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

Written2008-03Fernando Calvo, Piero Crespo
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC) - IDICAN - Universidad de Cantabria, Departamento de Biología Molecular, Facultad de Medicina.Santander, 39011, Cantabria, Spain

(Note : for Links provided by Atlas : click)

Identity

Alias_namesGRF1
Alias_symbol (synonym)CDC25L
CDC25
GRF55
H-GRF55
GNRP
PP13187
Other alias
HGNC (Hugo) RASGRF1
LocusID (NCBI) 5923
Atlas_Id 43453
Location 15q25.1  [Link to chromosome band 15q25]
Location_base_pair Starts at 78959947 and ends at 79090873 bp from pter ( according to hg19-Feb_2009)  [Mapping RASGRF1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CTSH (15q25.1) / RASGRF1 (15q25.1)RASGRF1 (15q25.1) / HNRNPD (4q21.22)RASGRF1 (15q25.1) / HOMER2 (15q25.2)

DNA/RNA

Note 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.
Description 128.44 Kb, 28 exons.
Transcription mRNA size: 4022 bases.

Protein

Note 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.
 
  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.
Description 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.
Expression 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.
Localisation 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.
Function 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.
Homology 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).

Mutations

Note 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

Note
  
Entity Cancers
Note See above
  
  
Entity Glucose homeostasis
Disease 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 Neurodegenerative diseases
Disease Role in learning and memory processes in mature neurons. Possible link to neurodegenerative diseases such as Alzheimer disease (AD) or Creutzfeldt-Jacobs disease (CJD).
  

Bibliography

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PMID 9430727
 
Neuronal nuclear organization is controlled by cyclin-dependent kinase 5 phosphorylation of Ras Guanine nucleotide releasing factor-1.
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PMID 16921254
 
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Citation

This paper should be referenced as such :
Calvo, F ; Crespo, P
RASGRF1 (Ras protein-specific guanine nucleotide-releasing factor 1)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(1):47-51.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/RASGRF1ID43453ch15q25.html


