
    PI 3-kinase
    phosphoinositide 3-kinase
    MEK
    mitogen-activated protein kinase kinase
    • Received June 21, 2001.
    • Accepted October 17, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
    Vol. 300, Issue 1
    1 Jan 2002
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    Research ArticleCELLULAR AND MOLECULAR

    Extracellular Signal-Regulated Kinases and G Protein-Coupled Receptors in Megakaryocytic Human Erythroleukemia Cells: Selective Activation, Differential Regulation, and Dissociation from Mitogenesis

    Hung Wu, Huang-Wei Shen, Tin-Feng Wu, Lawrence F. Brass and Kuo-Chun Sung
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 339-345; DOI: https://doi.org/10.1124/jpet.300.1.339

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    Research ArticleCELLULAR AND MOLECULAR

    Extracellular Signal-Regulated Kinases and G Protein-Coupled Receptors in Megakaryocytic Human Erythroleukemia Cells: Selective Activation, Differential Regulation, and Dissociation from Mitogenesis

    Hung Wu, Huang-Wei Shen, Tin-Feng Wu, Lawrence F. Brass and Kuo-Chun Sung
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 339-345; DOI: https://doi.org/10.1124/jpet.300.1.339
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