RGRF2_HUMAN
ID RGRF2_HUMAN Reviewed; 1237 AA.
AC O14827; B9EG89; Q9UK56;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 04-DEC-2007, sequence version 2.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Ras-specific guanine nucleotide-releasing factor 2;
DE Short=Ras-GRF2;
DE AltName: Full=Ras guanine nucleotide exchange factor 2;
GN Name=RASGRF2; Synonyms=GRF2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], OLIGOMERIZATION, INTERACTION WITH RASGRF1, AND
RP TISSUE SPECIFICITY.
RC TISSUE=Hippocampus;
RX PubMed=10373510; DOI=10.1128/mcb.19.7.4611;
RA Anborgh P.H., Qian X., Papageorge A.G., Vass W.C., DeClue J.E., Lowy D.R.;
RT "Ras-specific exchange factor GRF: oligomerization through its Dbl homology
RT domain and calcium-dependent activation of Raf.";
RL Mol. Cell. Biol. 19:4611-4622(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH EPB49, SUBCELLULAR LOCATION,
RP AND TISSUE SPECIFICITY.
RC TISSUE=Fetal brain;
RX PubMed=11856323; DOI=10.1046/j.0014-2956.2001.02694.x;
RA Lutchman M., Kim A.C., Cheng L., Whitehead I.P., Oh S.S., Hanspal M.,
RA Boukharov A.A., Hanada T., Chishti A.H.;
RT "Dematin interacts with the Ras-guanine nucleotide exchange factor Ras-GRF2
RT and modulates mitogen-activated protein kinase pathways.";
RL Eur. J. Biochem. 269:638-649(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=12176907; DOI=10.1182/blood-2001-12-0193;
RA Rabiet M.-J., Tardif M., Braun L., Boulay F.;
RT "Inhibitory effects of a dominant-interfering form of the Rho-GTPase Cdc42
RT in the chemoattractant-elicited signaling pathways leading to NADPH oxidase
RT activation in differentiated HL-60 cells.";
RL Blood 100:1835-1844(2002).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CDK5R1, PHOSPHORYLATION AT
RP SER-737 BY CDK5, AND MUTAGENESIS OF SER-737.
RX PubMed=15128856; DOI=10.1523/jneurosci.0690-04.2004;
RA Kesavapany S., Amin N., Zheng Y.-L., Nijhara R., Jaffe H., Sihag R.,
RA Gutkind J.S., Takahashi S., Kulkarni A., Grant P., Pant H.C.;
RT "p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide
RT releasing factor 2 (RasGRF2) mediates Rac-dependent extracellular signal-
RT regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated
RT protein 1b distribution in neurons.";
RL J. Neurosci. 24:4421-4431(2004).
RN [7]
RP SUBCELLULAR LOCATION.
RX PubMed=14749369; DOI=10.1128/mcb.24.4.1516-1530.2004;
RA Arozarena I., Matallanas D., Berciano M.T., Sanz-Moreno V., Calvo F.,
RA Munoz M.T., Egea G., Lafarga M., Crespo P.;
RT "Activation of H-Ras in the endoplasmic reticulum by the RasGRF family
RT guanine nucleotide exchange factors.";
RL Mol. Cell. Biol. 24:1516-1530(2004).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-746, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [9]
RP VARIANTS [LARGE SCALE ANALYSIS] HIS-114; ASN-538 AND GLU-1216.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Functions as a calcium-regulated nucleotide exchange factor
CC activating both Ras and RAC1 through the exchange of bound GDP for GTP.
CC Preferentially activates HRAS in vivo compared to RRAS based on their
CC different types of prenylation. Functions in synaptic plasticity by
CC contributing to the induction of long term potentiation.
CC {ECO:0000269|PubMed:15128856}.
CC -!- SUBUNIT: Homooligomer and heterooligomer with RASGRF1. Interacts with
CC Ras and RAC1. Interacts in a calcium-dependent manner with calmodulin
CC (By similarity). Interacts with CDK5R1 and EPB49. Interacts with the
CC AMPA receptor through GRIA1 (By similarity). Interacts with
CC microtubules (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane; Peripheral membrane
CC protein. Endoplasmic reticulum membrane; Peripheral membrane protein.
