Integration of calcium and RAS signalling

Calcium is a universal intracellular signal that is responsible for controlling a plethora of cellular processes. Understanding how such a simple ion can regulate so many diverse cellular processes is a key goal of calcium- and cell-biologists. One molecule that is sensitive to changes in intracellular calcium levels is Ras. This small GTPase operates as a binary molecular switch, and regulates cell proliferation and differentiation. Here, we focus on examining the link between calcium and Ras signalling and, in particular, we speculate as to how the complexity of calcium signalling could regulate Ras activity.

[1]  J. Bos,et al.  Calcium inhibits epidermal growth factor-induced activation of p21ras in human primary keratinocytes , 1994, Molecular and cellular biology.

[2]  H. Bading,et al.  A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication , 2001, Nature Neuroscience.

[3]  P. Parker,et al.  The extended protein kinase C superfamily. , 1998, The Biochemical journal.

[4]  T. Alber,et al.  The many faces of Ras: recognition of small GTP-binding proteins. , 2001, Trends in biochemical sciences.

[5]  G. Hajnóczky,et al.  Quasi‐synaptic calcium signal transmission between endoplasmic reticulum and mitochondria , 1999, The EMBO journal.

[6]  Y. Kaziro,et al.  Induction of Rac-Guanine Nucleotide Exchange Activity of Ras-GRF1/CDC25Mm following Phosphorylation by the Nonreceptor Tyrosine Kinase Src* , 2000, The Journal of Biological Chemistry.

[7]  Y. Kaziro,et al.  G protein bg subunit-dependent Rac-guanine nucleotide exchange activity of Ras-GRF1yCDC25 Mm (Dblyguanine nucleotide exchange factor) , 1999 .

[8]  D. Lowy,et al.  Ras-Specific Exchange Factor GRF: Oligomerization through Its Dbl Homology Domain and Calcium-Dependent Activation of Raf , 1999, Molecular and Cellular Biology.

[9]  R. Buchsbaum,et al.  The N-terminal pleckstrin, coiled-coil, and IQ domains of the exchange factor Ras-GRF act cooperatively to facilitate activation by calcium , 1996, Molecular and cellular biology.

[10]  K. Jakobs,et al.  A new phospholipase-C–calcium signalling pathway mediated by cyclic AMP and a Rap GTPase , 2001, Nature Cell Biology.

[11]  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.

[12]  M. Berridge Neuronal Calcium Signaling , 1998, Neuron.

[13]  M. Moran,et al.  Calmodulin-Independent Coordination of Ras and Extracellular Signal-Regulated Kinase Activation by Ras-GRF2 , 2000, Molecular and Cellular Biology.

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

[15]  J. Putney,et al.  Mechanisms of capacitative calcium entry. , 2001, Journal of cell science.

[16]  E. Jacquet,et al.  Sites of Phosphorylation by Protein Kinase A in CDC25Mm/GRF1, a Guanine Nucleotide Exchange Factor for Ras* , 2001, The Journal of Biological Chemistry.

[17]  L. Mahadevan,et al.  Transcription: MAPK-regulated transcription: a continuously variable gene switch? , 2002, Nature Reviews Molecular Cell Biology.

[18]  M. Lemmon,et al.  Signal-dependent membrane targeting by pleckstrin homology (PH) domains. , 2000, The Biochemical journal.

[19]  J. Bos,et al.  Ras and Rap1: two highly related small GTPases with distinct function. , 1999, Experimental cell research.

[20]  H. Hamm,et al.  A Novel Bifunctional Phospholipase C That Is Regulated by Gα12 and Stimulates the Ras/Mitogen-activated Protein Kinase Pathway* , 2001, The Journal of Biological Chemistry.

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

[22]  M. Kennedy,et al.  A Synaptic Ras-GTPase Activating Protein (p135 SynGAP) Inhibited by CaM Kinase II , 1998, Neuron.

[23]  A. Smrcka,et al.  Phospholipase Cϵ: a novel Ras effector , 2001 .

[24]  A. West,et al.  Calcium regulation of neuronal gene expression , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  P. Cullen Bridging the GAP in inositol 1,3,4,5-tetrakisphosphate signalling. , 1998, Biochimica et biophysica acta.

[26]  D. Cooper,et al.  Regulation of a Ca2+-sensitive Adenylyl Cyclase in an Excitable Cell , 2000, The Journal of Biological Chemistry.

[27]  A. Boynton,et al.  Different calcium requirements for proliferation of conditionally and unconditionally tumorigenic mouse cells. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[28]  T. Morimoto,et al.  Endomembrane Trafficking of Ras The CAAX Motif Targets Proteins to the ER and Golgi , 1999, Cell.

[29]  M. Caligiuri,et al.  RasGRP4 Is a Novel Ras Activator Isolated from Acute Myeloid Leukemia* , 2002, The Journal of Biological Chemistry.

