RASGRF1 (Ras protein-specific guanine nucleotide-releasing factor 1)

2008-03-01   Fernando Calvo , Piero Crespo 





Differential imprinted methylation of the paternal and maternal alleles in neonatal brain. The methylation of promoter of the paternal allele prevents the binding and gene silencing caused by CTCF in the unmethylated maternal allele.


128.44 Kb, 28 exons.


mRNA size: 4022 bases.



In the early 90s, several groups identified in murine brain extracts, a protein of a molecular weight between 100-160 kDa, named Ras-GRF (Ras-Guanine nucleotide Releasing Factor) and Cdc25Mm, based on its ability to induce GDP release in p21ras and on its high homology with the Sacharomyces cerevisiae gene CDC25, whose deficiency it could rescue.
Atlas Image
The diagram shows the functional modules present in Ras-GRF1. The flanking amino-acid limits shown correspond to the human protein. Arrows indicate the phosphorylation sites that have been characterized and, in brackets, the kinases responsible. It should be noted that Ras-GRF1 has approximately 83 predicted phosphorylation sites; 63 serines, 19 threonines and 11 tyrosines. The regions essential for inducing GDP/GTP release in Rac and Ras GTPases are underlined. Other interacting proteins and the regions involved in such interactions are shown by broken lines. PM, Plasma Membrane; CaM, Calmodulin. The descriptions of Ras-GRF domains can be found in the text.


Ras-GRF1 is a protein that contains multiple modular motifs. The Ras-GEF region, includes the Cdc25 domain which exhibits guanine nucleotide exchange factor (GEF) activity towards the Ras family GTPase and a REM (Ras Exchanger-stabilization Motif) domain, responsible for the stabilization of the core of the Cdc25 domain. Separating these domains, there is a region rich in proline, glutamic acid, serine and treonine aminoacids (PEST) that constitutes a hypothetical target for proteolysis.
Ras-GRF1 also possesses: two pleckstrin-homology (PH) domains, which have been suggested to interact with polyphosphoinositides and other types of phospholipids and may play some role in Ras-GRF1 interactions with membranes: the α-helical coiled-coil (CC) motif plays a role in protein-protein interactions; a Isoleucine-Glutamin (IQ) domain, which binds Calmodulin and is responsible for the calcium-dependent activation of Ras-GRF1; and a dbl-homology (DH) region, which exhibits GEF activity towards Rho family GTPases, in particular Rac-1. The DH domain also mediates in Ras-GRF dimerization that ensues upon activation. The DH domain and the second PH domain constitute the catalytic module, archetypically present in all Rho-GEFs, which entails nucleotide exchange activity over Rho family GTPases. Ras-GRF1, along with Ras-GRF2 and Sos, are the only known exchange factors that combine Rho and Ras exchanger activity in the same protein.


Ras-GRF1 is fundamentally expressed in the central nervous system and, at a reduced level, also in the spinal cord. It is more abundant in hippocampus, some deep nuclei, neocortex, and the granule cell layer of the anterior lobules of the cerebellum. Its expression is low during embryonary development and increased drastically in the first days after birth. Its presence has also been reported in pancreatic beta cells. Alternative splicing variants are expressed in brain, lung, pancreas, as well as several tumour cell lines.


By immunofluorescence, Ras-GRF1 exhibits a predominant cytoplasmic distribution, particularly at the perinuclear area, and mostly excluded from lamelipodia and peripheral structures. However, significant amounts are also associated to the plasma-membrane and in the endoplasmic reticulum, but not the Golgi Apparatus. Such a distribution can be ascertained by biochemical fractionation, which shows Ras-GRF1 in both soluble and particulate fractions, its proportions vary depending on the cell type. Its association with membranes does not increase upon activation. In addition, it is also remarkably present in the synaptic junctions of mature neurons.


