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Article

  • The EMBO Journal (2004) 23, 1749 - 1760
  • doi:10.1038/sj.emboj.7600197

Published online: 1 April 2004

Identification of a Ras GTPase-activating protein regulated by receptor-mediated Ca2+ oscillations

Simon A Walker1, Sabine Kupzig1, Dalila Bouyoucef1, Louise C Davies1, Takashi Tsuboi2, Trever G Bivona3, Gyles E Cozier1, Peter J Lockyer4, Alan Buckler5, Guy A Rutter2, Maxine J Allen6, Mark R Philips3 and Peter J Cullen1

  1. Inositide Group, Henry Wellcome Integrated Signalling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, UK
  2. Henry Wellcome Integrated Signalling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, UK
  3. Department of Medicine, Cell Biology and Pharmacology, New York University School of Medicine, New York, NY, USA
  4. Signalling Programme, The Babraham Institute, Babraham, Cambridge, UK
  5. Ardais Corporation, One Ledgemont Center, Lexington, MA, USA
  6. Oxagen Limited, Abingdon, Oxford, UK

Correspondence to:

Peter J Cullen, Inositide Group, Henry Wellcome Integrated Signalling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK. Tel.: +44 117 954 6426; Fax: +44 117 928 8274; E-mail: Pete.Cullen@bris.ac.uk

Received 20 January 2004; Accepted 5 March 2004

Receptor-mediated increases in the concentration of intracellular free calcium ([Ca2+]i) are responsible for controlling a plethora of physiological processes including gene expression, secretion, contraction, proliferation, neural signalling, and learning. Increases in [Ca2+]i often occur as repetitive Ca2+ spikes or oscillations. Induced by electrical or receptor stimuli, these repetitive Ca2+ spikes increase their frequency with the amplitude of the receptor stimuli, a phenomenon that appears critical for the induction of selective cellular functions. Here we report the characterisation of RASAL, a Ras GTPase-activating protein that senses the frequency of repetitive Ca2+ spikes by undergoing synchronous oscillatory associations with the plasma membrane. Importantly, we show that only during periods of plasma membrane association does RASAL inactivate Ras signalling. Thus, RASAL senses the frequency of complex Ca2+ signals, decoding them through a regulation of the activation state of Ras. Our data provide a hitherto unrecognised link between complex Ca2+ signals and the regulation of Ras.

  • Keywords:

    • calcium,
    • CAPRI,
    • oscillations,
    • Ras,
    • RASAL