ras grf1


Summary: A guanine nucleotide exchange factor that is expressed primarily in neuronal tissue and may be specific for the Ha-ras homolog of the RAS PROTEINS.

Top Publications

  1. Dunphy W, Kumagai A. The cdc25 protein contains an intrinsic phosphatase activity. Cell. 1991;67:189-96 pubmed
    ..These observations indicate that the cdc25 protein can function as a tyrosine phosphatase in the absence of any other protein. ..
  2. Yoon B, Herman H, Sikora A, Smith L, Plass C, Soloway P. Regulation of DNA methylation of Rasgrf1. Nat Genet. 2002;30:92-6 pubmed
    ..In addition, DMD methylation is required for imprinted Rasgrf1 expression. Together the DMD and repeat element constitute a binary switch that regulates imprinting at the locus. ..
  3. van der Geer P, Henkemeyer M, Jacks T, Pawson T. Aberrant Ras regulation and reduced p190 tyrosine phosphorylation in cells lacking p120-Gap. Mol Cell Biol. 1997;17:1840-7 pubmed
  4. Baouz S, Jacquet E, Bernardi A, Parmeggiani A. The N-terminal moiety of CDC25(Mm), a GDP/GTP exchange factor of Ras proteins, controls the activity of the catalytic domain. Modulation by calmodulin and calpain. J Biol Chem. 1997;272:6671-6 pubmed
    ..Together, these results emphasize the role of the other domains of CDC25(Mm) in controlling the activity of the catalytic domain and support the involvement of calmodulin and calpain in the in vivo regulation of the CDC25(Mm) activity. ..
  5. Cullen P, Lockyer P. Integration of calcium and Ras signalling. Nat Rev Mol Cell Biol. 2002;3:339-48 pubmed
    ..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. ..
  6. Yang H, Jiang W, Gentry M, Hallberg R. Loss of a protein phosphatase 2A regulatory subunit (Cdc55p) elicits improper regulation of Swe1p degradation. Mol Cell Biol. 2000;20:8143-56 pubmed
    ..We also present evidence indicating that, in cdc55-null cells, misregulated PP2A phosphatase activity is the cause of both the ectopic stabilization of Swe1p and the production of the morphologically abnormal phenotype. ..
  7. Kiyono M, Satoh T, Kaziro Y. G protein beta gamma subunit-dependent Rac-guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm). Proc Natl Acad Sci U S A. 1999;96:4826-31 pubmed
    ..These results suggest a role of Ras-GRF1 for regulating Rac-dependent as well as Ras-dependent signaling pathways, particularly in the brain functions. ..
  8. Kellogg D. Wee1-dependent mechanisms required for coordination of cell growth and cell division. J Cell Sci. 2003;116:4883-90 pubmed
    ..Further understanding of these signaling networks may provide important clues to how cell growth and cell division are coordinated. ..
  9. Wolfe B, Gould K. Fission yeast Clp1p phosphatase affects G2/M transition and mitotic exit through Cdc25p inactivation. EMBO J. 2004;23:919-29 pubmed
    ..This may be a widely conserved mechanism whereby Cdc14 proteins contribute to Cdk1p inactivation. ..

More Information


  1. Rossman K, Der C, Sondek J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol. 2005;6:167-80 pubmed
    ..The failure to do so can have significant consequences and is reflected in the aberrant function of Dbl-family GEFs in some human diseases. ..
  2. Holmes R, Chang Y, Soloway P. Timing and sequence requirements defined for embryonic maintenance of imprinted DNA methylation at Rasgrf1. Mol Cell Biol. 2006;26:9564-70 pubmed
    ..Our data show that the Rasgrf1 repeats serve at least two functions: first, to establish Rasgrf1 DNA methylation in the male germ line, and second, to resist global demethylation in the preimplantation embryo. ..
