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Gene Review

RASGRF1  -  Ras protein-specific guanine nucleotide...

Homo sapiens

Synonyms: CDC25, CDC25L, GNRP, GRF1, GRF55, ...
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Disease relevance of RASGRF1

  • We provide here biochemical and functional evidence demonstrating that human immunodeficiency virus type 1 (HIV-1) Vpr mediates G(2) arrest by forming a complex with protein phosphatase 2A (PP2A), an upstream regulator of cdc25 [1].
  • Demonstrating the direct oncogenic potential of a cdc25 gene, we identify a gain-of-function mutant allele of the Caenorhabditis elegans gene cdc-25.1 that causes a deregulated proliferation of intestinal cells resulting in hyperplasia, while other aspects of intestinal cell function are retained [2].
  • Many PTPs are recognized as potential drug targets; however, inhibitor development has focused only on a small number of enzymes, most notably PTP1B for type II diabetes and obesity, and MKP1 and CDC25 for cancer [3].
  • cdc25 cell cycle-activating phosphatases and c-myc expression in human non-Hodgkin's lymphomas [4].
  • We now report that the caulibugulones are selective in vitro inhibitors of the Cdc25 family of cell cycle-controlling protein phosphatases compared with either human vaccinia H1-related phosphatase (VHR) or tyrosine phosphatase 1B (PTP1B) [5].

Psychiatry related information on RASGRF1

  • Here, we review the function and regulation of CDC25 phosphatases, their involvement in cancer and Alzheimer's disease, and the properties of several recently identified inhibitors [6].

High impact information on RASGRF1


Chemical compound and disease context of RASGRF1


Biological context of RASGRF1

  • Point mutations within the Cdc25 domain that eliminate Ras binding also eliminate ubiquitination, demonstrating that binding to Ras is necessary for ubiquitination of GRF2 [11].
  • Induction of rac-guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) following phosphorylation by the nonreceptor tyrosine kinase Src [12].
  • The cdc25 M-phase inducer: an unconventional protein phosphatase [13].
  • In some crystals, the catalytic Cys-430 forms a disulfide bond with the invariant Cys-384, suggesting that Cdc25 may be self-inhibited during oxidative stress [14].
  • These findings identify Cdc25, but not Wee1, as a target of the DNA damage checkpoint [15].

Anatomical context of RASGRF1


Associations of RASGRF1 with chemical compounds

  • The Cdc25 domain possesses guanine nucleotide exchange factor activity and interacts with Ras [11].
  • It is a multidomain protein composed of several recognizable sequence motifs in the following order (NH(2) to COOH): pleckstrin homology (PH), coiled-coil, ilimaquinone (IQ), Dbl homology (DH), PH, REM (Ras exchanger motif), PEST/destruction box, Cdc25 [20].
  • Ras-GEF activity of Ras-GRF1 is augmented in response to Ca(2+) influx and G protein betagamma subunit (Gbetagamma) stimulation [12].
  • The recombinant c-Src protein phosphorylated affinity-purified glutathione S-transferase-tagged Ras-GRF1 in vitro and thereby elicited Rac-GEF activity [12].
  • When tsBN2 cells arrested in S phase were incubated at 40 degrees C in the presence of cycloheximide, Cdc25B, but not Cdc25A and C, among a family of dual-specificity phosphatases, Cdc25, was lost coincidentally with the lack of the activation of p34(cdc2)/cyclin B [21].

Physical interactions of RASGRF1


Enzymatic interactions of RASGRF1

  • CDC25 phosphatases belong to the tyrosine phosphatase family and play a critical role in regulating cell cycle progression by dephosphorylating cyclin-dependent kinases at inhibitory residues [27].
  • Our data suggest that Vpr mediates G(2) arrest by enhancing the nuclear import of PP2A and by positively modulating its catalytic activity towards active phosphorylated nuclear cdc25 [1].
  • Affinity-purified human GST-cdc25 was able to dephosphorylate and activate cdk2 isolated from interphase cells [28].
  • Here we report that upon Etoposide treatment CDC2 is phosphorylated on tyrosine 15 and is dephosphorylated and activated in vitro by recombinant CDC25 phosphatase [29].
  • The dual specificity CDC25 phosphatases dephosphorylate two inhibitory phospho-amino acids of cyclin-dependent kinases, a major family of cell cycle regulators [30].