The main function of Ras-GRF1, relays in its ability to activate GTPases in response to signals emanating from G protein-coupled receptors and from calcium fluxes. Ras-GRF1 also plays an important role linking signals from AMPA and NMDA receptors to the MAPK/ERK cascade in mature neurons. Initially, it was believed that Ras-GRF1 was unresponsive to signals generated by tyrosine kinase receptors, but lately, it has been demonstrated that Trk-family receptors can phosphorylate and directly associate to Ras-GRF1. Ras-GRF1 acts as a bifunctional protein with the ability to activate both Ras and Rac-1 GTPases. In vitro, Ras-GRF1 can activate H-Ras, K-Ras and N-Ras GTPases, but in vivo, its specificity is reduced to H-Ras, probably as a consequence of microlocalization processes taking place. Ras-GRF1 can also activate the R-Ras subfamily GTPases, namely: , TC21 and M-Ras. On the other hand, Ras-GRF1 acts as a Rac-GEF when activated in a Gβγ-dependent fashion. Another Rho-family GTPase, Cdc42, exhibits a functional relationship with Ras-GRF1 activity, by being capable of negatively regulating Ras-GRF1 Ras-GEF functions. The mechanisms whereby such a regulation is achieved are yet unknown.
Ras-GRF1 knock-out mice are viable and show no major developmental alterations. They do show some mental restrains: they are severely impaired in amygdala-dependent long-term synaptic plasticity and show higher basal synaptic activity at both amygdala and hippocampal synapses, showing faults in the process of memory consolidation. They also show a higher neuronal excitability, are more susceptible to convulsionant drugs and do not exhibit tolerance to chronic exposure to cannabinoids. It has also shown a protective role in the stroke-associated neuronal degeneration. With respect to non-CNS effects, Ras-GRF1 knock-out mice exhibit body weight loss, hypoinsulinemia and glucose intolerance, owing to a reduction of pancreatic beta-cells.
As a regulator of the activation of Ras GTPases, Ras-GRF1 could, conceptually, participate in all the processes regulated by those, including proliferation, survival and transformation. However, its restricted expression to the brain and localization in the synaptic junctions, suggest a more specific role. By regulating the activation state of the Rac GTPases, Ras-GRF1 could participate in processes that require cytoskeletal reorganization. Thus, by coordinating the activation of Rac and H-Ras, it can control neuronal morphology and neurite outgrowth in PC12 cells, in response to NGF. Experiments in Knock-out mice also demonstrate that Ras-GRF1 controls synaptic plasticity by regulating a Rac- and p38-dependent long-term depression. Through its association with the p38 scaffolf protein IB2/JIP2, Ras-GRF1 leads to a Rac-dependant activation of the p38 cascade. Moreover, it has been demonstrated that the microtubule-destabilizing factor SCLIP can interact with Ras-GRF1, reducing its ability to activate the Rac/p38 cascade while not affecting the Ras/ERK pathway. The splice variant p75-Ras-GRF1 plays a role in the c-jun-dependent non-adherent growth in Rat1A cells. Recently, it has been shown that, in human melanoma cells, the protein Filamin-A regulates the ubiquination and destabilization of Ras-GRF1 that correlated with a decrease in the expression of MMP-9, a matrix metalloproteinase associated to different biological processes such as growth, invasion and angiogenesis.


Ras-GRF1 has a highly homologous protein: Ras-GRF2 (86% homology), which, unlike Ras-GRF1, is more ubiquitously expressed. This protein is similar in its structure to Ras-GRF1, thus also functioning as signal transducer protein. It has been also described in pancreatic beta cells, a protein of 178 aminoacids whose N terminus is identical to that of GRF1 and whose C terminus is unrelated to known proteins (GRF β).



No Ras-GRF1 mutations have been reported hitherto in human tumours. Even though overexpression of Ras-GRF1 can induce transformation of murine fibroblats and morphological changes resembling transformation processes in other cellular types, no direct associations with human malignancies have been reported thus far.

