title: Identification of a Ras GTPase-activating protein regulated by receptor-mediated Ca2+ oscillations.
abstract: 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.
authors.affiliation: Inositide Group, Henry Wellcome Integrated Signalling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, UK.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Walker
authors.forename: Sabine
authors.initials: S
authors.lastname: Kupzig
authors.forename: Dalila
authors.initials: D
authors.lastname: Bouyoucef
authors.forename: Louise C
authors.initials: LC
authors.lastname: Davies
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuboi
authors.forename: Trever G
authors.initials: TG
authors.lastname: Bivona
authors.forename: Gyles E
authors.initials: GE
authors.lastname: Cozier
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lockyer
authors.forename: Alan
authors.initials: A
authors.lastname: Buckler
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.forename: Maxine J
authors.initials: MJ
authors.lastname: Allen
authors.forename: Mark R
authors.initials: MR
authors.lastname: Philips
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cullen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004594:Electrophysiology; D004789:Enzyme Activation; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D008969:Molecular Sequence Data; D010713:Phosphatidylcholines / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D016415:Sequence Alignment; D020703:ras GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D008081:Liposomes; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D034741:RNA, Small Interfering; D020703:ras GTPase-Activating Proteins; D018631:ras Proteins; D002118:Calcium