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Gene Review

Rasgrf1  -  RAS protein-specific guanine nucleotide...

Mus musculus

Synonyms: AI844718, CDC25, CDC25Mm, Cdc25, GNRP, ...
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Disease relevance of Rasgrf1

  • The minimal active domain (GEF domain) of the mouse Ras exchange factor CDC25Mm was purified to homogeneity from recombinant Escherichia coli culture [1].
  • RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function [2].
  • Both serum and LPA-induced Ras activations in CDC25Mm overexpressing cells can be completely inhibited by pertussis toxin [3].
  • Using newly derived anti-bcr monoclonal and anti-abl polyclonal antibodies it was demonstrated that both the original leukaemic cells and the derived cell line expressed the p190 form of the bcr-abl protein found in a proportion of cases of Philadelphia chromosome positive ALL [4].
  • The deduced amino acid sequence contains a motif for a conserved catalytic domain of DSPs and shows highest similarity to human Vaccinia HI-related phosphatase (45.5% identity) but low homology to the mitogen-activated protein kinase phosphatase and CDC25 subfamilies of DSPs [5].

Psychiatry related information on Rasgrf1

  • Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact [6].
  • We investigated the role of the Ras/extracellular-regulated kinase (ERK) pathway in the development of tolerance to Delta(9)-tetrahydrocannabinol (THC)-induced reduction in spontaneous locomotor activity by a genetic (Ras-specific guanine nucleotide exchange factor (Ras-GRF1) knock-out mice) and pharmacological approach [7].

High impact information on Rasgrf1


Chemical compound and disease context of Rasgrf1

  • The substrate requirements for the catalytic activity of the mouse Cdc25 homolog Guanine nucleotide Release Factor, GRF, were determined using the catalytic domain of GRF expressed in insect cells and E. coli expressed H-Ras mutants [11].
  • The data presented indicate that CDC25Mm does not participate in connecting tyrosine kinase receptors with Ras, while it could mediate Ras activation induced by pertussis toxin sensitive Gi-coupled receptors [3].
  • Both the serum induced super-activation of Ras, and the hyperphosphorylation of Ras-GRF were blocked by pretreatment of cells with the Gi,o inhibitor pertussis toxin, but not by pretreatment with the tyrosine kinase inhibitor genistein [12].
  • The increase in Ras-GRF phosphorylation state, which occurs on serine residues, and the increase in exchange factor activity are blocked by pretreatment with pertussis toxin [13].

Biological context of Rasgrf1


Anatomical context of Rasgrf1

  • The mammalian Grf1 and Grf2 proteins are Ras guanine nucleotide exchange factors (GEFs) sharing a high degree of structural homology, as well as an elevated expression level in central nervous system tissues [17].
  • Requirement for Ras guanine nucleotide releasing protein 3 in coupling phospholipase C-gamma2 to Ras in B cell receptor signaling [18].
  • We found that in all cell lines, EGF induced a rapid and transient condensation of p190 and RasGAP into cytoplasmic, arclike structures [19].
  • However, for directional movement, the turnover of stress fibers and focal adhesions to produce an elongate morphology was dependent on the constitutive association between Ras-GAP and p190, independent of Ras regulation [20].
  • Disruption of the phosphotyrosine-mediated Ras-GAP/p190 complex by microinjecting synthetic peptides derived from p190 sequences in wild-type cells caused a suppression of actin filament reorientation and migration [20].

Associations of Rasgrf1 with chemical compounds

  • Furthermore, we show that CP-AMPARs are also the major AMPAR type to activate Ras/Erk signaling in pubescent mice; however, at this developmental stage Ras-GRF (guanine nucleotide-releasing factor) proteins are not involved [21].
  • Age-dependent participation of Ras-GRF proteins in coupling calcium-permeable AMPA glutamate receptors to Ras/Erk signaling in cortical neurons [21].
  • Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure [6].
  • To begin investigating these questions, we used biochemical approaches to characterize the number and relative levels of in vivo-phosphorylated tyrosine residues on endogenous p190 from C3H10T1/2 murine fibroblasts [22].
  • We show that, in p190-deficient fibroblasts, the typical functional activities mediated by plexins (such as cell collapse and inhibition of integrin-based adhesion) are blocked or greatly impaired [23].

Physical interactions of Rasgrf1


Regulatory relationships of Rasgrf1


Other interactions of Rasgrf1

  • We examined methylation of the Rasgrf1 and Gtl2 differentially methylated regions (DMR) to determine whether methylation is erased in male germ cells at e12.5 and when the paternal allele acquires methylation [30].
  • Consistent with this function for Ras-GRFs and the known neuroprotective effect of CREB activity, ischemia-induced CREB activation is reduced in the brains of adult Ras-GRF knockout mice and neuronal damage is enhanced [31].
  • These findings show that, despite their similar functional domain organization, Ras-GRF1 and Ras-GRF2 mediate opposing forms of synaptic plasticity by coupling different classes of NMDARs to distinct MAP kinase pathways [32].
  • Curiously, they are also present in the p190 family of cytoplasmic Rho GTPase activating proteins (GAPs) [33].
  • Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 are highly similar calcium-stimulated exchange factors that activate Ras and Rac GTPases [32].

