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Protein

Ras-specific guanine nucleotide-releasing factor 2

Gene

RASGRF2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Functions as a calcium-regulated nucleotide exchange factor activating both Ras and RAC1 through the exchange of bound GDP for GTP. Preferentially activates HRAS in vivo compared to RRAS based on their different types of prenylation. Functions in synaptic plasticity by contributing to the induction of long term potentiation.1 Publication

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Guanine-nucleotide releasing factor

Keywords - Ligandi

Calcium, Calmodulin-binding

Enzyme and pathway databases

ReactomeiR-HSA-193648. NRAGE signals death through JNK.
R-HSA-194840. Rho GTPase cycle.
R-HSA-416482. G alpha (12/13) signalling events.
R-HSA-442982. Ras activation uopn Ca2+ infux through NMDA receptor.
R-HSA-5673001. RAF/MAP kinase cascade.

Names & Taxonomyi

Protein namesi
Recommended name:
Ras-specific guanine nucleotide-releasing factor 2
Short name:
Ras-GRF2
Alternative name(s):
Ras guanine nucleotide exchange factor 2
Gene namesi
Name:RASGRF2
Synonyms:GRF2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

HGNCiHGNC:9876. RASGRF2.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Endoplasmic reticulum, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi737 – 7371S → A: Loss of phosphorylation by CDK5. 1 Publication

Organism-specific databases

PharmGKBiPA34239.

Polymorphism and mutation databases

BioMutaiRASGRF2.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 12371237Ras-specific guanine nucleotide-releasing factor 2PRO_0000312863Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei726 – 7261PhosphoserineBy similarity
Modified residuei727 – 7271PhosphoserineBy similarity
Modified residuei737 – 7371Phosphoserine; by CDK51 Publication
Modified residuei746 – 7461PhosphoserineCombined sources
Modified residuei848 – 8481PhosphoserineBy similarity
Modified residuei852 – 8521PhosphoserineBy similarity
Modified residuei972 – 9721PhosphoserineBy similarity

Post-translational modificationi

Phosphorylated by CDK5; down-regulates RASGRF2-mediated RAC1 activation.1 Publication
Ubiquitinated upon interaction with Ras. Ubiquitination leads to degradation through the 26S proteasome (By similarity).By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO14827.
PaxDbiO14827.
PRIDEiO14827.

PTM databases

iPTMnetiO14827.
PhosphoSiteiO14827.

Expressioni

Tissue specificityi

Widely expressed with higher expression in brain, followed by heart, lung, pancreas and kidney. Detected in placenta. Expressed in brain and lung (at protein level).2 Publications

Gene expression databases

BgeeiO14827.
CleanExiHS_RASGRF2.
ExpressionAtlasiO14827. baseline and differential.
GenevisibleiO14827. HS.

Organism-specific databases

HPAiHPA018679.

Interactioni

Subunit structurei

Homooligomer and heterooligomer with RASGRF1. Interacts with Ras and RAC1. Interacts in a calcium-dependent manner with calmodulin (By similarity). Interacts with CDK5R1 and EPB49. Interacts with the AMPA receptor through GRIA1 (By similarity). Interacts with microtubules (By similarity).By similarity

Protein-protein interaction databases

BioGridi111859. 5 interactions.
IntActiO14827. 2 interactions.
STRINGi9606.ENSP00000265080.

Structurei

3D structure databases

ProteinModelPortaliO14827.
SMRiO14827. Positions 1002-1234.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini22 – 133112PH 1PROSITE-ProRule annotationAdd
BLAST
Domaini205 – 23430IQPROSITE-ProRule annotationAdd
BLAST
Domaini243 – 429187DHPROSITE-ProRule annotationAdd
BLAST
Domaini470 – 588119PH 2PROSITE-ProRule annotationAdd
BLAST
Domaini635 – 756122N-terminal Ras-GEFPROSITE-ProRule annotationAdd
BLAST
Domaini1002 – 1234233Ras-GEFPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni744 – 7529Regulates proteasomal degradationBy similarity
Regioni1099 – 112830Responsible of the affinity for farnesylated versus geranylgeranylated RasBy similarityAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili155 – 19339Sequence analysisAdd
BLAST

Domaini

The Ras-GEF domain and the N-terminal Ras-GEF domain form a Ras-binding site and mediate Ras activation.By similarity
The IQ domain mediates the calcium-dependent interaction with calmodulin but is dispensable for the Ras-GEF activity.By similarity
The DH (DBL-homology) domain mediates interaction with RASGRF1 and EPB49 and is required for RAC1 activation.