  3. Tanaka K, Petersen J, Maciver F, Mulvihill D, Glover D, Hagan I. The role of Plo1 kinase in mitotic commitment and septation in Schizosaccharomyces pombe. EMBO J. 2001;20:1259-70 pubmed
    ..The ability of plo1(+) overexpression to induce septation was severely compromised by SIN inactivation. We propose that Plo1 acts before the SIN to control septation. ..
  4. Zhu T, He H, Kole S, D Souza T, Agarwal R, Morin P, et al. Filamin A-mediated down-regulation of the exchange factor Ras-GRF1 correlates with decreased matrix metalloproteinase-9 expression in human melanoma cells. J Biol Chem. 2007;282:14816-26 pubmed
    ..Our results indicate that expression of FLNa regulates constitutive activation of the Ras/ERK pathway partly through a Ras-GRF1 mechanism to modulate the production of MMP-9. ..
  5. Roof R, Haskell M, Dukes B, Sherman N, Kinter M, Parsons S. Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. Mol Cell Biol. 1998;18:7052-63 pubmed
    ..These studies describe a specific mechanism by which c-Src can regulate p190-p120 association and also document a significant role for p-Tyr-independent means of p190-p120 binding. ..
  6. Rubino T, Forlani G, Vigano D, Zippel R, Parolaro D. Ras/ERK signalling in cannabinoid tolerance: from behaviour to cellular aspects. J Neurochem. 2005;93:984-91 pubmed
    ..These findings suggest that at least in the caudate putamen and cerebellum, the Ras/ERK pathway is essential for triggering the alteration in CB1 receptor function responsible for tolerance to THC-induced hypomotility. ..
  7. Chua G, Lingner C, Frazer C, Young P. The sal3(+) gene encodes an importin-beta implicated in the nuclear import of Cdc25 in Schizosaccharomyces pombe. Genetics. 2002;162:689-703 pubmed
    ..These results demonstrate that the nuclear translocation of Cdc25 is important for the timing of mitotic entry and that Sal3 plays an important role in this process. ..
  8. Tikoo A, Czekay S, Viars C, White S, Heath J, Arden K, et al. p190-A, a human tumor suppressor gene, maps to the chromosomal region 19q13.3 that is reportedly deleted in some gliomas. Gene. 2000;257:23-31 pubmed
  9. Pal G, Paraz M, Kellogg D. Regulation of Mih1/Cdc25 by protein phosphatase 2A and casein kinase 1. J Cell Biol. 2008;180:931-45 pubmed publisher
    ..Because casein kinase 1 is associated with sites of polar growth, it may regulate Mih1 as part of a signaling mechanism that links successful completion of growth-related events to cell cycle progression. ..
  10. Jin T, Satoh T, Liao Y, Song C, Gao X, Kariya K, et al. Role of the CDC25 homology domain of phospholipase Cepsilon in amplification of Rap1-dependent signaling. J Biol Chem. 2001;276:30301-7 pubmed
    ..These results suggest a pivotal role of the CDC25 homology domain in amplifying Rap1-dependent signal transduction, including the activation of PLCepsilon itself, at specific subcellular locations such as the Golgi apparatus. ..
  11. Clapcott S, Peters J, Orban P, Brambilla R, Graham C. Two ENU-induced mutations in Rasgrf1 and early mouse growth retardation. Mamm Genome. 2003;14:495-505 pubmed
    ..Mutant mice had near normal body weight at birth, but their weight started to lag behind that of wild-type littermates during the first week, and they were about 15% lighter as adults. ..
  12. Munder T, Furst P. The Saccharomyces cerevisiae CDC25 gene product binds specifically to catalytically inactive ras proteins in vivo. Mol Cell Biol. 1992;12:2091-9 pubmed
    ..Cdc25 binds predominantly to the catalytically inactive GDP-bound form of Ras2, whereas a conformational change of Ras2 to its activated GTP-bound state results in its loss of binding affinity to Cdc25. ..