[30]  P. Cullen Ras effectors: Buying shares in Ras plc , 2001, Current Biology.

[31]  R. Skidgel,et al.  Novel Mode of Action of Angiotensin I Converting Enzyme Inhibitors , 2002, The Journal of Biological Chemistry.

[32]  M. Berridge,et al.  Calcium signalling and cell proliferation , 1995, BioEssays : news and reviews in molecular, cellular and developmental biology.

[33]  M. Brini,et al.  Monitoring dynamic changes in free Ca2+ concentration in the endoplasmic reticulum of intact cells. , 1995, The EMBO journal.

[34]  M. Berridge,et al.  Elementary and global aspects of calcium signalling. , 1997, The Journal of experimental biology.

[35]  Channing J Der,et al.  Increasing complexity of Ras signaling , 1998, Oncogene.

[36]  C. Der,et al.  Activation of Phospholipase C-ε by Heterotrimeric G Protein βγ-Subunits* , 2001, The Journal of Biological Chemistry.

[37]  S. Moss,et al.  The Ca2+-dependent lipid binding domain of P120GAP mediates protein-protein interactions with Ca2+-dependent membrane-binding proteins. Evidence for a direct interaction between annexin VI and P120GAP. , 1996, The Journal of biological chemistry.

[38]  S. Lev,et al.  A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation , 1996, Nature.

[39]  C. Der,et al.  The Ras branch of small GTPases: Ras family members don't fall far from the tree. , 2000, Current opinion in cell biology.

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

[41]  M. Berridge Elementary and global aspects of calcium signalling. , 1997, The Journal of physiology.

[42]  R. Dolmetsch,et al.  Signaling to the Nucleus by an L-type Calcium Channel-Calmodulin Complex Through the MAP Kinase Pathway , 2001, Science.

[43]  P. Cullen,et al.  CAPRI regulates Ca2+-dependent inactivation of the Ras-MAPK pathway , 2001, Current Biology.

[44]  M. Greenberg,et al.  Ca2+-Dependent Routes to Ras: Mechanisms for Neuronal Survival, Differentiation, and Plasticity? , 1996, Neuron.

[45]  H. Bading,et al.  CREB/CBP and SRE‐interacting transcriptional regulators are fast on–off switches: duration of calcium transients specifies the magnitude of transcriptional responses , 2001, Journal of neurochemistry.

[46]  R. Tsien,et al.  Fluorescent indicators for Ca2+based on green fluorescent proteins and calmodulin , 1997, Nature.

[47]  Rafael Yuste,et al.  From form to function: calcium compartmentalization in dendritic spines , 2000, Nature Neuroscience.

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

[49]  F. McCormick,et al.  Specific changes of Ras GTPase-activating protein (GAP) and a GAP-associated p62 protein during calcium-induced keratinocyte differentiation , 1992, Molecular and cellular biology.

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

[51]  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.

[52]  Peng Li,et al.  Identification of a mammalian gene structurally and functionally related to the CDC25 gene of Saccharomyces cerevisiae. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[53]  C. Der,et al.  Understanding Ras: 'it ain't over 'til it's over'. , 2000, Trends in cell biology.

[54]  P. Cullen,et al.  Inositol 1,3,4,5-tetrakisphosphate and Ca2+ homoeostasis: the role of GAP1IP4BP. , 1997, Biochemical Society transactions.

[55]  P. Cullen,et al.  GAP1IP4BP contains a novel group I pleckstrin homology domain that directs constitutive plasma membrane association. , 2000, The Journal of biological chemistry.

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

[57]  B. Weissman,et al.  Members of the src and ras oncogene families supplant the epidermal growth factor requirement of BALB/MK-2 keratinocytes and induce distinct alterations in their terminal differentiation program , 1985, Molecular and cellular biology.

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

[59]  L. Feig,et al.  Activation of the exchange factor Ras‐GRF by calcium requires an intact Dbl homology domain , 1997, FEBS letters.

[60]  K. Deisseroth,et al.  Activity-dependent CREB phosphorylation: Convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[61]  N. Marrion,et al.  Selective activation of Ca2+-activated K+ channels by co-localized Ca2+ channels in hippocampal neurons , 1998, Nature.

[62]  M. Moran,et al.  Mutation-deletion analysis of a Ca(2+)-dependent phospholipid binding (CaLB) domain within p120 GAP, a GTPase-activating protein for p21 ras. , 1995, The Biochemical journal.

[63]  Alcino J. Silva,et al.  Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1) , 2001, Neuropharmacology.

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

[65]  Peter J. Cullen,et al.  Identification of a specific lns(l,3,4,5)P4-binding protein as a member of the GAP1 family , 1995, Nature.

