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Research ArticleCELLULAR AND MOLECULAR

A Novel cAMP-Stimulated Pathway in Protein Phosphatase 2A Activation

Marina S. Feschenko, Elizabeth Stevenson, Angus C. Nairn and Kathleen J. Sweadner
Journal of Pharmacology and Experimental Therapeutics July 2002, 302 (1) 111-118; DOI: https://doi.org/10.1124/jpet.302.1.111
Marina S. Feschenko
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Elizabeth Stevenson
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Angus C. Nairn
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Kathleen J. Sweadner
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Abstract

Elevated cAMP in NRK-52E and L6 cells causes a marked reduction in the phosphorylation of numerous phosphoproteins, as detected initially with phosphoserine-specific antibodies. Here, we show that elevation of cAMP in NRK cells by forskolin/3-isobutyl-1-methylxanthine (IBMX) treatment decreased phosphorylation of substrates for different protein kinases, pointing to a common protein phosphatase as a target for cAMP-dependent regulation. Forskolin/IBMX treatment completely dephosphorylated a selective protein phosphatase 2A (PP2A) substrate, elongation factor-2 (EF-2), at its Ca2+ calmodulin-dependent kinase site, and decreased phosphorylation of substrates for cyclin-dependent kinases, including retinoblastoma (Rb) protein. As reported before, forskolin/IBMX also decreased phosphorylation of a protein kinase C substrate, the Na,K-ATPase. The cAMP-stimulated dephosphorylation was blocked by the protein phosphatases 1 (PP1) and PP2A inhibitor okadaic acid at concentrations selective for PP2A but was not blocked by tautomycin at concentrations selective for PP1. The data implicate PP2A as a cAMP-activated phosphatase. Contrary to expectation, we found evidence that cAMP-dependent activation of PP2A did not depend on protein kinase A (PKA). Pretreatment of cells with the PKA inhibitor H89 abolished PKA activity measured in cell extracts and significantly decreased cAMP-activated phosphorylation of a known PKA substrate, ARPP-19, in cells, but failed to block the cAMP-stimulated dephosphorylation of EF-2, Rb, and other proteins. This novel pathway of PP2A activation, acting on the time scale of minutes, represents yet another example of a cAMP-mediated, PKA-independent signaling mechanism. Because PP2A is active toward a variety of endogenous substrates, cAMP-stimulated dephosphorylation may have complicated the interpretation of many prior studies.

Footnotes

  • This work was supported by National Institutes of Health Grant NS27653 (to K.J.S.), by American Cancer Association Grant IRG-173-J (to M.S.F.), and by National Institutes of Health Grant GM50402 (to A.C.N.).

  • Abbreviations:
    PKA
    cAMP-dependent protein kinase
    PKC
    protein kinase C
    PP1 and PP2A
    protein phosphatases 1 and 2A
    cdk
    cyclin-dependent kinase
    EF-2
    elongation factor 2
    Rb
    retinoblastoma protein
    IBMX
    3-isobutyl-1-methylxanthine
    DMEM
    Dulbecco's modified Eagle's medium
    cAMP-GEF
    cyclic nucleotide-regulated guanine exchange factors
    • Received January 28, 2002.
    • Accepted March 25, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 1
1 Jul 2002
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Research ArticleCELLULAR AND MOLECULAR

A Novel cAMP-Stimulated Pathway in Protein Phosphatase 2A Activation

Marina S. Feschenko, Elizabeth Stevenson, Angus C. Nairn and Kathleen J. Sweadner
Journal of Pharmacology and Experimental Therapeutics July 1, 2002, 302 (1) 111-118; DOI: https://doi.org/10.1124/jpet.302.1.111

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Research ArticleCELLULAR AND MOLECULAR

A Novel cAMP-Stimulated Pathway in Protein Phosphatase 2A Activation

Marina S. Feschenko, Elizabeth Stevenson, Angus C. Nairn and Kathleen J. Sweadner
Journal of Pharmacology and Experimental Therapeutics July 1, 2002, 302 (1) 111-118; DOI: https://doi.org/10.1124/jpet.302.1.111
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