External links

Nomenclature
HGNC (Hugo)RASGRF1   9875
Cards
AtlasRASGRF1ID43453ch15q25
Entrez_Gene (NCBI)RASGRF1  5923  Ras protein specific guanine nucleotide releasing factor 1
AliasesCDC25; CDC25L; GNRP; GRF1; 
GRF55; H-GRF55; PP13187; ras-GRF1
GeneCards (Weizmann)RASGRF1
Ensembl hg19 (Hinxton)ENSG00000058335 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000058335 [Gene_View]  chr15:78959947-79090873 [Contig_View]  RASGRF1 [Vega]
ICGC DataPortalENSG00000058335
TCGA cBioPortalRASGRF1
AceView (NCBI)RASGRF1
Genatlas (Paris)RASGRF1
WikiGenes5923
SOURCE (Princeton)RASGRF1
Genetics Home Reference (NIH)RASGRF1
Genomic and cartography
GoldenPath hg38 (UCSC)RASGRF1  -     chr15:78959947-79090873 -  15q25.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)RASGRF1  -     15q25.1   [Description]    (hg19-Feb_2009)
EnsemblRASGRF1 - 15q25.1 [CytoView hg19]  RASGRF1 - 15q25.1 [CytoView hg38]
Mapping of homologs : NCBIRASGRF1 [Mapview hg19]  RASGRF1 [Mapview hg38]
OMIM606600   
Gene and transcription
Genbank (Entrez)AF370414 AK092325 AK226101 AK290135 AK301205
RefSeq transcript (Entrez)NM_001145648 NM_002891 NM_153815
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)RASGRF1
Cluster EST : UnigeneHs.459035 [ NCBI ]
CGAP (NCI)Hs.459035
Alternative Splicing GalleryENSG00000058335
Gene ExpressionRASGRF1 [ NCBI-GEO ]   RASGRF1 [ EBI - ARRAY_EXPRESS ]   RASGRF1 [ SEEK ]   RASGRF1 [ MEM ]
Gene Expression Viewer (FireBrowse)RASGRF1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5923
GTEX Portal (Tissue expression)RASGRF1
Human Protein AtlasENSG00000058335-RASGRF1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13972   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ13972  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ13972
Splice isoforms : SwissVarQ13972
PhosPhoSitePlusQ13972
Domaine pattern : Prosite (Expaxy)DH_1 (PS00741)    DH_2 (PS50010)    IQ (PS50096)    PH_DOMAIN (PS50003)    RASGEF (PS00720)    RASGEF_CAT (PS50009)    RASGEF_NTER (PS50212)   
Domains : Interpro (EBI)DH-domain    GDS_CDC24_CS    IQ_motif_EF-hand-BS    PH_dom-like    PH_domain    Ras-like_Gua-exchang_fac_N    Ras_G-nucl-exch_fac_CS    Ras_GEF_dom    RASGEF_cat_dom    RasGRF1   
Domain families : Pfam (Sanger)PH (PF00169)    RasGEF (PF00617)    RasGEF_N (PF00618)    RhoGEF (PF00621)   
Domain families : Pfam (NCBI)pfam00169    pfam00617    pfam00618    pfam00621   
Domain families : Smart (EMBL)PH (SM00233)  RasGEF (SM00147)  RasGEFN (SM00229)  RhoGEF (SM00325)  
Conserved Domain (NCBI)RASGRF1
DMDM Disease mutations5923
Blocks (Seattle)RASGRF1
SuperfamilyQ13972
Human Protein Atlas [tissue]ENSG00000058335-RASGRF1 [tissue]
Peptide AtlasQ13972
IPIIPI00016784   IPI00171312   IPI00435928   IPI00795882   
Protein Interaction databases
DIP (DOE-UCLA)Q13972
IntAct (EBI)Q13972
FunCoupENSG00000058335
BioGRIDRASGRF1
STRING (EMBL)RASGRF1
ZODIACRASGRF1
Ontologies - Pathways
QuickGOQ13972
Ontology : AmiGOMAPK cascade  guanyl-nucleotide exchange factor activity  Ras guanyl-nucleotide exchange factor activity  Rho guanyl-nucleotide exchange factor activity  cytosol  plasma membrane  plasma membrane  signal transduction  small GTPase mediated signal transduction  long-term memory  cell proliferation  growth cone  neuron projection development  regulation of Rac protein signal transduction  regulation of Rho protein signal transduction  glutamate receptor binding  neuron projection  positive regulation of GTPase activity  regulation of Ras protein signal transduction  positive regulation of Ras protein signal transduction  positive regulation of Ras protein signal transduction  regulation of synaptic plasticity  regulation of neuronal synaptic plasticity  activation of GTPase activity  regulation of NMDA receptor activity  
Ontology : EGO-EBIMAPK cascade  guanyl-nucleotide exchange factor activity  Ras guanyl-nucleotide exchange factor activity  Rho guanyl-nucleotide exchange factor activity  cytosol  plasma membrane  plasma membrane  signal transduction  small GTPase mediated signal transduction  long-term memory  cell proliferation  growth cone  neuron projection development  regulation of Rac protein signal transduction  regulation of Rho protein signal transduction  glutamate receptor binding  neuron projection  positive regulation of GTPase activity  regulation of Ras protein signal transduction  positive regulation of Ras protein signal transduction  positive regulation of Ras protein signal transduction  regulation of synaptic plasticity  regulation of neuronal synaptic plasticity  activation of GTPase activity  regulation of NMDA receptor activity  
Pathways : KEGGMAPK signaling pathway    Ras signaling pathway    Focal adhesion   
REACTOMEQ13972 [protein]
REACTOME PathwaysR-HSA-5673001 [pathway]   
NDEx NetworkRASGRF1
Atlas of Cancer Signalling NetworkRASGRF1
Wikipedia pathwaysRASGRF1
Orthology - Evolution
OrthoDB5923
GeneTree (enSembl)ENSG00000058335
Phylogenetic Trees/Animal Genes : TreeFamRASGRF1
HOVERGENQ13972
HOGENOMQ13972
Homologs : HomoloGeneRASGRF1
Homology/Alignments : Family Browser (UCSC)RASGRF1
Gene fusions - Rearrangements
Fusion : MitelmanCTSH/RASGRF1 [15q25.1/15q25.1]  [t(15;15)(q25;q25)]  
Fusion : MitelmanRASGRF1/HOMER2 [15q25.1/15q25.2]  [t(15;15)(q25;q25)]  
Fusion: TCGA_MDACCCTSH 15q25.1 RASGRF1 15q25.1 BRCA LUAD
Fusion: TCGA_MDACCRASGRF1 15q25.1 HOMER2 15q25.2 PRAD
Tumor Fusion PortalRASGRF1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRASGRF1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RASGRF1
dbVarRASGRF1
ClinVarRASGRF1
1000_GenomesRASGRF1 
Exome Variant ServerRASGRF1
ExAC (Exome Aggregation Consortium)ENSG00000058335
GNOMAD BrowserENSG00000058335
Genetic variants : HAPMAP5923
Genomic Variants (DGV)RASGRF1 [DGVbeta]
DECIPHERRASGRF1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisRASGRF1 
Mutations
ICGC Data PortalRASGRF1 
TCGA Data PortalRASGRF1 
Broad Tumor PortalRASGRF1
OASIS PortalRASGRF1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRASGRF1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDRASGRF1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch RASGRF1
DgiDB (Drug Gene Interaction Database)RASGRF1
DoCM (Curated mutations)RASGRF1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)RASGRF1 (select a term)
intoGenRASGRF1
NCG5 (London)RASGRF1
Cancer3DRASGRF1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606600   
Orphanet
DisGeNETRASGRF1
MedgenRASGRF1
Genetic Testing Registry RASGRF1
NextProtQ13972 [Medical]
TSGene5923
GENETestsRASGRF1
Target ValidationRASGRF1
Huge Navigator RASGRF1 [HugePedia]
snp3D : Map Gene to Disease5923
BioCentury BCIQRASGRF1
ClinGenRASGRF1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5923
Chemical/Pharm GKB GenePA34238
Clinical trialRASGRF1
Miscellaneous
canSAR (ICR)RASGRF1 (select the gene name)
Probes
Litterature
PubMed54 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineRASGRF1
EVEXRASGRF1
GoPubMedRASGRF1
iHOPRASGRF1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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