  13. Freedman T, Sondermann H, Friedland G, Kortemme T, Bar Sagi D, Marqusee S, et al. A Ras-induced conformational switch in the Ras activator Son of sevenless. Proc Natl Acad Sci U S A. 2006;103:16692-7 pubmed
    ..These results indicate that RasGRF1 lacks the allosteric activation switch that is crucial for Sos activity. ..
  14. Zhang G, Hoffmann J, Parelkar N, Liu X, Mao L, Fibuch E, et al. Cocaine increases Ras-guanine nucleotide-releasing factor 1 protein expression in the rat striatum in vivo. Neurosci Lett. 2007;427:117-21 pubmed
    ..These data identify the Ras activator, Ras-GRF1, although not Ras-GRF2, as a susceptible target to cocaine stimulation in striatal neurons. ..
  15. Lavagni P, Indrigo M, Colombo G, Martegani E, Rosenblum K, Gnesutta N, et al. Identification of novel RasGRF1 interacting partners by large-scale proteomic analysis. J Mol Neurosci. 2009;37:212-24 pubmed publisher
    ..These data indicate that RasGRF1 can interact with different protein categories and exhibits a potential RNA-binding property. ..
  16. Fan W, Koch C, de Hoog C, Fam N, Moran M. The exchange factor Ras-GRF2 activates Ras-dependent and Rac-dependent mitogen-activated protein kinase pathways. Curr Biol. 1998;8:935-8 pubmed
  17. Shibata H, Yoda Y, Kato R, Ueda T, Kamiya M, Hiraiwa N, et al. A methylation imprint mark in the mouse imprinted gene Grf1/Cdc25Mm locus shares a common feature with the U2afbp-rs gene: an association with a short tandem repeat and a hypermethylated region. Genomics. 1998;49:30-7 pubmed
    ..These common features in methylation imprint regions may be a clue to identifying regions carrying primary information for the imprinting regulation. ..
  18. Farnsworth C, Freshney N, Rosen L, Ghosh A, Greenberg M, Feig L. Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF. Nature. 1995;376:524-7 pubmed
    ..So far, full-length Ras-GRF has been detected only in brain neurons. Our findings implicate Ras-GRF in the regulation of neuronal functions that are influenced by Ca2+ signals. ..
  19. Kohler F. A yeast-based growth assay for the analysis of site-specific proteases. Nucleic Acids Res. 2003;31:e16 pubmed
    ..It has significant potential for the selection of inhibitors of cytoplasmic and membrane-associated proteases of biotechnical and clinical relevance. ..
  20. Gotoh T, Hattori S, Nakamura S, Kitayama H, Noda M, Takai Y, et al. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. Mol Cell Biol. 1995;15:6746-53 pubmed
    ..Furthermore, expression of C3G with a membrane localization signal in a v-Ki-ras transformant, DT, induced a reversion of the cells to the flat form, possibly through the activation of endogenous Rap1. ..
  21. Stoica C, Carmichael J, Parker H, Pare J, Hobman T. Interactions between the RNA interference effector protein Ago1 and 14-3-3 proteins: consequences for cell cycle progression. J Biol Chem. 2006;281:37646-51 pubmed
    ..We hypothesize that 14-3-3 proteins are required for Argonaute protein functions in cell cycle and/or gene-silencing pathways. ..
  22. Hudson J, Feilotter H, Lingner C, Rowley R, Young P. stf1: a new suppressor of the mitotic control gene, cdc25, in Schizosaccharomyces pombe. Cold Spring Harb Symp Quant Biol. 1991;56:599-604 pubmed
    ..It does not appear to play a role in the nutritional sensing pathway nor in the pathway mediating radiation-induced G2 delay. ..
  23. Folch Mallol J, Martínez L, Casas S, Yang R, Martinez Anaya C, Lopez L, et al. New roles for CDC25 in growth control, galactose regulation and cellular differentiation in Saccharomyces cerevisiae. Microbiology. 2004;150:2865-79 pubmed
    ..In conclusion, the function of the catalytic, C-terminal domain of Cdc25p is not only important for fermentative growth, but also for growth in non-fermentable carbon sources and to trigger galactose derepression. ..