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

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

[68]  R. Seger,et al.  GRFβ, a Novel Regulator of Calcium Signaling, Is Expressed in Pancreatic Beta Cells and Brain* , 1999, The Journal of Biological Chemistry.

[69]  M. Moran,et al.  CaLB: a 43 amino acid calcium-dependent membrane/phospholipid binding domain in p120 Ras GTPase-activating protein. , 1995, Oncogene.

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

[71]  M. Barbacid,et al.  Differential response of the Ras exchange factor, Ras-GRF to tyrosine kinase and G protein mediated signals. , 1995, Oncogene.

[72]  Lawrence M. Lifshitz,et al.  Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. , 1998, Science.

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

[74]  E. Peles,et al.  Protein tyrosine kinase PYK2 involved in Ca2+-induced regulation of ion channel and MAP kinase functions , 1995, Nature.

[75]  J. D. Clark,et al.  Cytosolic phospholipase A2. , 1995, Journal of lipid mediators and cell signalling.

[76]  D. Gawler,et al.  Investigating the role played by protein-lipid and protein-protein interactions in the membrane association of the p120GAP CaLB domain. , 1999, Cellular signalling.

[77]  D. Matallanas,et al.  Maintenance of Cdc42 GDP-bound State by Rho-GDI Inhibits MAP Kinase Activation by the Exchange Factor Ras-GRF , 2001, The Journal of Biological Chemistry.

[78]  E. Neher,et al.  Linearized Buffered Ca2+ Diffusion in Microdomains and Its Implications for Calculation of [Ca2+] at the Mouth of a Calcium Channel , 1997, The Journal of Neuroscience.

[79]  A. C. Braun,et al.  Roles of calcium, serum, plasma, and folic acid in the control of proliferation of normal and Rous sarcoma virus-infected chicken fibroblasts. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

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

[81]  I. Macara,et al.  Phosphorylation-dependent activation of the Ras-GRF/CDC25Mm exchange factor by muscarinic receptors and G-protein βγ subunits , 1996, Nature.

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

[83]  Lubert Stryer,et al.  Dual role of calmodulin in autophosphorylation of multifunctional cam kinase may underlie decoding of calcium signals , 1994, Neuron.

[84]  R. Lefkowitz,et al.  Regulation of tyrosine kinase cascades by G-protein-coupled receptors. , 1999, Current opinion in cell biology.

[85]  H. Thoenen,et al.  The regulation of neuronal gene expression , 1982, Trends in Neurosciences.

[86]  S. Grant,et al.  Proteomic analysis of NMDA receptor–adhesion protein signaling complexes , 2000, Nature Neuroscience.

[87]  P. J. Cullen,et al.  Distinct subcellular localisations of the putative inositol 1,3,4,5-tetrakisphosphate receptors GAP1IP4BP and GAP1m result from the GAP1IP4BP PH domain directing plasma membrane targeting , 1997, Current Biology.

[88]  D. Cooper,et al.  Regulation of the Ca2+-inhibitable Adenylyl Cyclase Type VI by Capacitative Ca2+ Entry Requires Localization in Cholesterol-rich Domains* , 2000, The Journal of Biological Chemistry.

[89]  G. Carpenter,et al.  Role of basal calcium in the EGF activation of MAP kinases , 2000, Oncogene.

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

[91]  M. Moran,et al.  The exchange factor Ras-GRF2 activates Ras-dependent and Rac-dependent mitogen-activated protein kinase pathways , 1998, Current Biology.

[92]  Shin-Young Park,et al.  RAFTK/Pyk2-mediated cellular signalling. , 2000, Cellular signalling.

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

[94]  R. Mattingly Phosphorylation of Serine 916 of Ras-GRF1 Contributes to the Activation of Exchange Factor Activity by Muscarinic Receptors* , 1999, The Journal of Biological Chemistry.

[95]  J. Gutkind Regulation of Mitogen-Activated Protein Kinase Signaling Networks by G Protein-Coupled Receptors , 2000, Science's STKE.

[96]  S. Grant,et al.  A role for the Ras signalling pathway in synaptic transmission and long-term memory , 1997, Nature.

[97]  Christopher C. Goodnow,et al.  Differential activation of transcription factors induced by Ca2+ response amplitude and duration , 1997, Nature.

[98]  T. Kataoka,et al.  Regulation of a Novel Human Phospholipase C, PLCε, through Membrane Targeting by Ras* , 2001, The Journal of Biological Chemistry.

[99]  M. Villereal,et al.  Activation of MAP kinases by calcium-dependent and calcium-independent pathways. Stimulation by thapsigargin and epidermal growth factor. , 1992, The Journal of biological chemistry.

[100]  Lisa Junker It Ain't Over 'Til It's Over , 2001 .

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

[102]  B. Tocqué,et al.  Imprinted gene in postnatal growth role , 1998, Nature.