CC Note=Translocates to membranes when activated. Found both at cell
CC periphery and along the axon of neurons (By similarity). {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Widely expressed with higher expression in brain,
CC followed by heart, lung, pancreas and kidney. Detected in placenta.
CC Expressed in brain and lung (at protein level).
CC {ECO:0000269|PubMed:10373510, ECO:0000269|PubMed:11856323}.
CC -!- DOMAIN: The Ras-GEF domain and the N-terminal Ras-GEF domain form a
CC Ras-binding site and mediate Ras activation. {ECO:0000250}.
CC -!- DOMAIN: The IQ domain mediates the calcium-dependent interaction with
CC calmodulin but is dispensable for the Ras-GEF activity. {ECO:0000250}.
CC -!- DOMAIN: The DH (DBL-homology) domain mediates interaction with RASGRF1
CC and EPB49 and is required for RAC1 activation.
CC -!- PTM: Phosphorylated by CDK5; down-regulates RASGRF2-mediated RAC1
CC activation. {ECO:0000269|PubMed:15128856}.
CC -!- PTM: Ubiquitinated upon interaction with Ras. Ubiquitination leads to
CC degradation through the 26S proteasome (By similarity). {ECO:0000250}.
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DR EMBL; AF023130; AAB80953.1; -; mRNA.
DR EMBL; AF181250; AAD55268.1; -; mRNA.
DR EMBL; CH471084; EAW95863.1; -; mRNA.
DR EMBL; BC126112; AAI26113.1; -; mRNA.
DR EMBL; BC136296; AAI36297.1; -; mRNA.
DR CCDS; CCDS4052.1; -.
DR RefSeq; NP_008840.1; NM_006909.2.
DR AlphaFoldDB; O14827; -.
DR SMR; O14827; -.
DR BioGRID; 111859; 23.
DR IntAct; O14827; 12.
DR STRING; 9606.ENSP00000265080; -.
DR iPTMnet; O14827; -.
DR PhosphoSitePlus; O14827; -.
DR BioMuta; RASGRF2; -.
DR EPD; O14827; -.
DR jPOST; O14827; -.
DR MassIVE; O14827; -.
DR PaxDb; O14827; -.
DR PeptideAtlas; O14827; -.
DR PRIDE; O14827; -.
DR ProteomicsDB; 48258; -.
DR Antibodypedia; 12760; 40 antibodies from 13 providers.
DR DNASU; 5924; -.
DR Ensembl; ENST00000265080.9; ENSP00000265080.4; ENSG00000113319.13.
DR GeneID; 5924; -.
DR KEGG; hsa:5924; -.
DR MANE-Select; ENST00000265080.9; ENSP00000265080.4; NM_006909.3; NP_008840.1.
DR UCSC; uc003kha.3; human.
DR CTD; 5924; -.
DR DisGeNET; 5924; -.
DR GeneCards; RASGRF2; -.
DR HGNC; HGNC:9876; RASGRF2.
DR HPA; ENSG00000113319; Tissue enhanced (retina).
DR MIM; 606614; gene.
DR neXtProt; NX_O14827; -.
DR OpenTargets; ENSG00000113319; -.
DR PharmGKB; PA34239; -.
DR VEuPathDB; HostDB:ENSG00000113319; -.
DR eggNOG; KOG3417; Eukaryota.
DR GeneTree; ENSGT00940000155679; -.
DR HOGENOM; CLU_003405_0_1_1; -.
DR InParanoid; O14827; -.
DR OMA; WMKVDKM; -.
DR OrthoDB; 70788at2759; -.
DR PhylomeDB; O14827; -.
DR TreeFam; TF317296; -.
DR PathwayCommons; O14827; -.
DR Reactome; R-HSA-193648; NRAGE signals death through JNK.
DR Reactome; R-HSA-416482; G alpha (12/13) signalling events.
DR Reactome; R-HSA-442982; Ras activation upon Ca2+ influx through NMDA receptor.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-8980692; RHOA GTPase cycle.
DR Reactome; R-HSA-9013148; CDC42 GTPase cycle.
DR Reactome; R-HSA-9013149; RAC1 GTPase cycle.