Sequence similaritiesi

Contains 1 DH (DBL-homology) domain.PROSITE-ProRule annotation
Contains 1 IQ domain.PROSITE-ProRule annotation
Contains 1 N-terminal Ras-GEF domain.PROSITE-ProRule annotation
Contains 2 PH domains.PROSITE-ProRule annotation
Contains 1 Ras-GEF domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil, Repeat

Phylogenomic databases

eggNOGiENOG410IQ6Q. Eukaryota.
ENOG410XPWA. LUCA.
GeneTreeiENSGT00810000125349.
HOGENOMiHOG000046000.
HOVERGENiHBG005208.
InParanoidiO14827.
KOiK12326.
OMAiIIQLTDC.
OrthoDBiEOG7H1JKP.
PhylomeDBiO14827.
TreeFamiTF317296.

Family and domain databases

Gene3Di1.10.840.10. 1 hit.
1.20.900.10. 1 hit.
2.30.29.30. 2 hits.
InterProiIPR000219. DH-domain.
IPR000048. IQ_motif_EF-hand-BS.
IPR011993. PH_dom-like.
IPR001849. PH_domain.
IPR000651. Ras-like_Gua-exchang_fac_N.
IPR019804. Ras_G-nucl-exch_fac_CS.
IPR023578. Ras_GEF_dom.
IPR001895. RASGEF_cat_dom.
IPR030744. RasGRF2.
[Graphical view]
PANTHERiPTHR23113:SF187. PTHR23113:SF187. 3 hits.
PfamiPF00169. PH. 1 hit.
PF00617. RasGEF. 1 hit.
PF00618. RasGEF_N. 1 hit.
PF00621. RhoGEF. 1 hit.
[Graphical view]
SMARTiSM00233. PH. 2 hits.
SM00147. RasGEF. 1 hit.
SM00229. RasGEFN. 2 hits.
SM00325. RhoGEF. 1 hit.
[Graphical view]
SUPFAMiSSF48065. SSF48065. 1 hit.
SSF48366. SSF48366. 2 hits.
SSF50729. SSF50729. 2 hits.
PROSITEiPS50010. DH_2. 1 hit.
PS50096. IQ. 1 hit.
PS50003. PH_DOMAIN. 2 hits.
PS00720. RASGEF. 1 hit.
PS50009. RASGEF_CAT. 1 hit.
PS50212. RASGEF_NTER. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

O14827-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MQKSVRYNEG HALYLAFLAR KEGTKRGFLS KKTAEASRWH EKWFALYQNV
60 70 80 90 100
LFYFEGEQSC RPAGMYLLEG CSCERTPAPP RAGAGQGGVR DALDKQYYFT
110 120 130 140 150
VLFGHEGQKP LELRCEEEQD GKEWMEAIHQ ASYADILIER EVLMQKYIHL
160 170 180 190 200
VQIVETEKIA ANQLRHQLED QDTEIERLKS EIIALNKTKE RMRPYQSNQE
210 220 230 240 250
DEDPDIKKIK KVQSFMRGWL CRRKWKTIVQ DYICSPHAES MRKRNQIVFT
260 270 280 290 300
MVEAESEYVH QLYILVNGFL RPLRMAASSK KPPISHDDVS SIFLNSETIM
310 320 330 340 350
FLHEIFHQGL KARIANWPTL ILADLFDILL PMLNIYQEFV RNHQYSLQVL
360 370 380 390 400
ANCKQNRDFD KLLKQYEANP ACEGRMLETF LTYPMFQIPR YIITLHELLA
410 420 430 440 450
HTPHEHVERK SLEFAKSKLE ELSRVMHDEV SDTENIRKNL AIERMIVEGC
460 470 480 490 500
DILLDTSQTF IRQGSLIQVP SVERGKLSKV RLGSLSLKKE GERQCFLFTK
510 520 530 540 550
HFLICTRSSG GKLHLLKTGG VLSLIDCTLI EEPDASDDDS KGSGQVFGHL
560 570 580 590 600
DFKIVVEPPD AAAFTVVLLA PSRQEKAAWM SDISQCVDNI RCNGLMTIVF
610 620 630 640 650
EENSKVTVPH MIKSDARLHK DDTDICFSKT LNSCKVPQIR YASVERLLER
660 670 680 690 700
LTDLRFLSID FLNTFLHTYR IFTTAAVVLG KLSDIYKRPF TSIPVRSLEL
710 720 730 740 750
FFATSQNNRG EHLVDGKSPR LCRKFSSPPP LAVSRTSSPV RARKLSLTSP
760 770 780 790 800
LNSKIGALDL TTSSSPTTTT QSPAASPPPH TGQIPLDLSR GLSSPEQSPG
810 820 830 840 850
TVEENVDNPR VDLCNKLKRS IQKAVLESAP ADRAGVESSP AADTTELSPC
860 870 880 890 900
RSPSTPRHLR YRQPGGQTAD NAHCSVSPAS AFAIATAAAG HGSPPGFNNT
910 920 930 940 950
ERTCDKEFII RRTATNRVLN VLRHWVSKHA QDFELNNELK MNVLNLLEEV
960 970 980 990 1000
LRDPDLLPQE RKAAANILRA LSQDDQDDIH LKLEDIIQMT DCMKAECFES
1010 1020 1030 1040 1050
LSAMELAEQI TLLDHVIFRS IPYEEFLGQG WMKLDKNERT PYIMKTSQHF
1060 1070 1080 1090 1100
NDMSNLVASQ IMNYADVSSR ANAIEKWVAV ADICRCLHNY NGVLEITSAL
1110 1120 1130 1140 1150
NRSAIYRLKK TWAKVSKQTK ALMDKLQKTV SSEGRFKNLR ETLKNCNPPA
1160 1170 1180 1190 1200
VPYLGMYLTD LAFIEEGTPN FTEEGLVNFS KMRMISHIIR EIRQFQQTSY
1210 1220 1230
RIDHQPKVAQ YLLDKDLIID EDTLYELSLK IEPRLPA
Length:1,237
Mass (Da):140,764
Last modified:December 4, 2007 - v2
Checksum:iA136CF4FA111FDD9
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti561 – 5611A → R in AAB80953 (PubMed:10373510).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti114 – 1141R → H in a colorectal cancer sample; somatic mutation. 1 Publication
VAR_037595
Natural varianti538 – 5381D → N in a breast cancer sample; somatic mutation. 1 Publication
VAR_037596
Natural varianti713 – 7131L → W.
Corresponds to variant rs16878472 [ dbSNP | Ensembl ].
VAR_037597
Natural varianti1216 – 12161D → E in a breast cancer sample; somatic mutation. 1 Publication
VAR_037598

