RGRF2_RAT
ID RGRF2_RAT Reviewed; 1190 AA.
AC Q99JE4;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 136.
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 Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=11252168; DOI=10.1007/s003350010268;
RA Laes J.-F., Quan X., Ravoet M., van Vooren P., van Reeth T., Szpirer J.,
RA Szpirer C.;
RT "Analysis of candidate genes included in the mammary cancer susceptibility
RT 1 (Mcs1) region.";
RL Mamm. Genome 12:199-206(2001).
RN [2]
RP TISSUE SPECIFICITY.
RX PubMed=9032266; DOI=10.1128/mcb.17.3.1396;
RA Fam N.P., Fan W.-T., Wang Z., Zhang L.-J., Chen H., Moran M.F.;
RT "Cloning and characterization of Ras-GRF2, a novel guanine nucleotide
RT exchange factor for Ras.";
RL Mol. Cell. Biol. 17:1396-1406(1997).
RN [3]
RP OLIGOMERIZATION, AND INTERACTION WITH RASGRF1.
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 [4]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CDK5R1, AND
RP PHOSPHORYLATION BY CDK5.
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).
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 (By similarity). Interacts in a calcium-dependent manner
CC with calmodulin (By similarity). Interacts with CDK5R1 and probably
CC EPB49. Interacts with the AMPA receptor through GRIA1 (By similarity).
CC Interacts with microtubules (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15128856}. Cell
CC membrane {ECO:0000269|PubMed:15128856}; Peripheral membrane protein
CC {ECO:0000269|PubMed:15128856}. Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:15128856}; Peripheral membrane protein
CC {ECO:0000269|PubMed:15128856}. Note=Translocates to membranes when
CC activated (By similarity). Found both at cell periphery and along the
CC axon of neurons. {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Widely expressed. Detected in brain, lung, spleen,
CC pancreas, kidney, liver, heart, mammary gland and skeletal muscle.
CC {ECO:0000269|PubMed:9032266}.
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. {ECO:0000250}.
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; AJ276774; CAC37407.1; -; mRNA.
DR RefSeq; NP_446173.1; NM_053721.1.
DR AlphaFoldDB; Q99JE4; -.
DR SMR; Q99JE4; -.
DR BioGRID; 250359; 1.
DR STRING; 10116.ENSRNOP00000019087; -.
DR iPTMnet; Q99JE4; -.
DR PhosphoSitePlus; Q99JE4; -.
DR PaxDb; Q99JE4; -.
DR PRIDE; Q99JE4; -.
DR GeneID; 114513; -.
DR KEGG; rno:114513; -.
DR UCSC; RGD:69413; rat.
DR CTD; 5924; -.
DR RGD; 69413; Rasgrf2.
DR eggNOG; KOG3417; Eukaryota.
DR InParanoid; Q99JE4; -.
DR OrthoDB; 70788at2759; -.
DR PhylomeDB; Q99JE4; -.
DR Reactome; R-RNO-193648; NRAGE signals death through JNK.
DR Reactome; R-RNO-416482; G alpha (12/13) signalling events.
DR Reactome; R-RNO-5673001; RAF/MAP kinase cascade.
DR Reactome; R-RNO-8980692; RHOA GTPase cycle.
DR Reactome; R-RNO-9013148; CDC42 GTPase cycle.
DR Reactome; R-RNO-9013149; RAC1 GTPase cycle.
DR PRO; PR:Q99JE4; -.
DR Proteomes; UP000002494; Unplaced.
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; ISO:RGD.
DR GO; GO:0060291; P:long-term synaptic potentiation; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0035023; P:regulation of Rho protein signal transduction; IEA:InterPro.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; ISO:RGD.
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; 2.
DR PANTHER; PTHR23113:SF187; PTHR23113:SF187; 2.
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..1190
FT /note="Ras-specific guanine nucleotide-releasing factor 2"
FT /id="PRO_0000312865"
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..755
FT /note="N-terminal Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00135"
FT DOMAIN 955..1187
FT /note="Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00168"
FT REGION 713..744
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 743..751
FT /note="Regulates proteasomal degradation"
FT /evidence="ECO:0000250"
FT REGION 757..826
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1052..1081
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 729..744
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 757..777
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 800..814
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 725
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT MOD_RES 726
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT MOD_RES 736
FT /note="Phosphoserine; by CDK5"
FT /evidence="ECO:0000250|UniProtKB:O14827"
FT MOD_RES 745
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14827"
FT MOD_RES 749
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT MOD_RES 801
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT MOD_RES 805
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
FT MOD_RES 925
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70392"
SQ SEQUENCE 1190 AA; 135827 MW; 5A2A2C6C8AABBC2F CRC64;
MQKSVRYNEG HALYLAFLAR KEGTKRGFLS KKAAEASRWH EKWFALYQNV LFYFEGEQSG
RPAGMYLLEG CSCERTPAPP RTNAGPAGAR DALDKQYYFT VLFGHEGQKP LELRCEEEQA
GKEWMEAIHQ ASYADILIER EVLMQKYIHL VQIVETEKIA ANQLRHQLED QDTEIERLKS
EIVALNKTKE RMRPYHTHQE EEDPDIKKIK KVQSFMRGWL CRRKWKTIVQ DYICSPHAES
MRKRNQIVFT MVEAESEYVH QLYILVNGFL RPLRMAASSK KPPISHDDVS SIFLNSETIM
FLHEIFHQGL KARLANWPTL VLADLFDILL PMLNIYQEFV RNHQYSLQVL ANCKQNRDFD
KLLKQYEGNP ACEGRMLETF LTYPMFQIPR YIITLHELLA HTPHEHVERK SLEFAKSKLE
ELSRVMHDEV SDTENIRKNL AIERMIVEGC DILLDTSQTF IRQGSLIQVP SVERGKLSKV
RLGSLSLKKE GERQCFLFTK HFLICTRSSG GKLHLLKTGG VLSLIQCTLI EEPDTSDDDT
KGPGHMFGHL DFKIVVEPPD AAPFTVVLLA PSRQEKAAWM SDISQCVDNI RCNGLMTIVF
EENSKVTVPH MIKSDARLHK DDTDICFSKT LNSCKVPQIR YASVERLLER LTDLRFLSID
FLNTFLHTYR IFTTAAVVLG KLSDIYKRPF TSIPVRSLEL FFATSQNNRE HLVDGKSPRL
CRKFSSPPPL AVSRTSSPVR ARKLSLTSSL NSRIGALDLT TSSSSSSPTT TVHSPAASPP
PHTAVPESAP ADRAGDSTDM SPCRSPSTTP RHLRYRQPGG QVADSTHCAV SPASAFAIAT
AAAGHGSPPG FNNERTCDKE FIIRRTATNR VLNVLRHWVS KHSQDFELNN ELKMNVLNLL
EEVLRDPDLL PQERKATANI LRALSQDDQD DIHLKLEDII QMTDCPKAEC FETLSAMELA
EQITLLDHIV FRSIPYEEFL GQGWMKLDKN ERTPYIMKTS QHFNEMSNLV ASQIMNYADI
SSRANAIEKW VAVADICRCL HNYNGVLEIT SALNRSAIYR LKKTWTKVSK QTKALMDKLQ
KTVSSEGRFK NLRETLKNCN PPAVPYLGMY LTDLAFIEEG TPNFTEEGLV NFSKMRMISH
IIREIRQFQQ TAYRIDQQPK VIQYLLDKAL VIDEDTLYEL SLKIEPRLPA
