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Cyclic AMP activates Ras

Oncogene volume 19, pages 3609–3615 (2000)Cite this article

Abstract

In addition to protein kinase A (PKA), cAMP regulates the activity of cAMP-gated channels and Rap1-specific guanine nucleotide exchange factors. We tested the hypothesis that the targets of cAMP might also include regulators of the Ras protooncogene. In rat thyroid cells, thyrotropin (TSH) stimulates proliferation through a cAMP-mediated pathway that requires Ras activity. Interference with Ras impairs DNA synthesis stimulated by TSH as well as cAMP elevating agents and analogs, demonstrating that the requirement for Ras lies downstream of cAMP. Although cAMP stimulates proliferation, microinjection of the purified PKA catalytic subunit failed to do so, suggesting that factors in addition to PKA are required for cAMP-stimulated cell cycle progression. When added to thyroid cells expressing human Ha-Ras, TSH rapidly and markedly increased the proportion of GTP-bound Ras. Ras activity was increased within 1 min of TSH addition, maximal at 5–15 min, and declined to basal levels 30–60 min after hormone treatment. Cyclic AMP elevating agents elicited similar effects on Ras, indicating that TSH activates Ras through a cAMP-mediated pathway. Although cAMP-mediated, Ras activation by TSH and cAMP was independent of PKA activity. Moreover, cAMP-stimulated Ras activation was not impaired by tyrosine kinase inhibitors. These results indicate that cAMP activates targets in addition to PKA in thyroid cells, and that these targets may include regulators of Ras. The ability of cAMP elevating agents to activate Ras in addition to PKA may explain the inability of the PKA catalytic subunit to stimulate DNA synthesis in thyroid cells.

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Acknowledgements

Since submission of this manuscript, a cAMP regulated Ras GEF was described (N. Pham, 2000, Curr Biol: 10, 555). We are grateful for helpful suggestions from Dr Margaret Chou regarding the Ras activation assay and from Lisa Cass regarding preparation of this manuscript. This work was supported by PHS grants DK45696 and DK02494 awarded to JL Meinkoth.

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Author notes

  1. Erik Kupperman

    Present address: Department of Biochemistry and Biophysics, University of California, San Francisco, 94143-0448, San Francisco, CA, USA

  2. Wei Wen

    Present address: Department of Surgery, Harvard Medical School, Boston, 02115, MA, USA

Authors and Affiliations

  1. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, 19104-6084, Pennsylvania, PA, USA

    Oxana M Tsygankova, Erik Kupperman, Wei Wen & Judy L Meinkoth

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  1. Oxana M Tsygankova
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  2. Erik Kupperman
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  4. Judy L Meinkoth
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Tsygankova, O., Kupperman, E., Wen, W. et al. Cyclic AMP activates Ras. Oncogene 19, 3609–3615 (2000). https://doi.org/10.1038/sj.onc.1203680

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