Implicated in

Entity name
See above
Entity name
Glucose homeostasis
Role in maintaining glucose homeostasis by regulating pancreatic beta-cells mass. Ras-GRF1 knock-out mice show a phenotype similar to manifestations of preclinical type 2 diabetes.
Entity name
Neurodegenerative diseases
Role in learning and memory processes in mature neurons. Possible link to neurodegenerative diseases such as Alzheimer disease (AD) or Creutzfeldt-Jacobs disease (CJD).


Pubmed IDLast YearTitleAuthors
103735101999Ras-specific exchange factor GRF: oligomerization through its Dbl homology domain and calcium-dependent activation of Raf.Anborgh PH et al
147493692004Activation of H-Ras in the endoplasmic reticulum by the RasGRF family guanine nucleotide exchange factors.Arozarena I et al
171352672007SCLIP, a microtubule-destabilizing factor, interacts with RasGRF1 and inhibits its ability to promote Rac activation and neurite outgrowth.Baldassa S et al
110180282001Sites of phosphorylation by protein kinase A in CDC25Mm/GRF1, a guanine nucleotide exchange factor for Ras.Baouz S et al
93843791997A role for the Ras signalling pathway in synaptic transmission and long-term memory.Brambilla R et al
87566481996The N-terminal pleckstrin, coiled-coil, and IQ domains of the exchange factor Ras-GRF act cooperatively to facilitate activation by calcium.Buchsbaum R et al
125318972003Regulation of p70 S6 kinase by complex formation between the Rac guanine nucleotide exchange factor (Rac-GEF) Tiam1 and the scaffold spinophilin.Buchsbaum RJ et al
82469881993Regulated and constitutive activity by CDC25Mm (GRF), a Ras-specific exchange factor.Cen H et al
173210572007Laser microdissection and microarray analysis of the hippocampus of Ras-GRF1 knockout mice reveals gene expression changes affecting signal transduction pathways related to memory and learning.Fernández-Medarde A et al
98195571998To fear or not to fear: what was the question? A potential role for Ras-GRF in memory.Finkbeiner S et al
128052182003Ras-GRF1 signaling is required for normal beta-cell development and glucose homeostasis.Font de Mora J et al
166499902006The guanine nucleotide exchange factor RasGRF1 directly binds microtubules via DHPH2-mediated interaction.Forlani G et al
116409342001Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1).Giese KP et al
115004972001Cloning and characterization of mouse UBPy, a deubiquitinating enzyme that interacts with the ras guanine nucleotide exchange factor CDC25(Mm)/Ras-GRF1.Gnesutta N et al
86498021996Expression of alternative forms of Ras exchange factors GRF and SOS1 in different human tissues and cell lines.Guerrero C et al
94307271998Ras-GRF activates Ha-Ras, but not N-Ras or K-Ras 4B, protein in vivo.Jones MK et al
169212542006Neuronal nuclear organization is controlled by cyclin-dependent kinase 5 phosphorylation of Ras Guanine nucleotide releasing factor-1.Kesavapany S et al
106815202000Induction of rac-guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) following phosphorylation by the nonreceptor tyrosine kinase Src.Kiyono M et al
102203781999G protein beta gamma subunit-dependent Rac-guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm).Kiyono M et al
157982162005p75-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 VD et al
164675202006Distinct 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 et al
13762461992Cloning by functional complementation of a mouse cDNA encoding a homologue of CDC25, a Saccharomyces cerevisiae RAS activator.Martegani E et al
106013081999Phosphorylation of serine 916 of Ras-GRF1 contributes to the activation of exchange factor activity by muscarinic receptors.Mattingly RR et al
105570731999Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins.Movilla N et al
113601932001Sensitivity of wild type and mutant ras alleles to Ras specific exchange factors: Identification of factor specific requirements.Nielsen KH et al
158538142005Endogenous expression and protein kinase A-dependent phosphorylation of the guanine nucleotide exchange factor Ras-GRF1 in human embryonic kidney 293 cells.Norum JH et al
107774922000Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3.Ohba Y et al
121025582002A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases.Quilliam LA et al
155139152005Neurotrophin-dependent tyrosine phosphorylation of Ras guanine-releasing factor 1 and associated neurite outgrowth is dependent on the HIKE domain of TrkA.Robinson KN et al
150331642004Modulation of extracellular signal-regulated kinases cascade by chronic delta 9-tetrahydrocannabinol treatment.Rubino T et al
13793461992Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21.Shou C et al
77610901995Differential response of the Ras exchange factor, Ras-GRF to tyrosine kinase and G protein mediated signals.Shou C et al
92813591997The Ras Guanine nucleotide Exchange Factor CDC25Mm is present at the synaptic junction.Sturani E et al
164072082006Age-dependent participation of Ras-GRF proteins in coupling calcium-permeable AMPA glutamate receptors to Ras/Erk signaling in cortical neurons.Tian X et al
150292452004Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB.Tian X et al
117490432001Involvement of CDC25Mm/Ras-GRF1-dependent signaling in the control of neuronal excitability.Tonini R et al
13797311992Identification of a mammalian gene structurally and functionally related to the CDC25 gene of Saccharomyces cerevisiae.Wei W et al
82317371993Localization of the cellular expression pattern of cdc25NEF and ras in the juvenile rat brain.Wei W et al
21816671990A cytosolic protein catalyzes the release of GDP from p21ras.Wolfman A et al
117533862002Regulation of DNA methylation of Rasgrf1.Yoon BJ et al
173896012007Filamin A-mediated down-regulation of the exchange factor Ras-GRF1 correlates with decreased matrix metalloproteinase-9 expression in human melanoma cells.Zhu TN et al
93798341997Ras-GRF, the activator of Ras, is expressed preferentially in mature neurons of the central nervous system.Zippel R et al