  24. Segal M, Marbach I, Engelberg D, Simchen G, Levitzki A. Interaction between the Saccharomyces cerevisiae CDC25 gene product and mammalian ras. J Biol Chem. 1992;267:22747-51 pubmed
    ..It follows that the yeast system can be used for characterizing the interaction between guanyl nucleotide exchangers of Ras proteins and mammalian p21H-ras. ..
  25. Chen L, Zhang L, Greer P, Tung P, Moran M. A murine CDC25/ras-GRF-related protein implicated in Ras regulation. Dev Genet. 1993;14:339-46 pubmed
    ..Both GRF2 and CDC25Mm/ras-GRF are expressed in murine embryonic stem cells, suggesting that different Ras activators may regulate ras-dependent proliferation and differentiation in early mouse development. ..
  26. Wolthuis R, Bauer B, van T Veer L, de Vries Smits A, Cool R, Spaargaren M, et al. RalGDS-like factor (Rlf) is a novel Ras and Rap 1A-associating protein. Oncogene. 1996;13:353-62 pubmed
    ..6 microM and 0.4 microM, respectively. No significant association with Ras-GDP or Rap 1A-GDP could be detected. These binding characteristics indicate that Rlf is a putative effector for Ras and Rap 1A. ..
  27. de Hoog C, Koehler J, Goldstein M, Taylor P, Figeys D, Moran M. Ras binding triggers ubiquitination of the Ras exchange factor Ras-GRF2. Mol Cell Biol. 2001;21:2107-17 pubmed
    ..We conclude that conformational changes induced by GTPase binding expose the DB and thereby target GRF2 for destruction. ..
  28. Rhind N, Russell P. Roles of the mitotic inhibitors Wee1 and Mik1 in the G(2) DNA damage and replication checkpoints. Mol Cell Biol. 2001;21:1499-508 pubmed
    ..Mik1 appears to have two roles in the DNA damage checkpoint; one in the establishment of the checkpoint and another in its maintenance. In contrast, Wee1 does not appear to be involved in the establishment of either checkpoint. ..
  29. Li L, Yang Y, Stevens R. Cloning of rat Ras guanine nucleotide releasing protein 4, and evaluation of its expression in rat mast cells and their bone marrow progenitors. Mol Immunol. 2002;38:1283-8 pubmed
    ..Like its mouse ortholog, rRasGRP4 is a MC-restricted guanine exchange factor that contains Ca(2+) and phorbol ester/diacylglycerol-binding domains C-terminal of its CDC25-like catalytic domain. ..
  30. Mosteller R, Park W, Broek D. Analysis of interaction between Ras and CDC25 guanine nucleotide exchange factor using yeast GAL4 two-hybrid system. Methods Enzymol. 1995;255:135-48 pubmed
    ..We recommend that the two-hybrid system be employed in combination with other approaches, including molecular genetic analyses and in vitro binding experiments, for the study of Ras and CDC25-GEF interactions. ..
  31. Arozarena I, Matallanas D, Crespo P. Maintenance of CDC42 GDP-bound state by Rho-GDI inhibits MAP kinase activation by the exchange factor Ras-GRF. evidence for Ras-GRF function being inhibited by Cdc42-GDP but unaffected by CDC42-GTP. J Biol Chem. 2001;276:21878-84 pubmed
    ..Furthermore, the GDP-bound form may be acting as an inhibitory molecule down-modulating parallel signaling routes such as the Ras/MAPK pathway. ..
  32. Cheng Y, Wang K, Kellam L, Lee Y, Liang C, Han Z, et al. Effects of ooplasm manipulation on DNA methylation and growth of progeny in mice. Biol Reprod. 2009;80:464-72 pubmed publisher
    ..These results indicate that some ooplasm manipulation procedures may exert subtle effects on growth early in life, while intergenotype GVT can result in significant growth deficiencies after birth. ..
