Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi

RasGrf (RAS Protein-Specific Guanine Nucleotide-Releasing Factor)

  • Eugenio Santos
  • Alberto Fernández-Medarde
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_138


 CDC25;  CDC25L;  CDC25Mm;  GNRP;  GRF

Historical Background

The Ras guanine nucleotide releasing factor (RasGrf) proteins were isolated in an effort to find mammalian homolog(s) of the yeast CDC25 Ras activator protein. The search for mammalian Ras GEFs during the early 1990s led to the discovery and isolation of the Son of sevenless (Sos) and the RasGrf proteins. Whereas the Sos proteins had ubiquitous expression, RasGrf expression was restricted mainly to the central nervous system. Soon after the discovery of the first member of the RasGrf family (RasGrf1) in neural tissues, a second highly homologous member of this family was isolated from embryonic stem cells (RasGrf2). Later on, a number of distinct, alternatively spliced isoforms have been described for both genes in a variety of tissues or developmental stages. RasGrf1 and RasGrf2 are large, modular proteins composed by multiple functional domains accounting for protein–protein or protein–lipid interactions which are...

This is a preview of subscription content, log in to check access.


  1. 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(24):21878–84.PubMedCrossRefGoogle Scholar
  2. Brambilla R, Gnesutta N, Minichiello L, White G, Roylance AJ, Herron CE, et al. A role for the Ras signaling pathway in synaptic transmission and long-term memory. Nature. 1997;390:281–6.PubMedCrossRefGoogle Scholar
  3. de Hoog CL, Fan W-T, Goldstein MD, Moran MF, Koch CA. Calmodulin-independent coordination of Ras and extracellular signal-regulated kinase activation by Ras-GRF2. Mol Cell Biol. 2000;20:2727–33.PubMedCrossRefGoogle Scholar
  4. Fernandez-Medarde A, Barhoum R, Riquelme R, Porteros A, Nunez A, de Luis A, et al. RasGRF1 disruption causes retinal photoreception defects and associated transcriptomic alterations. J Neurochem. 2009;110(2):641–52.PubMedCrossRefGoogle Scholar
  5. Font de Mora J, Esteban LM, Burks DJ, Nunez A, Garces C, Garcia-Barrado MJ, et al. Ras-GRF1 signaling is required for normal beta-cell development and glucose homeostasis. EMBO J. 2003;22(12):3039–49.PubMedCrossRefGoogle Scholar
  6. Freshney NW, Goonesekera SD, Feig LA. Activation of the exchange factor Ras-GRF by calcium requires an intact Dbl homology domain. FEBS Lett. 1997;407:111–5.PubMedCrossRefGoogle Scholar
  7. Innocenti M, Zippel R, Brambilla R, Sturani E. CDC25(Mm)/Ras-GRF1 regulates both Ras and Rac signaling pathways. FEBS Lett. 1999;460(2):357–62.PubMedCrossRefGoogle Scholar
  8. Kesavapany S, Pareek TK, Zheng YL, Amin N, Gutkind JS, Ma W, et al. Neuronal nuclear organization is controlled by cyclin-dependent kinase 5 phosphorylation of Ras guanine nucleotide releasing factor-1. Neurosignals. 2006;15(4):157–73.PubMedCrossRefGoogle Scholar
  9. Kiyono M, Kaziro Y, Satoh T. Induction of rac-guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) following phosphorylation by the nonreceptor tyrosine kinase Src. J Biol Chem. 2000;275(8):5441–6.PubMedCrossRefGoogle Scholar
  10. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C, et al. The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron. 2003;40(4):775–84.PubMedCrossRefGoogle Scholar
  11. Li S, Tian X, Hartley DM, Feig LA. 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. J Neurosci. 2006;26(6):1721–9.PubMedCrossRefGoogle Scholar
  12. Mattingly RR. Phosphorylation of serine 916 of Ras-GRF1 contributes to the activation of exchange factor activity by muscarinic receptors. J Biol Chem. 1999;274:37379–84.PubMedCrossRefGoogle Scholar
  13. Norum JH, Dawood H, Mattingly RR, Sandnes D, Levy FO. Epac- and Rap- independent ERK1/2 phosphorylation induced by Gs-coupled receptor stimulation in HEK293 cells. FEBS Lett. 2007;581(1):15–20.PubMedCrossRefGoogle Scholar
  14. Robinson KN, Manto K, Buchsbaum RJ, MacDonald JI, Meakin SO. Neurotrophin-dependent tyrosine phosphorylation of Ras guanine-releasing factor 1 and associated neurite outgrowth is dependent on the HIKE domain of TrkA. J Biol Chem. 2005;280(1):225–35.PubMedCrossRefGoogle Scholar
  15. Ruiz S, Santos E, Bustelo XR. RasGRF2, a guanosine nucleotide exchange factor for Ras GTPases, participates in T-cell signaling responses. Mol Cell Biol. 2007;27(23):8127–42.PubMedCrossRefGoogle Scholar
  16. Santos E, Fernandez-Medarde A. RasGrf1. UCSD-nature molecule pages. 2009. doi:10.1038/mp.a002032.01.Google Scholar
  17. Santos E, Fernández-Medarde A. RasGrf2. UCSD-nature molecule pages. 2008. doi:10.1038/mp.a002441.01.Google Scholar
  18. Tonini R, Ciardo S, Cerovic M, Rubino T, Parolaro D, Mazzanti M, et al. ERK-dependent modulation of cerebellar synaptic plasticity after chronic Delta9-tetrahydrocannabinol exposure. J Neurosci. 2006;26(21):5810–8.PubMedCrossRefGoogle Scholar
  19. Yoon B, Herman H, Hu B, Park YJ, Lindroth A, Bell A, et al. Rasgrf1 imprinting is regulated by a CTCF-dependent methylation-sensitive enhancer blocker. Mol Cell Biol. 2005;25(24):11184–90.PubMedCrossRefGoogle Scholar
  20. Zippel R, Orecchia S, Sturani E, Martegani E. The brain specific Ras exchange factor CDC25 Mm: modulation of its activity through Gi-protein-mediated signals. Oncogene. 1996;12(12):2697–703.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Centro de Investigación del Cáncer, IBMCC (CSIC/USAL), University of SalamancaSalamancaSpain