DR SignaLink; O14827; -.
DR SIGNOR; O14827; -.
DR BioGRID-ORCS; 5924; 7 hits in 1063 CRISPR screens.
DR ChiTaRS; RASGRF2; human.
DR GeneWiki; RASGRF2; -.
DR GenomeRNAi; 5924; -.
DR Pharos; O14827; Tbio.
DR PRO; PR:O14827; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; O14827; protein.
DR Bgee; ENSG00000113319; Expressed in middle temporal gyrus and 142 other tissues.
DR ExpressionAtlas; O14827; baseline and differential.
DR Genevisible; O14827; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IMP:BHF-UCL.
DR GO; GO:0060291; P:long-term synaptic potentiation; IEA:Ensembl.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IBA:GO_Central.
DR GO; GO:0007265; P:Ras protein signal transduction; IBA:GO_Central.
DR GO; GO:2000310; P:regulation of NMDA receptor activity; IEA:Ensembl.
DR GO; GO:0035023; P:regulation of Rho protein signal transduction; IEA:InterPro.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:BHF-UCL.
DR CDD; cd00155; RasGEF; 1.
DR CDD; cd00160; RhoGEF; 1.
DR Gene3D; 1.10.840.10; -; 1.
DR Gene3D; 1.20.900.10; -; 1.
DR Gene3D; 2.30.29.30; -; 2.
DR InterPro; IPR035899; DBL_dom_sf.
DR InterPro; IPR000219; DH-domain.
DR InterPro; IPR000048; IQ_motif_EF-hand-BS.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR008937; Ras-like_GEF.
DR InterPro; IPR000651; Ras-like_Gua-exchang_fac_N.
DR InterPro; IPR019804; Ras_G-nucl-exch_fac_CS.
DR InterPro; IPR023578; Ras_GEF_dom_sf.
DR InterPro; IPR001895; RASGEF_cat_dom.
DR InterPro; IPR036964; RASGEF_cat_dom_sf.
DR InterPro; IPR030744; RasGRF2.
DR PANTHER; PTHR23113; PTHR23113; 1.
DR PANTHER; PTHR23113:SF187; PTHR23113:SF187; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00617; RasGEF; 1.
DR Pfam; PF00618; RasGEF_N; 1.
DR Pfam; PF00621; RhoGEF; 1.
DR SMART; SM00233; PH; 2.
DR SMART; SM00147; RasGEF; 1.
DR SMART; SM00229; RasGEFN; 2.
DR SMART; SM00325; RhoGEF; 1.
DR SUPFAM; SSF48065; SSF48065; 1.
DR SUPFAM; SSF48366; SSF48366; 1.
DR PROSITE; PS50010; DH_2; 1.
DR PROSITE; PS50096; IQ; 1.
DR PROSITE; PS50003; PH_DOMAIN; 2.
DR PROSITE; PS00720; RASGEF; 1.
DR PROSITE; PS50009; RASGEF_CAT; 1.
DR PROSITE; PS50212; RASGEF_NTER; 1.
PE 1: Evidence at protein level;
KW Calcium; Calmodulin-binding; Cell membrane; Coiled coil; Cytoplasm;
KW Endoplasmic reticulum; Guanine-nucleotide releasing factor; Membrane;
KW Phosphoprotein; Reference proteome; Repeat; Ubl conjugation.