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF023130 mRNA. Translation: AAB80953.1.
AF181250 mRNA. Translation: AAD55268.1.
CH471084 mRNA. Translation: EAW95863.1.
BC126112 mRNA. Translation: AAI26113.1.
BC136296 mRNA. Translation: AAI36297.1.
CCDSiCCDS4052.1.
RefSeqiNP_008840.1. NM_006909.2.
UniGeneiHs.162129.

Genome annotation databases

EnsembliENST00000265080; ENSP00000265080; ENSG00000113319.
GeneIDi5924.
KEGGihsa:5924.
UCSCiuc003kha.3. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF023130 mRNA. Translation: AAB80953.1.
AF181250 mRNA. Translation: AAD55268.1.
CH471084 mRNA. Translation: EAW95863.1.
BC126112 mRNA. Translation: AAI26113.1.
BC136296 mRNA. Translation: AAI36297.1.
CCDSiCCDS4052.1.
RefSeqiNP_008840.1. NM_006909.2.
UniGeneiHs.162129.

3D structure databases

ProteinModelPortaliO14827.
SMRiO14827. Positions 1002-1234.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi111859. 5 interactions.
IntActiO14827. 2 interactions.
STRINGi9606.ENSP00000265080.

PTM databases

iPTMnetiO14827.
PhosphoSiteiO14827.

Polymorphism and mutation databases

BioMutaiRASGRF2.

Proteomic databases

EPDiO14827.
PaxDbiO14827.
PRIDEiO14827.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000265080; ENSP00000265080; ENSG00000113319.
GeneIDi5924.
KEGGihsa:5924.
UCSCiuc003kha.3. human.

Organism-specific databases

CTDi5924.
GeneCardsiRASGRF2.
HGNCiHGNC:9876. RASGRF2.
HPAiHPA018679.
MIMi606614. gene.
neXtProtiNX_O14827.
PharmGKBiPA34239.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IQ6Q. Eukaryota.
ENOG410XPWA. LUCA.
GeneTreeiENSGT00810000125349.
HOGENOMiHOG000046000.
HOVERGENiHBG005208.
InParanoidiO14827.
KOiK12326.
OMAiIIQLTDC.
OrthoDBiEOG7H1JKP.
PhylomeDBiO14827.
TreeFamiTF317296.

Enzyme and pathway databases

ReactomeiR-HSA-193648. NRAGE signals death through JNK.
R-HSA-194840. Rho GTPase cycle.
R-HSA-416482. G alpha (12/13) signalling events.
R-HSA-442982. Ras activation uopn Ca2+ infux through NMDA receptor.
R-HSA-5673001. RAF/MAP kinase cascade.

