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Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP

Author

Listed:
  • Johan de Rooij

    (Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht University)

  • Fried J. T. Zwartkruis

    (Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht University)

  • Mark H. G. Verheijen

    (Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht University
    Hubrecht Laboratory, Netherlands Institute for Developmental Biology)

  • Robbert H. Cool

    (Max Planck Institute für Moleculare Physiologie)

  • Sebastian M. B. Nijman

    (Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht University)

  • Alfred Wittinghofer

    (Max Planck Institute für Moleculare Physiologie)

  • Johannes L. Bos

    (Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht University)

Abstract

Rap1 is a small, Ras-like GTPase that was first identified as a protein that could suppress the oncogenic transformation of cells by Ras1. Rap1 is activated by several extracellular stimuli2,3,4,5,6,7 and may be involved in cellular processes such as cell proliferation8, cell differentiation4, T-cell anergy2 and platelet activation7. At least three different second messengers, namely diacylglycerol, calcium and cyclic AMP5,6,7,8,9 are able to activate Rap1 by promoting its release of the guanine nucleotide GDP and its binding to GTP. Here we report that activation of Rap1 by forskolin and cAMP occurs independently of protein kinase A (also known as cAMP-activated protein kinase). We have cloned the gene encoding a guanine-nucleotide-exchange factor (GEF) which we have named Epac (exchange protein directly activated by cAMP). This protein contains a cAMP-binding site and a domain that is homologous to domains of known GEFs for Ras and Rap1. Epac binds cAMP in vitro and exhibits in vivo and in vitro GEF activity towards Rap1. cAMP strongly induces the GEF activity of Epac towards Rap1 both in vivo and in vitro. We conclude that Epac is a GEF for Rap1 that is regulated directly by cAMP and that Epac is a new target protein for cAMP.

Suggested Citation

  • Johan de Rooij & Fried J. T. Zwartkruis & Mark H. G. Verheijen & Robbert H. Cool & Sebastian M. B. Nijman & Alfred Wittinghofer & Johannes L. Bos, 1998. "Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP," Nature, Nature, vol. 396(6710), pages 474-477, December.
    • Handle: RePEc:nat:nature:v:396:y:1998:i:6710:d:10.1038_24884
    DOI: 10.1038/24884
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    Cited by:

    1. Reidun Aesoy & Haruna Muwonge & Kathrine S Asrud & Misbah Sabir & Solveig L Witsoe & Ronja Bjornstad & Reidun K Kopperud & Erling A Hoivik & Stein Ove Doskeland & Marit Bakke, 2018. "Deletion of exchange proteins directly activated by cAMP (Epac) causes defects in hippocampal signaling in female mice," PLOS ONE, Public Library of Science, vol. 13(7), pages 1-25, July.
    2. Alaullah Sheikh & Brunda Tumala & Tim J. Vickers & John C. Martin & Bruce A. Rosa & Subrata Sabui & Supratim Basu & Rita D. Simoes & Makedonka Mitreva & Chad Storer & Erik Tyksen & Richard D. Head & W, 2022. "Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Willem-Jan Pannekoek & Jelena R Linnemann & Patricia M Brouwer & Johannes L Bos & Holger Rehmann, 2013. "Rap1 and Rap2 Antagonistically Control Endothelial Barrier Resistance," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-10, February.
    4. Candice Sartre & François Peurois & Marie Ley & Marie-Hélène Kryszke & Wenhua Zhang & Delphine Courilleau & Rodolphe Fischmeister & Yves Ambroise & Mahel Zeghouf & Sarah Cianferani & Yann Ferrandez & , 2023. "Membranes prime the RapGEF EPAC1 to transduce cAMP signaling," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Liliana Felicia Iannucci & Anna Maria D’Erchia & Ernesto Picardi & Daniela Bettio & Filippo Conca & Nicoletta Concetta Surdo & Giulietta Benedetto & Deborah Musso & Cristina Arrigoni & Marco Lolicato , 2023. "Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Chih-Hao Wang & Tadataka Tsuji & Li-Hong Wu & Cheng-Ying Yang & Tian Lian Huang & Mari Sato & Farnaz Shamsi & Yu-Hua Tseng, 2024. "Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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