FT CHAIN 1..1237
FT /note="Ras-specific guanine nucleotide-releasing factor 2"
FT /id="PRO_0000312863"
FT DOMAIN 22..133
FT /note="PH 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 205..234
FT /note="IQ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00116"
FT DOMAIN 243..429
FT /note="DH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00062"
FT DOMAIN 470..588
FT /note="PH 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 635..756
FT /note="N-terminal Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00135"
FT DOMAIN 1002..1234
FT /note="Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00168"
FT REGION 710..809
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 744..752
FT /note="Regulates proteasomal degradation"
FT /evidence="ECO:0000250"
FT REGION 829..873
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1099..1128
FT /note="Responsible of the affinity for farnesylated versus
FT geranylgeranylated Ras"
FT /evidence="ECO:0000250"
FT COILED 155..193
FT /evidence="ECO:0000255"
FT COMPBIAS 730..777
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 787..804
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 726
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT MOD_RES 727
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT MOD_RES 737
FT /note="Phosphoserine; by CDK5"
FT /evidence="ECO:0000269|PubMed:15128856"
FT MOD_RES 746
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 848
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT MOD_RES 852
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT MOD_RES 972
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT VARIANT 114
FT /note="R -> H (in a colorectal cancer sample; somatic
FT mutation; dbSNP:rs779986744)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_037595"
FT VARIANT 538
FT /note="D -> N (in a breast cancer sample; somatic mutation;
FT dbSNP:rs1466151520)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_037596"
FT VARIANT 713
FT /note="L -> W (in dbSNP:rs16878472)"
FT /id="VAR_037597"
FT VARIANT 1216
FT /note="D -> E (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_037598"
FT MUTAGEN 737
FT /note="S->A: Loss of phosphorylation by CDK5."
FT /evidence="ECO:0000269|PubMed:15128856"
FT CONFLICT 561
FT /note="A -> R (in Ref. 1; AAB80953)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1237 AA; 140764 MW; A136CF4FA111FDD9 CRC64;
MQKSVRYNEG HALYLAFLAR KEGTKRGFLS KKTAEASRWH EKWFALYQNV LFYFEGEQSC
RPAGMYLLEG CSCERTPAPP RAGAGQGGVR DALDKQYYFT VLFGHEGQKP LELRCEEEQD
GKEWMEAIHQ ASYADILIER EVLMQKYIHL VQIVETEKIA ANQLRHQLED QDTEIERLKS
EIIALNKTKE RMRPYQSNQE DEDPDIKKIK KVQSFMRGWL CRRKWKTIVQ DYICSPHAES
MRKRNQIVFT MVEAESEYVH QLYILVNGFL RPLRMAASSK KPPISHDDVS SIFLNSETIM
FLHEIFHQGL KARIANWPTL ILADLFDILL PMLNIYQEFV RNHQYSLQVL ANCKQNRDFD
KLLKQYEANP ACEGRMLETF LTYPMFQIPR YIITLHELLA HTPHEHVERK SLEFAKSKLE
ELSRVMHDEV SDTENIRKNL AIERMIVEGC DILLDTSQTF IRQGSLIQVP SVERGKLSKV
RLGSLSLKKE GERQCFLFTK HFLICTRSSG GKLHLLKTGG VLSLIDCTLI EEPDASDDDS
KGSGQVFGHL DFKIVVEPPD AAAFTVVLLA PSRQEKAAWM SDISQCVDNI RCNGLMTIVF
EENSKVTVPH MIKSDARLHK DDTDICFSKT LNSCKVPQIR YASVERLLER LTDLRFLSID
FLNTFLHTYR IFTTAAVVLG KLSDIYKRPF TSIPVRSLEL FFATSQNNRG EHLVDGKSPR
LCRKFSSPPP LAVSRTSSPV RARKLSLTSP LNSKIGALDL TTSSSPTTTT QSPAASPPPH
TGQIPLDLSR GLSSPEQSPG TVEENVDNPR VDLCNKLKRS IQKAVLESAP ADRAGVESSP
AADTTELSPC RSPSTPRHLR YRQPGGQTAD NAHCSVSPAS AFAIATAAAG HGSPPGFNNT
ERTCDKEFII RRTATNRVLN VLRHWVSKHA QDFELNNELK MNVLNLLEEV LRDPDLLPQE
RKAAANILRA LSQDDQDDIH LKLEDIIQMT DCMKAECFES LSAMELAEQI TLLDHVIFRS
IPYEEFLGQG WMKLDKNERT PYIMKTSQHF NDMSNLVASQ IMNYADVSSR ANAIEKWVAV
ADICRCLHNY NGVLEITSAL NRSAIYRLKK TWAKVSKQTK ALMDKLQKTV SSEGRFKNLR
ETLKNCNPPA VPYLGMYLTD LAFIEEGTPN FTEEGLVNFS KMRMISHIIR EIRQFQQTSY
RIDHQPKVAQ YLLDKDLIID EDTLYELSLK IEPRLPA