  33. Tian X, Gotoh T, Tsuji K, Lo E, Huang S, Feig L. Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB. EMBO J. 2004;23:1567-75 pubmed
    ..Interestingly, in cortical neurons of neonatal animals NMDARs signal through Sos rather than Ras-GRF exchange factors, implying that Ras-GRFs endow NMDARs with functions unique to mature neurons. ..
  34. Gariboldi M, Sturani E, Canzian F, De Gregorio L, Manenti G, Dragani T, et al. Genetic mapping of the mouse CDC25Mm gene, a ras-specific guanine nucleotide-releasing factor, to chromosome 9. Genomics. 1994;21:451-3 pubmed
  35. Shirayama M, Matsui Y, Tanaka K, Toh e A. Isolation of a CDC25 family gene, MSI2/LTE1, as a multicopy suppressor of ira1. Yeast. 1994;10:451-61 pubmed
    ..These results suggest that MSI2 is involved in the termination of M phase and that this process is regulated by a ras superfamily gene product. ..
  36. Abreu J, de Launay D, Sanders M, Grabiec A, van de Sande M, Tak P, et al. The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue. Arthritis Res Ther. 2009;11:R121 pubmed publisher
    ..Enhanced expression and post-translational modification of RasGRF1 contributes to MMP-3 production in RA synovial tissue and the semi-transformed phenotype of RA FLS. ..
  37. López Avilés S, Lambea E, Moldón A, Grande M, Fajardo A, Rodríguez Gabriel M, et al. Activation of Srk1 by the mitogen-activated protein kinase Sty1/Spc1 precedes its dissociation from the kinase and signals its degradation. Mol Biol Cell. 2008;19:1670-9 pubmed publisher
  38. Wilkins A, Chubb J, Insall R. A novel Dictyostelium RasGEF is required for normal endocytosis, cell motility and multicellular development. Curr Biol. 2000;10:1427-37 pubmed
    ..RasGEFB appears to be the principal activator of the RasS protein, which regulates macropinocytosis and cell speed, but it also appears to regulate one or more other Ras proteins. ..
  39. Gadea B, Ruderman J. Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts. Mol Biol Cell. 2005;16:1305-18 pubmed
    ..These results show that Aurora kinase activity is required to ensure the maintenance of condensed chromosomes, the generation of chromosome-induced spindle microtubules, and activation of the spindle integrity checkpoint. ..
  40. Cen H, Papageorge A, Vass W, Zhang K, Lowy D. Regulated and constitutive activity by CDC25Mm (GRF), a Ras-specific exchange factor. Mol Cell Biol. 1993;13:7718-24 pubmed
    ..Ras, and the serum-dependent increase in GTP.Ras by exogenous CDC25Mm or by endogenous exchange factors probably requires membrane association of both Ras and the exchange factor. ..
  41. Cherfils J, Chardin P. GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem Sci. 1999;24:306-11 pubmed
    ..These structures, together with biochemical studies, have allowed a deeper understanding of the mechanisms of activation of Ras-like GTP-binding proteins and suggested how they might represent targets for therapeutic intervention. ..
  42. Crechet J, Jacquet E, Bernardi A, Parmeggiani A. Analysis of the role of the hypervariable region of yeast Ras2p and its farnesylation in the interaction with exchange factors and adenylyl cyclase. J Biol Chem. 2000;275:17754-61 pubmed
    ..The use of Ha-Ras/Ras2p chimaeras of different length emphasized the key role of the hypervariable region of Ras2p in inducing maximum activation of adenylyl cyclase and for a productive interaction with membrane-bound GEF. ..
  43. Kohler F. A co-localization assay for the analysis of protein-protein interactions. Gene. 2007;388:14-8 pubmed
    ..The flexibility of the general scheme of this approach may allow for its application in many different assay scenarios and may represent a suitable alternative in cases where other approaches fail. ..
