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.

[1]  S. Walker,et al.  Visualizing Ras signalling in real-time , 2004, Journal of Cell Science.

[2]  Guy A Rutter,et al.  Identification of a Ras GTPase‐activating protein regulated by receptor‐mediated Ca2+ oscillations , 2004, The EMBO journal.

[3]  R. Huganir,et al.  MAPK cascade signalling and synaptic plasticity , 2004, Nature Reviews Neuroscience.

[4]  D. Matallanas,et al.  Activation of H-Ras in the Endoplasmic Reticulum by the RasGRF Family Guanine Nucleotide Exchange Factors , 2004, Molecular and Cellular Biology.

[5]  Geneviève Dupont,et al.  Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations: a simple model. , 2003, Cell calcium.

[6]  P. Cullen,et al.  The Ras binary switch: an ideal processor for decoding complex Ca2+ signals? , 2003, Biochemical Society transactions.

[7]  Peter J. Cullen,et al.  Phospholipase Cγ activates Ras on the Golgi apparatus by means of RasGRP1 , 2003, Nature.

[8]  Taichiro Tomida,et al.  NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation , 2003, The EMBO journal.

[9]  M. Berridge,et al.  Calcium signalling: dynamics, homeostasis and remodelling , 2003, Nature reviews. Molecular cell biology.

[10]  Roger Y. Tsien,et al.  A genetically encoded fluorescent reporter reveals oscillatory phosphorylation by protein kinase C , 2003, The Journal of cell biology.

[11]  A. Muscella,et al.  Activation of P2Y2 receptor induces c‐FOS protein through a pathway involving mitogen‐activated protein kinases and phosphoinositide 3‐kinases in HeLa cells , 2003, Journal of cellular physiology.

[12]  J. Hancock,et al.  Ras proteins: different signals from different locations , 2003, Nature Reviews Molecular Cell Biology.

[13]  T. Bivona,et al.  Ras pathway signaling on endomembranes. , 2003, Current opinion in cell biology.

[14]  O. Petersen,et al.  Decoding of Short-lived Ca2+ Influx Signals into Long Term Substrate Phosphorylation through Activation of Two Distinct Classes of Protein Kinase C* 210 , 2003, The Journal of Biological Chemistry.

[15]  M. Matsuda,et al.  Mechanism of the spatio‐temporal regulation of Ras and Rap1 , 2003, The EMBO journal.

[16]  S. Ferguson,et al.  Protein Kinase C Isoform-specific Differences in the Spatial-Temporal Regulation and Decoding of Metabotropic Glutamate Receptor1a-stimulated Second Messenger Responses* , 2003, The Journal of Biological Chemistry.

[17]  J. Rostas,et al.  Histamine activates tyrosine hydroxylase in bovine adrenal chromaffin cells through a pathway that involves ERK1/2 but not p38 or JNK , 2003, Journal of neurochemistry.

[18]  D. Tuveson,et al.  Ras redux: rethinking how and where Ras acts. , 2003, Current opinion in genetics & development.

[19]  J. Downward Targeting RAS signalling pathways in cancer therapy , 2003, Nature Reviews Cancer.

[20]  P. Cullen,et al.  Analyzing the Role of the Putative Inositol 1,3,4,5-Tetrakisphosphate Receptor GAP1IP4BP in Intracellular Ca2+ Homeostasis* , 2002, The Journal of Biological Chemistry.

[21]  G. Rutter,et al.  Dynamics of Glucose-induced Membrane Recruitment of Protein Kinase C βII in Living Pancreatic Islet β-Cells* 210 , 2002, The Journal of Biological Chemistry.

[22]  H. Tokumitsu,et al.  STO-609, a Specific Inhibitor of the Ca2+/Calmodulin-dependent Protein Kinase Kinase* , 2002, The Journal of Biological Chemistry.

[23]  J. B. Sajous,et al.  Ras signalling on the endoplasmic reticulum and the Golgi , 2002, Nature Cell Biology.

[24]  Peter J. Cullen,et al.  Integration of calcium and RAS signalling , 2002, Nature Reviews Molecular Cell Biology.

[25]  A. Miyawaki,et al.  Spatio-temporal images of growth-factor-induced activation of Ras and Rap1 , 2001, Nature.

[26]  M. Berridge,et al.  The organisation and functions of local Ca(2+) signals. , 2001, Journal of cell science.

[27]  P. Tompa,et al.  Frequency decoding of fast calcium oscillations by calpain. , 2001, Cell calcium.

[28]  P. Blumberg,et al.  Phorbol esters modulate the Ras exchange factor RasGRP3. , 2001, Cancer research.

[29]  N. Hayward,et al.  Characterization of RasGRP2, a Plasma Membrane-targeted, Dual Specificity Ras/Rap Exchange Factor* , 2000, The Journal of Biological Chemistry.

[30]  M. Berridge,et al.  The versatility and universality of calcium signalling , 2000, Nature Reviews Molecular Cell Biology.

[31]  M. Matsuda,et al.  CalDAG-GEFIII Activation of Ras, R-Ras, and Rap1* , 2000, The Journal of Biological Chemistry.

[32]  M. Matsuda,et al.  Regulatory Proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3* , 2000, The Journal of Biological Chemistry.

[33]  O. Gerasimenko,et al.  Hormone-induced secretory and nuclear translocation of calmodulin: oscillations of calmodulin concentration with the nucleus as an integrator. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[34]  C. Der,et al.  Regulation of RasGRP via a Phorbol Ester-Responsive C1 Domain , 1998, Molecular and Cellular Biology.

[35]  Tobias Meyer,et al.  Protein Kinase C as a Molecular Machine for Decoding Calcium and Diacylglycerol Signals , 1998, Cell.

[36]  A. Graybiel,et al.  A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[37]  F. Hobbs,et al.  Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase* , 1998, The Journal of Biological Chemistry.

[38]  J. Stone,et al.  RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. , 1998, Science.

[39]  Roger Y. Tsien,et al.  Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression , 1998, Nature.

[40]  Keli Xu,et al.  Calcium oscillations increase the efficiency and specificity of gene expression , 1998, Nature.

[41]  P. De Koninck,et al.  Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. , 1998, Science.

[42]  M. Moran,et al.  Cloning and characterization of Ras-GRF2, a novel guanine nucleotide exchange factor for Ras , 1997, Molecular and cellular biology.

[43]  M. Berridge,et al.  Extracellular calcium concentration controls the frequency of intracellular calcium spiking independently of inositol 1,4,5-trisphosphate production in HeLa cells. , 1996, The Biochemical journal.

[44]  György Hajnóczky,et al.  Decoding of cytosolic calcium oscillations in the mitochondria , 1995, Cell.

[45]  Anirvan Ghosh,et al.  Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF , 1995, Nature.

[46]  M. Greenberg,et al.  Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras , 1994, Neuron.

[47]  B. Neel,et al.  Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21 , 1992, Nature.

[48]  E. Martegani,et al.  Cloning by functional complementation of a mouse cDNA encoding a homologue of CDC25, a Saccharomyces cerevisiae RAS activator. , 1992, The EMBO journal.

[49]  P. Cullen,et al.  Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[50]  H. Tokumitsu,et al.  KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II. , 1990, The Journal of biological chemistry.

[51]  P. Cobbold,et al.  Repetitive transient rises in cytoplasmic free calcium in hormone-stimulated hepatocytes , 1986, Nature.

[52]  M. Berridge,et al.  Transepithelial potential changes during stimulation of isolated salivary glands with 5-hydroxytryptamine and cyclic AMP. , 1972, The Journal of experimental biology.