Other Information

Locus ID:

NCBI: 5923
MIM: 606600
HGNC: 9875
Ensembl: ENSG00000058335


dbSNP: 5923
ClinVar: 5923
TCGA: ENSG00000058335


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Focal adhesionKEGGko04510
MAPK signaling pathwayKEGGhsa04010
Focal adhesionKEGGhsa04510
Ras signaling pathwayKEGGhsa04014
Neuronal SystemREACTOMER-HSA-112316
Transmission across Chemical SynapsesREACTOMER-HSA-112315
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic CellREACTOMER-HSA-112314
Activation of NMDA receptor upon glutamate binding and postsynaptic eventsREACTOMER-HSA-442755
Post NMDA receptor activation eventsREACTOMER-HSA-438064
CREB phosphorylation through the activation of RasREACTOMER-HSA-442742
Ras activation uopn Ca2+ infux through NMDA receptorREACTOMER-HSA-442982
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
208352362010A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25.92
208352362010A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25.92
168550282006RNA interference knockdown of hU2AF35 impairs cell cycle progression and modulates alternative splicing of Cdc25 transcripts.45
147493692004Activation of H-Ras in the endoplasmic reticulum by the RasGRF family guanine nucleotide exchange factors.41
252677922014CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity.38
216858912011RasGRF suppresses Cdc42-mediated tumour cell movement, cytoskeletal dynamics and transformation.36
265210382016Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians.17
176116842007Zoledronate-induced S phase arrest and apoptosis accompanied by DNA damage and activation of the ATM/Chk1/cdc25 pathway in human osteosarcoma cells.15
229617792012Aberrant methylation of RASGRF1 is associated with an epigenetic field defect and increased risk of gastric cancer.15
170306182006Timing and sequence requirements defined for embryonic maintenance of imprinted DNA methylation at Rasgrf1.14


Fernando Calvo ; Piero Crespo

RASGRF1 (Ras protein-specific guanine nucleotide-releasing factor 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-03-01

Online version: http://atlasgeneticsoncology.org/gene/43453/rasgrf1-(ras-protein-specific-guanine-nucleotide-releasing-factor-1)