Regulatory relationships of RASGRF1

  • Furthermore, Ras-dependent activation of ERK2 by Ras-GRF1 was enhanced following co-expression of activated ACK1 [16].
  • In addition, it is likely that other regulatory mechanisms cooperate with the wee1/cdc25 phosphorylation systems to control the action of cdc2 [31].
  • Similarly, CDK2 is activated in vitro by dephosphorylation of Y15 and T14 by the phosphatase CDC25 [32].
  • CDC25 phosphatases activate cyclin-dependent kinases by removing inhibitory phosphate groups on the molecules and positively regulate the cell cycle progression [33].
  • We then describe a simple assay in which we demonstrate that growth of the humanised CDC25A strain is strongly repressed in a CDC25-dependent manner by BN2003, a potent chemical inhibitor of CDC25 belonging to the benzothiazoledione family [34].

Other interactions of RASGRF1

  • Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1 [16].
  • Ras-GRF1 has been implicated as a Ras-specific guanine nucleotide exchange factor (GEF), which mediates calcium- and muscarinic receptor-triggered signals in the brain [35].
  • GRF2 lacking the Cdc25 domain is not ubiquitinated, suggesting that a protein that cannot bind Ras cannot be properly targeted for destruction [11].
  • G protein beta gamma subunit-dependent Rac-guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) [35].
  • In addition, Ras-GRF1 acts as a GEF for Rac when tyrosine-phosphorylated following G protein-coupled receptor stimulation [16].