Miscellaneous databases

ChiTaRSiRASGRF2. human.
GeneWikiiRASGRF2.
GenomeRNAii5924.
NextBioi23072.
PROiO14827.
SOURCEiSearch...

Gene expression databases

BgeeiO14827.
CleanExiHS_RASGRF2.
ExpressionAtlasiO14827. baseline and differential.
GenevisibleiO14827. HS.

Family and domain databases

Gene3Di1.10.840.10. 1 hit.
1.20.900.10. 1 hit.
2.30.29.30. 2 hits.
InterProiIPR000219. DH-domain.
IPR000048. IQ_motif_EF-hand-BS.
IPR011993. PH_dom-like.
IPR001849. PH_domain.
IPR000651. Ras-like_Gua-exchang_fac_N.
IPR019804. Ras_G-nucl-exch_fac_CS.
IPR023578. Ras_GEF_dom.
IPR001895. RASGEF_cat_dom.
IPR030744. RasGRF2.
[Graphical view]
PANTHERiPTHR23113:SF187. PTHR23113:SF187. 3 hits.
PfamiPF00169. PH. 1 hit.
PF00617. RasGEF. 1 hit.
PF00618. RasGEF_N. 1 hit.
PF00621. RhoGEF. 1 hit.
[Graphical view]
SMARTiSM00233. PH. 2 hits.
SM00147. RasGEF. 1 hit.
SM00229. RasGEFN. 2 hits.
SM00325. RhoGEF. 1 hit.
[Graphical view]
SUPFAMiSSF48065. SSF48065. 1 hit.
SSF48366. SSF48366. 2 hits.
SSF50729. SSF50729. 2 hits.
PROSITEiPS50010. DH_2. 1 hit.
PS50096. IQ. 1 hit.
PS50003. PH_DOMAIN. 2 hits.
PS00720. RASGEF. 1 hit.
PS50009. RASGEF_CAT. 1 hit.
PS50212. RASGEF_NTER. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Ras-specific exchange factor GRF: oligomerization through its Dbl homology domain and calcium-dependent activation of Raf."
    Anborgh P.H., Qian X., Papageorge A.G., Vass W.C., DeClue J.E., Lowy D.R.
    Mol. Cell. Biol. 19:4611-4622(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], OLIGOMERIZATION, INTERACTION WITH RASGRF1, TISSUE SPECIFICITY.
    Tissue: Hippocampus.
  2. "Dematin interacts with the Ras-guanine nucleotide exchange factor Ras-GRF2 and modulates mitogen-activated protein kinase pathways."
    Lutchman M., Kim A.C., Cheng L., Whitehead I.P., Oh S.S., Hanspal M., Boukharov A.A., Hanada T., Chishti A.H.
    Eur. J. Biochem. 269:638-649(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH EPB49, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
    Tissue: Fetal brain.
  3. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Brain.
  5. "Inhibitory effects of a dominant-interfering form of the Rho-GTPase Cdc42 in the chemoattractant-elicited signaling pathways leading to NADPH oxidase activation in differentiated HL-60 cells."
    Rabiet M.-J., Tardif M., Braun L., Boulay F.
    Blood 100:1835-1844(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  6. "p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor 2 (RasGRF2) mediates Rac-dependent extracellular signal-regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated protein 1b distribution in neurons."
    Kesavapany S., Amin N., Zheng Y.-L., Nijhara R., Jaffe H., Sihag R., Gutkind J.S., Takahashi S., Kulkarni A., Grant P., Pant H.C.
    J. Neurosci. 24:4421-4431(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CDK5R1, PHOSPHORYLATION AT SER-737 BY CDK5, MUTAGENESIS OF SER-737.
  7. "Activation of H-Ras in the endoplasmic reticulum by the RasGRF family guanine nucleotide exchange factors."
    Arozarena I., Matallanas D., Berciano M.T., Sanz-Moreno V., Calvo F., Munoz M.T., Egea G., Lafarga M., Crespo P.
    Mol. Cell. Biol. 24:1516-1530(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  8. "System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
    Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
    Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-746, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  9. Cited for: VARIANTS [LARGE SCALE ANALYSIS] HIS-114; ASN-538 AND GLU-1216.

Entry informationi

Entry nameiRGRF2_HUMAN
AccessioniPrimary (citable) accession number: O14827
Secondary accession number(s): B9EG89, Q9UK56
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 4, 2007
Last sequence update: December 4, 2007
Last modified: May 11, 2016
This is version 135 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 5
    Human chromosome 5: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.