The frequencies of calcium oscillations are optimized for efficient calcium-mediated activation of Ras and the ERK/MAPK cascade.
Ras proteins are binary switches that, by cycling through inactive GDP- and active GTP-bound conformations, regulate multiple cellular signaling pathways, including those that control growth and differentiation. For some time, it has been known that receptor-mediated increases in the concentration of intracellular free calcium ([Ca(2+)](i)) can modulate Ras activation. Increases in [Ca(2+)](i) often occur as repetitive Ca(2+) spikes or oscillations. Induced by electrical or receptor stimuli, these repetitive Ca(2+) oscillations increase in frequency with the amplitude of receptor stimuli, a phenomenon critical for the induction of selective cellular functions. Here, we show that Ca(2+) oscillations are optimized for Ca(2+)-mediated activation of Ras and signaling through the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade. We present additional evidence that Ca(2+) oscillations reduce the effective Ca(2+) threshold for the activation of Ras and that the oscillatory frequency is optimized for activation of Ras and the ERK/MAPK pathway. Our results describe a hitherto unrecognized link between complex Ca(2+) signals and the modulation of the Ras/ERK/MAPK signaling cascade.
Kupzig
Sabine
S
Henry Wellcome Integrated Signalling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Walker
Simon A
SA
Cullen
Peter J
PJ
D001562:Benzimidazoles / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005982:Glutathione Transferase; D006367:HeLa Cells; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D053644:Naphthalimides; D009570:Nitriles / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D020663:ras Guanine Nucleotide Exchange Factors / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*; D000096926:Benzenesulfonamides
D001562:Benzimidazoles; D001596:Benzylamines; D002070:Butadienes; D002118:Calcium; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D005982:Glutathione Transferase; D007546:Isoquinolines; D053644:Naphthalimides; D009570:Nitriles; D017346:Protein Serine-Threonine Kinases; D013449:Sulfonamides; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins; C425780:KN 92; C458525:STO 609; C113580:U 0126; C072105:KN 93; D000096926:Benzenesulfonamides