Analytical, diagnostic and therapeutic context of RASGRF1


  1. Human immunodeficiency virus type 1 Vpr-mediated G(2) cell cycle arrest: Vpr interferes with cell cycle signaling cascades by interacting with the B subunit of serine/threonine protein phosphatase 2A. Hrimech, M., Yao, X.J., Branton, P.E., Cohen, E.A. EMBO J. (2000) [Pubmed]
  2. Oncogenic potential of a C.elegans cdc25 gene is demonstrated by a gain-of-function allele. Clucas, C., Cabello, J., Büssing, I., Schnabel, R., Johnstone, I.L. EMBO J. (2002) [Pubmed]
  3. MAPK-specific tyrosine phosphatases: new targets for drug discovery? Barr, A.J., Knapp, S. Trends Pharmacol. Sci. (2006) [Pubmed]
  4. cdc25 cell cycle-activating phosphatases and c-myc expression in human non-Hodgkin's lymphomas. Hernández, S., Hernández, L., Beà, S., Cazorla, M., Fernández, P.L., Nadal, A., Muntané, J., Mallofré, C., Montserrat, E., Cardesa, A., Campo, E. Cancer Res. (1998) [Pubmed]
  5. Independent mechanistic inhibition of cdc25 phosphatases by a natural product caulibugulone. Brisson, M., Foster, C., Wipf, P., Joo, B., Tomko, R.J., Nguyen, T., Lazo, J.S. Mol. Pharmacol. (2007) [Pubmed]
  6. Inhibitors of the CDC25 phosphatases. Prevost, G.P., Brezak, M.C., Goubin, F., Mondesert, O., Galcera, M.O., Quaranta, M., Alby, F., Lavergne, O., Ducommun, B. Progress in cell cycle research. (2003) [Pubmed]
  7. PTEN and myotubularin: novel phosphoinositide phosphatases. Maehama, T., Taylor, G.S., Dixon, J.E. Annu. Rev. Biochem. (2001) [Pubmed]
  8. Regulation of Cdc25C by ERK-MAP Kinases during the G(2)/M Transition. Wang, R., He, G., Nelman-Gonzalez, M., Ashorn, C.L., Gallick, G.E., Stukenberg, P.T., Kirschner, M.W., Kuang, J. Cell (2007) [Pubmed]
  9. Role for the PP2A/B56delta Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis. Margolis, S.S., Perry, J.A., Forester, C.M., Nutt, L.K., Guo, Y., Jardim, M.J., Thomenius, M.J., Freel, C.D., Darbandi, R., Ahn, J.H., Arroyo, J.D., Wang, X.F., Shenolikar, S., Nairn, A.C., Dunphy, W.G., Hahn, W.C., Virshup, D.M., Kornbluth, S. Cell (2006) [Pubmed]
  10. H32, a Non-Quinone Sulfone Analog of Vitamin K3, Inhibits Human Hepatoma Cell Growth by Inhibiting Cdc25 and Activating ERK. Kar, S., Wang, M., Ham, S.W., Carr, B.I. Cancer Biol. Ther. (2006) [Pubmed]
  11. Ras binding triggers ubiquitination of the Ras exchange factor Ras-GRF2. de Hoog, C.L., Koehler, J.A., Goldstein, M.D., Taylor, P., Figeys, D., Moran, M.F. Mol. Cell. Biol. (2001) [Pubmed]
  12. Induction of rac-guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) following phosphorylation by the nonreceptor tyrosine kinase Src. Kiyono, M., Kaziro, Y., Satoh, T. J. Biol. Chem. (2000) [Pubmed]
  13. The cdc25 M-phase inducer: an unconventional protein phosphatase. Millar, J.B., Russell, P. Cell (1992) [Pubmed]
  14. Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A. Fauman, E.B., Cogswell, J.P., Lovejoy, B., Rocque, W.J., Holmes, W., Montana, V.G., Piwnica-Worms, H., Rink, M.J., Saper, M.A. Cell (1998) [Pubmed]
  15. Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase. Furnari, B., Rhind, N., Russell, P. Science (1997) [Pubmed]
  16. Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1. Kiyono, M., Kato, J., Kataoka, T., Kaziro, Y., Satoh, T. J. Biol. Chem. (2000) [Pubmed]
  17. Mitotic phosphatases: no longer silent partners. Trinkle-Mulcahy, L., Lamond, A.I. Curr. Opin. Cell Biol. (2006) [Pubmed]
  18. Dual mode of degradation of Cdc25 A phosphatase. Donzelli, M., Squatrito, M., Ganoth, D., Hershko, A., Pagano, M., Draetta, G.F. EMBO J. (2002) [Pubmed]
  19. Human homolog of fission yeast cdc25 mitotic inducer is predominantly expressed in G2. Sadhu, K., Reed, S.I., Richardson, H., Russell, P. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  20. Calmodulin-independent coordination of Ras and extracellular signal-regulated kinase activation by Ras-GRF2. de Hoog, C.L., Fan, W.T., Goldstein, M.D., Moran, M.F., Koch, C.A. Mol. Cell. Biol. (2000) [Pubmed]
  21. A dual-specificity phosphatase Cdc25B is an unstable protein and triggers p34(cdc2)/cyclin B activation in hamster BHK21 cells arrested with hydroxyurea. Nishijima, H., Nishitani, H., Seki, T., Nishimoto, T. J. Cell Biol. (1997) [Pubmed]