Analytical, diagnostic and therapeutic context of Rasgrf1


  1. Analysis of the secondary structure of the catalytic domain of mouse Ras exchange factor CDC25Mm. Coccetti, P., Monzani, E., Alberghina, L., Casella, L., Martegani, E. Biochim. Biophys. Acta (1998) [Pubmed]
  2. RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function. Yang, Y., Li, L., Wong, G.W., Krilis, S.A., Madhusudhan, M.S., Sali, A., Stevens, R.L. J. Biol. Chem. (2002) [Pubmed]
  3. The brain specific Ras exchange factor CDC25 Mm: modulation of its activity through Gi-protein-mediated signals. Zippel, R., Orecchia, S., Sturani, E., Martegani, E. Oncogene (1996) [Pubmed]
  4. Establishment of a lymphoblastoid cell line, SD-1, expressing the p190 bcr-abl chimaeric protein. Dhut, S., Gibbons, B., Chaplin, T., Young, B.D. Leukemia (1991) [Pubmed]
  5. Molecular cloning and characterization of a novel dual-specificity protein phosphatase possibly involved in spermatogenesis. Nakamura, K., Shima, H., Watanabe, M., Haneji, T., Kikuchi, K. Biochem. J. (1999) [Pubmed]
  6. A role for the Ras signalling pathway in synaptic transmission and long-term memory. Brambilla, R., Gnesutta, N., Minichiello, L., White, G., Roylance, A.J., Herron, C.E., Ramsey, M., Wolfer, D.P., Cestari, V., Rossi-Arnaud, C., Grant, S.G., Chapman, P.F., Lipp, H.P., Sturani, E., Klein, R. Nature (1997) [Pubmed]
  7. Ras/ERK signalling in cannabinoid tolerance: from behaviour to cellular aspects. Rubino, T., Forlani, G., Viganò, D., Zippel, R., Parolaro, D. J. Neurochem. (2005) [Pubmed]
  8. Trans allele methylation and paramutation-like effects in mice. Herman, H., Lu, M., Anggraini, M., Sikora, A., Chang, Y., Yoon, B.J., Soloway, P.D. Nat. Genet. (2003) [Pubmed]
  9. Regulation of DNA methylation of Rasgrf1. Yoon, B.J., Herman, H., Sikora, A., Smith, L.T., Plass, C., Soloway, P.D. Nat. Genet. (2002) [Pubmed]
  10. Identification of Grf1 on mouse chromosome 9 as an imprinted gene by RLGS-M. Plass, C., Shibata, H., Kalcheva, I., Mullins, L., Kotelevtseva, N., Mullins, J., Kato, R., Sasaki, H., Hirotsune, S., Okazaki, Y., Held, W.A., Hayashizaki, Y., Chapman, V.M. Nat. Genet. (1996) [Pubmed]
  11. Rasp21 sequences opposite the nucleotide binding pocket are required for GRF-mediated nucleotide release. Leonardsen, L., DeClue, J.E., Lybaek, H., Lowy, D.R., Willumsen, B.M. Oncogene (1996) [Pubmed]
  12. Differential response of the Ras exchange factor, Ras-GRF to tyrosine kinase and G protein mediated signals. Shou, C., Wurmser, A., Suen, K.L., Barbacid, M., Feig, L.A., Ling, K. Oncogene (1995) [Pubmed]
  13. Activation of the Ras-GRF/CDC25Mm exchange factor by lysophosphatidic acid. Mattingly, R.R., Saini, V., Macara, I.G. Cell. Signal. (1999) [Pubmed]
  14. Rasgrf1 imprinting is regulated by a CTCF-dependent methylation-sensitive enhancer blocker. Yoon, B., Herman, H., Hu, B., Park, Y.J., Lindroth, A., Bell, A., West, A.G., Chang, Y., Stablewski, A., Piel, J.C., Loukinov, D.I., Lobanenkov, V.V., Soloway, P.D. Mol. Cell. Biol. (2005) [Pubmed]
  15. Structural characterization of Rasgrf1 and a novel linked imprinted locus. de la Puente, A., Hall, J., Wu, Y.Z., Leone, G., Peters, J., Yoon, B.J., Soloway, P., Plass, C. Gene (2002) [Pubmed]
  16. Ras-GRF1 signaling is required for normal beta-cell development and glucose homeostasis. Font de Mora, J., Esteban, L.M., Burks, D.J., Núñez, A., Garcés, C., García-Barrado, M.J., Iglesias-Osma, M.C., Moratinos, J., Ward, J.M., Santos, E. EMBO J. (2003) [Pubmed]
  17. Targeted disruption of Ras-Grf2 shows its dispensability for mouse growth and development. Fernández-Medarde, A., Esteban, L.M., Núñez, A., Porteros, A., Tessarollo, L., Santos, E. Mol. Cell. Biol. (2002) [Pubmed]
  18. Requirement for Ras guanine nucleotide releasing protein 3 in coupling phospholipase C-gamma2 to Ras in B cell receptor signaling. Oh-hora, M., Johmura, S., Hashimoto, A., Hikida, M., Kurosaki, T. J. Exp. Med. (2003) [Pubmed]
