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The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways

Author

Listed:
  • Kimberly L. Dodge-Kafka

    (Howard Hughes Medical Institute, Vollum Institute
    University of Connecticut Health Center)

  • Joseph Soughayer

    (Howard Hughes Medical Institute, Vollum Institute)

  • Genevieve C. Pare

    (Oregon Health and Sciences University)

  • Jennifer J. Carlisle Michel

    (Howard Hughes Medical Institute, Vollum Institute)

  • Lorene K. Langeberg

    (Howard Hughes Medical Institute, Vollum Institute)

  • Michael S. Kapiloff

    (Oregon Health and Sciences University)

  • John D. Scott

    (Howard Hughes Medical Institute, Vollum Institute)

Abstract

Cyclic adenosine 3′, 5′-monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP-dependent protein kinases (PKAs)1,2 but also activates certain ion channels and guanine nucleotide exchange factors (Epacs)3. Metabolism of cAMP is catalysed by phosphodiesterases (PDEs)4,5. Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated.

Suggested Citation

  • Kimberly L. Dodge-Kafka & Joseph Soughayer & Genevieve C. Pare & Jennifer J. Carlisle Michel & Lorene K. Langeberg & Michael S. Kapiloff & John D. Scott, 2005. "The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways," Nature, Nature, vol. 437(7058), pages 574-578, September.
    • Handle: RePEc:nat:nature:v:437:y:2005:i:7058:d:10.1038_nature03966
    DOI: 10.1038/nature03966
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    Cited by:

    1. Jason W Locasale & Arup K Chakraborty, 2008. "Regulation of Signal Duration and the Statistical Dynamics of Kinase Activation by Scaffold Proteins," PLOS Computational Biology, Public Library of Science, vol. 4(6), pages 1-12, June.
    2. 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.
    3. Julian Brands & Sergi Bravo & Lars Jürgenliemke & Lukas Grätz & Hannes Schihada & Fabian Frechen & Judith Alenfelder & Cy Pfeil & Paul Georg Ohse & Suzune Hiratsuka & Kouki Kawakami & Luna C. Schmacke, 2024. "A molecular mechanism to diversify Ca2+ signaling downstream of Gs protein-coupled receptors," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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