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Protein Kinase A and B-Raf Mediate Extracellular Signal-Regulated Kinase Activation by Thyrotropin

Lisa A. Vuchak, Oxana M. Tsygankova, Gregory V. Prendergast and Judy L. Meinkoth
Molecular Pharmacology November 2009, 76 (5) 1123-1129; DOI: https://doi.org/10.1124/mol.109.060129
Lisa A. Vuchak
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Oxana M. Tsygankova
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Gregory V. Prendergast
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Judy L. Meinkoth
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Abstract

Thyrotropin (TSH) regulates thyroid cell proliferation and function through cAMP-mediated signaling pathways that activate protein kinase A (PKA) and Epac/Rap1. The respective roles of PKA versus Epac/Rap1 in TSH signaling remain unclear. We set out to determine whether PKA and/or Rap1 mediate extracellular signal-regulated kinase (ERK) activation by TSH. Neither blocking Rap1 activity nor silencing the expression of Rap1 impaired TSH or forskolin-induced ERK activation in Wistar rat thyroid cells. Direct activation of Epac1 failed to stimulate ERK activity in starved cells, suggesting that Epac-induced Rap1 activity is not coupled to ERK activation in rat thyroid cells. By contrast, PKA activity was required for cAMP-stimulated ERK phosphorylation and was sufficient to increase ERK phosphorylation in starved cells. Expression of dominant-negative Ras inhibited ERK activation by TSH, forskolin, and N6-monobutyryl (6MB)-cAMP, a selective activator of PKA. Silencing the expression of B-Raf also inhibited ERK activation by TSH, forskolin, and 6MB-cAMP, but not that stimulated by insulin or serum. Depletion of B-Raf impaired TSH-induced DNA synthesis, indicating a functional role for B-Raf in TSH-regulated proliferation. Collectively, these results position PKA, Ras, and B-Raf as upstream regulators of ERK activation and identify B-Raf as a selective target of cAMP-elevating agents in thyroid cells. These data provide the first evidence for a functional role for B-Raf in TSH signaling.

  • TSH, thyrotropin
  • EcAMP, 8-(4-chlorophenylthio)-2′-O-methyl-cAMP
  • Epac, exchange protein activated by cAMP
  • ERK, extracellular signal-regulated kinase
  • PKA, protein kinase A
  • PKI, heat-stable protein kinase A inhibitor
  • WRT, Wistar rat thyroid
  • 6MB-cAMP, N6-monobutyryl-cAMP
  • WRT, Wistar rat thyroid
  • MEK, mitogen-activated protein kinase kinase
  • HA, hemagglutinin
  • siRNA, short interfering RNA
  • U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK55757] and the National Institutes of Health National Cancer Institute Cancer Education and Career Development Program, Training Program in Cancer Pharmacology [Grant 5R25-CA101871].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.060129

  • ABBREVIATIONS:

  • ↵1 Current affiliation: Trait Discovery-Insect Control DuPont Experimental Station, Wilmington, Delaware.

    • Received August 7, 2009.
    • Accepted August 31, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (5)
Molecular Pharmacology
Vol. 76, Issue 5
November 2009
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Protein Kinase A and B-Raf Mediate Extracellular Signal-Regulated Kinase Activation by Thyrotropin

Lisa A. Vuchak, Oxana M. Tsygankova, Gregory V. Prendergast and Judy L. Meinkoth
Molecular Pharmacology November 1, 2009, 76 (5) 1123-1129; DOI: https://doi.org/10.1124/mol.109.060129

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Protein Kinase A and B-Raf Mediate Extracellular Signal-Regulated Kinase Activation by Thyrotropin

Lisa A. Vuchak, Oxana M. Tsygankova, Gregory V. Prendergast and Judy L. Meinkoth
Molecular Pharmacology November 1, 2009, 76 (5) 1123-1129; DOI: https://doi.org/10.1124/mol.109.060129
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