  19. c-Src regulates the simultaneous rearrangement of actin cytoskeleton, p190RhoGAP, and p120RasGAP following epidermal growth factor stimulation. Chang, J.H., Gill, S., Settleman, J., Parsons, S.J. J. Cell Biol. (1995) [Pubmed]
  20. Role of p120 Ras-GAP in directed cell movement. Kulkarni, S.V., Gish, G., van der Geer, P., Henkemeyer, M., Pawson, T. J. Cell Biol. (2000) [Pubmed]
  21. Age-dependent participation of Ras-GRF proteins in coupling calcium-permeable AMPA glutamate receptors to Ras/Erk signaling in cortical neurons. Tian, X., Feig, L.A. J. Biol. Chem. (2006) [Pubmed]
  22. 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. Roof, R.W., Haskell, M.D., Dukes, B.D., Sherman, N., Kinter, M., Parsons, S.J. Mol. Cell. Biol. (1998) [Pubmed]
  23. p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling. Barberis, D., Casazza, A., Sordella, R., Corso, S., Artigiani, S., Settleman, J., Comoglio, P.M., Tamagnone, L. J. Cell. Sci. (2005) [Pubmed]
  24. The N-terminal pleckstrin, coiled-coil, and IQ domains of the exchange factor Ras-GRF act cooperatively to facilitate activation by calcium. Buchsbaum, R., Telliez, J.B., Goonesekera, S., Feig, L.A. Mol. Cell. Biol. (1996) [Pubmed]
  25. Phosphorylation of p190 on Tyr1105 by c-Src is necessary but not sufficient for EGF-induced actin disassembly in C3H10T1/2 fibroblasts. Haskell, M.D., Nickles, A.L., Agati, J.M., Su, L., Dukes, B.D., Parsons, S.J. J. Cell. Sci. (2001) [Pubmed]
  26. p75-Ras-GRF1 is a c-Jun/AP-1 target protein: its up regulation results in increased Ras activity and is necessary for c-Jun-induced nonadherent growth of Rat1a cells. Leaner, V.D., Donninger, H., Ellis, C.A., Clark, G.J., Birrer, M.J. Mol. Cell. Biol. (2005) [Pubmed]
  27. CDC25(Mm)/Ras-GRF1 regulates both Ras and Rac signaling pathways. Innocenti, M., Zippel, R., Brambilla, R., Sturani, E. FEBS Lett. (1999) [Pubmed]
  28. c-Fos/activator protein-1 transactivates wee1 kinase at G(1)/S to inhibit premature mitosis in antigen-specific Th1 cells. Kawasaki, H., Komai, K., Ouyang, Z., Murata, M., Hikasa, M., Ohgiri, M., Shiozawa, S. EMBO J. (2001) [Pubmed]
  29. Phosphorylation of the Ras-GRF1 exchange factor at Ser916/898 reveals activation of Ras signaling in the cerebral cortex. Yang, H., Cooley, D., Legakis, J.E., Ge, Q., Andrade, R., Mattingly, R.R. J. Biol. Chem. (2003) [Pubmed]
  30. Timing of establishment of paternal methylation imprints in the mouse. Li, J.Y., Lees-Murdock, D.J., Xu, G.L., Walsh, C.P. Genomics (2004) [Pubmed]
  31. Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB. Tian, X., Gotoh, T., Tsuji, K., Lo, E.H., Huang, S., Feig, L.A. EMBO J. (2004) [Pubmed]
  32. Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. Li, S., Tian, X., Hartley, D.M., Feig, L.A. J. Neurosci. (2006) [Pubmed]
  33. An FF domain-dependent protein interaction mediates a signaling pathway for growth factor-induced gene expression. Jiang, W., Sordella, R., Chen, G.C., Hakre, S., Roy, A.L., Settleman, J. Mol. Cell (2005) [Pubmed]
  34. The guanine nucleotide exchange factor RasGRF1 directly binds microtubules via DHPH2-mediated interaction. Forlani, G., Baldassa, S., Lavagni, P., Sturani, E., Zippel, R. FEBS J. (2006) [Pubmed]
  35. A novel synthetic inhibitor of CDC25 phosphatases: BN82002. Brezak, M.C., Quaranta, M., Mondésert, O., Galcera, M.O., Lavergne, O., Alby, F., Cazales, M., Baldin, V., Thurieau, C., Harnett, J., Lanco, C., Kasprzyk, P.G., Prevost, G.P., Ducommun, B. Cancer Res. (2004) [Pubmed]
  36. Restricted oncogenicity of BCR/ABL p190 in transgenic mice. Voncken, J.W., Griffiths, S., Greaves, M.F., Pattengale, P.K., Heisterkamp, N., Groffen, J. Cancer Res. (1992) [Pubmed]
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