  22. The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Shen, M., Stukenberg, P.T., Kirschner, M.W., Lu, K.P. Genes Dev. (1998) [Pubmed]
  23. Study of the cytolethal distending toxin-induced cell cycle arrest in HeLa cells: involvement of the CDC25 phosphatase. Escalas, N., Davezac, N., De Rycke, J., Baldin, V., Mazars, R., Ducommun, B. Exp. Cell Res. (2000) [Pubmed]
  24. Differential interaction of Crkl with Cbl or C3G, Hef-1, and gamma subunit immunoreceptor tyrosine-based activation motif in signaling of myeloid high affinity Fc receptor for IgG (Fc gamma RI). Kyono, W.T., de Jong, R., Park, R.K., Liu, Y., Heisterkamp, N., Groffen, J., Durden, D.L. J. Immunol. (1998) [Pubmed]
  25. HABP1/p32/gC1qR induces aberrant growth and morphology in Schizosaccharomyces pombe through its N-terminal alpha helix. Mallick, J., Datta, K. Exp. Cell Res. (2005) [Pubmed]
  26. HIV-1 Vpr induces cell cycle G2 arrest in fission yeast (Schizosaccharomyces pombe) through a pathway involving regulatory and catalytic subunits of PP2A and acting on both Wee1 and Cdc25. Elder, R.T., Yu, M., Chen, M., Zhu, X., Yanagida, M., Zhao, Y. Virology (2001) [Pubmed]
  27. Increased expression and activity of CDC25C phosphatase and an alternatively spliced variant in prostate cancer. Ozen, M., Ittmann, M. Clin. Cancer Res. (2005) [Pubmed]
  28. Cdc25 regulates the phosphorylation and activity of the Xenopus cdk2 protein kinase complex. Gabrielli, B.G., Lee, M.S., Walker, D.H., Piwnica-Worms, H., Maller, J.L. J. Biol. Chem. (1992) [Pubmed]
  29. Use of CDC2 from etoposide-treated cells as substrate to assay CDC25 phosphatase activity. Cans, C., Sert, V., De Rycke, J., Baldin, V., Ducommun, B. Anticancer Res. (1999) [Pubmed]
  30. Coscinosulfate, a CDC25 phosphatase inhibitor from the sponge Coscinoderma mathewsi. Loukaci, A., Le Saout, I., Samadi, M., Leclerc, S., Damiens, E., Meijer, L., Debitus, C., Guyot, M. Bioorg. Med. Chem. (2001) [Pubmed]
  31. Cdc2 regulatory factors. Coleman, T.R., Dunphy, W.G. Curr. Opin. Cell Biol. (1994) [Pubmed]
  32. Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15. Gu, Y., Rosenblatt, J., Morgan, D.O. EMBO J. (1992) [Pubmed]
  33. Overexpression of cyclin-dependent kinase-activating CDC25B phosphatase in human gastric carcinomas. Kudo, Y., Yasui, W., Ue, T., Yamamoto, S., Yokozaki, H., Nikai, H., Tahara, E. Jpn. J. Cancer Res. (1997) [Pubmed]
  34. A fission yeast strain expressing human CDC25A phosphatase: a tool for selectivity studies of pharmacological inhibitors of CDC25. Mondesert, O., Lemaire, M., Brezak, M.C., Galera-Contour, M.O., Prevost, G., Ducommun, B., Bugler, B. Curr. Genet. (2004) [Pubmed]
  35. G protein beta gamma subunit-dependent Rac-guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm). Kiyono, M., Satoh, T., Kaziro, Y. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  36. Activation of p34cdc2 protein kinase by microinjection of human cdc25C into mammalian cells. Requirement for prior phosphorylation of cdc25C by p34cdc2 on sites phosphorylated at mitosis. Strausfeld, U., Fernandez, A., Capony, J.P., Girard, F., Lautredou, N., Derancourt, J., Labbe, J.C., Lamb, N.J. J. Biol. Chem. (1994) [Pubmed]
  37. Mapping of the human C3G gene coding a guanine nucleotide releasing protein for Ras family to 9q34.3 by fluorescence in situ hybridization. Takai, S., Tanaka, M., Sugimura, H., Yamada, K., Naito, Y., Kino, I., Matsuda, M. Hum. Genet. (1994) [Pubmed]
  38. Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells. Mizuno, R., Oya, M., Hara, S., Matsumoto, M., Horiguchi, A., Ohigashi, T., Marumo, K., Murai, M. Oncol. Rep. (2005) [Pubmed]
  39. Higher eucaryotic cdc25 proteins are structurally related to phosphoseryl/threonyl protein phosphatases. Bellé, R., Ollivier, E., Guerrucci, M.A. Biol. Cell (1992) [Pubmed]
  40. Failure to inactivate CDK activity is responsible for the enhanced apoptotic response in U937 cells mediated by silencing ATM gene. Deng, J., Zhou, J., Meng, F., Li, D., Sun, H. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban. (2002) [Pubmed]
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