  44. Bernards A, Settleman J. GAPs in growth factor signalling. Growth Factors. 2005;23:143-9 pubmed
    ..Here, some of these mechanisms of GAP regulation in the context of signaling responses to growth factors are reviewed. ..
  45. Suchomelova P, Velgová D, Masek T, Francis D, Rogers H, Marchbank A, et al. Expression of the fission yeast cell cycle regulator cdc25 induces de novo shoot formation in tobacco: evidence of a cytokinin-like effect by this mitotic activator. Plant Physiol Biochem. 2004;42:49-55 pubmed
    ..The observed cytokinin-like effects of Spcdc25 transformation are consistent with the concept of an interaction between cell cycle regulators and phytohormones during plant development. ..
  46. Kiang L, Heichinger C, Watt S, Bahler J, Nurse P. Cyclin-dependent kinase inhibits reinitiation of a normal S-phase program during G2 in fission yeast. Mol Cell Biol. 2009;29:4025-32 pubmed publisher
    ..We conclude that CDK inhibits reinitiation of S phase during G(2), and if G(2)/M CDK is depleted, replication results from induction of a largely normal S-phase program with only small differences in origin usage and efficiency. ..
  47. Wei W, Das B, Park W, Broek D. Cloning and analysis of human cDNAs encoding a 140-kDa brain guanine nucleotide-exchange factor, Cdc25GEF, which regulates the function of Ras. Gene. 1994;151:279-84 pubmed
    ..Further, the Cdc25-fusion protein binds tightly to the nucleotide-free form of H-Ras in vitro, and this binding is reversed by the addition of GTP. ..
  48. Rubino T, Vigano D, Premoli F, Castiglioni C, Bianchessi S, Zippel R, et al. Changes in the expression of G protein-coupled receptor kinases and beta-arrestins in mouse brain during cannabinoid tolerance: a role for RAS-ERK cascade. Mol Neurobiol. 2006;33:199-213 pubmed
  49. Prigozy T, Gonzales E, Broek D. Identification and analysis of a DNA fragment from Saccharomyces kluyveri that can complement the loss of CDC25 function in Saccharomyces cerevisiae. Gene. 1992;117:67-72 pubmed
    ..The identification of the highly conserved C-terminal sequences, which direct bona fide CDC25 activity within these proteins, will aid in the isolation of CDC25 genes from higher eukaryotes. ..
  50. Kim H, Oh M, Lu Q, Kim K. E-Cadherin negatively modulates delta-catenin-induced morphological changes and RhoA activity reduction by competing with p190RhoGEF for delta-catenin. Biochem Biophys Res Commun. 2008;377:636-641 pubmed publisher
    ..These results suggest that delta-catenin is more dominantly bound to E-cadherin than to p190RhoGEF, and that delta-catenin's function is dependent on its cellular binding partner. ..
  51. Deminoff S, Ramachandran V, Herman P. Distal recognition sites in substrates are required for efficient phosphorylation by the cAMP-dependent protein kinase. Genetics. 2009;182:529-39 pubmed publisher
  52. Warbrick E, Glover D. A Drosophila gene encoding a DEAD box RNA helicase can suppress loss of wee1/mik1 function in Schizosaccharomyces pombe. Mol Gen Genet. 1994;245:654-7 pubmed
    ..It is possible that the RNA helicase described here may regulate entry into mitosis by down regulating the expression of other genes whose activity may be rate-limiting for entry into mitosis. ..
  53. Selvanathan S, Thakurta A, Dhakshnamoorthy J, Zhou M, Veenstra T, Dhar R. Schizosaccharomyces pombe Dss1p is a DNA damage checkpoint protein that recruits Rad24p, Cdc25p, and Rae1p to DNA double-strand breaks. J Biol Chem. 2010;285:14122-33 pubmed publisher
    ..We suggest that the sequestration of Cdc25p to DNA damage sites could provide a mechanism for S. pombe cells to arrest at G(2)/M boundary in response to DNA damage. ..