GRP1_RAT
ID GRP1_RAT Reviewed; 795 AA.
AC Q9R1K8; O88469;
DT 05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=RAS guanyl-releasing protein 1;
DE AltName: Full=Calcium and DAG-regulated guanine nucleotide exchange factor II;
DE Short=CalDAG-GEFII;
DE AltName: Full=Ras guanyl-releasing protein;
GN Name=Rasgrp1; Synonyms=Rasgrp;
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], FUNCTION AS RAS ACTIVATOR, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=9789079; DOI=10.1073/pnas.95.22.13278;
RA Kawasaki H., Springett G.M., Toki S., Canales J.J., Harlan P.,
RA Blumenstiel J.P., Chen E.J., Bany I.A., Mochizuki N., Ashbacher A.,
RA Matsuda M., Housman D.E., Graybiel A.M.;
RT "A Rap guanine nucleotide exchange factor enriched highly in the basal
RT ganglia.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:13278-13283(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION AS RAS ACTIVATOR, ACTIVITY REGULATION,
RP SUBCELLULAR LOCATION, INTERACTION WITH RAS, CALCIUM-BINDING, AND
RP MUTAGENESIS OF 510-ASP--GLU-521.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=9582122; DOI=10.1126/science.280.5366.1082;
RA Ebinu J.O., Bottorff D.A., Chan E.Y.W., Stang S.L., Dunn R.J., Stone J.C.;
RT "RasGRP, a Ras guanyl nucleotide-releasing protein with calcium- and
RT diacylglycerol-binding motifs.";
RL Science 280:1082-1086(1998).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=11279364; DOI=10.1023/a:1007245728751;
RA Pierret P., Dunn R.J., Djordjevic B., Stone J.C., Richardson P.M.;
RT "Distribution of ras guanyl releasing protein (RasGRP) mRNA in the adult
RT rat central nervous system.";
RL J. Neurocytol. 29:485-497(2000).
RN [4]
RP DIACYLGLYCEROL-BINDING.
RX PubMed=10779365;
RA Lorenzo P.S., Beheshti M., Pettit G.R., Stone J.C., Blumberg P.M.;
RT "The guanine nucleotide exchange factor RasGRP is a high -affinity target
RT for diacylglycerol and phorbol esters.";
RL Mol. Pharmacol. 57:840-846(2000).
RN [5]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=11738253; DOI=10.1016/s0306-4522(01)00429-8;
RA Pierret P., Vallee A., Mechawar N., Dower N.A., Stone J.C.,
RA Richardson P.M., Dunn R.J.;
RT "Cellular and subcellular localization of Ras guanyl nucleotide-releasing
RT protein in the rat hippocampus.";
RL Neuroscience 108:381-390(2001).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=12626538; DOI=10.4049/jimmunol.170.6.2877;
RA Sanjuan M.A., Pradet-Balade B., Jones D.R., Martinez-A C., Stone J.C.,
RA Garcia-Sanz J.A., Merida I.;
RT "T cell activation in vivo targets diacylglycerol kinase alpha to the
RT membrane: a novel mechanism for Ras attenuation.";
RL J. Immunol. 170:2877-2883(2003).
RN [7]
RP SUBCELLULAR LOCATION, AND TOPOLOGY.
RX PubMed=15064353; DOI=10.1091/mbc.e03-11-0844;
RA Carrasco S., Merida I.;
RT "Diacylglycerol-dependent binding recruits PKCtheta and RasGRP1 C1 domains
RT to specific subcellular localizations in living T lymphocytes.";
RL Mol. Biol. Cell 15:2932-2942(2004).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-597, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Functions as a calcium- and diacylglycerol (DAG)-regulated
CC nucleotide exchange factor specifically activating Ras through the
CC exchange of bound GDP for GTP (PubMed:9789079, PubMed:9582122).
CC Activates the Erk/MAP kinase cascade. Regulates T-cell/B-cell
CC development, homeostasis and differentiation by coupling T-
CC lymphocyte/B-lymphocyte antigen receptors to Ras. Regulates NK cell
CC cytotoxicity and ITAM-dependent cytokine production by activation of
CC Ras-mediated ERK and JNK pathways (By similarity). Functions in mast
CC cell degranulation and cytokine secretion, regulating FcERI-evoked
CC allergic responses. May also function in differentiation of other cell
CC types. Proto-oncogene, which promotes T-cell lymphomagenesis when its
CC expression is deregulated (By similarity).
CC {ECO:0000250|UniProtKB:O95267, ECO:0000250|UniProtKB:Q9Z1S3,
CC ECO:0000269|PubMed:9582122, ECO:0000269|PubMed:9789079}.
CC -!- ACTIVITY REGULATION: Autoinhibited (By similarity). Activated by
CC diacylglycerol and calcium binding, which induces a conformational
CC change releasing the autoinhibitory state (PubMed:9582122). Regulated
CC by DGKA. Regulated by DGKZ. Regulated by PLC gamma and F-actin
CC polymerization (By similarity). {ECO:0000250|UniProtKB:O95267,
CC ECO:0000269|PubMed:9582122}.
CC -!- SUBUNIT: Homodimer. Forms a signaling complex with DGKZ and HRAS.
CC Interacts with F-actin. Interacts with SKAP1 (By similarity).
CC {ECO:0000250|UniProtKB:O95267}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Cell membrane; Peripheral
CC membrane protein. Golgi apparatus membrane {ECO:0000250}; Peripheral
CC membrane protein {ECO:0000250}. Endoplasmic reticulum membrane
CC {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. Note=Found
CC both in the cytosol and associated with membranes. Relocalization to
CC the cell membrane upon activation is F-actin-dependent (By similarity).
CC Translocates to the Golgi in response to phorbol ester or nerve growth
CC factor (By similarity). Localizes to somata and dendrites but not to
CC axons of hippocampal pyramidal cells. {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Specifically expressed in brain with higher density
CC in hippocampal CA1 and CA3 fields. Detected in interneurons and
CC projection neurons with no restriction to any neuronal type or
CC neurotransmitter phenotype but not detected in glial cells. Expressed
CC in the hematopoietic system. Expressed in several neuronal types of the
CC hippocampus and entorhinal cortex (at protein level).
CC {ECO:0000269|PubMed:11279364, ECO:0000269|PubMed:11738253,
CC ECO:0000269|PubMed:9789079}.
CC -!- DEVELOPMENTAL STAGE: Expression appears in neurons of the hippocampus
CC during the first 2 weeks after birth (at protein level).
CC {ECO:0000269|PubMed:11738253}.
CC -!- DOMAIN: The phorbol-ester/DAG-type zinc finger is the principal
CC mediator of the targeting to membranes and is required for functional
CC activation through DAG-binding.
CC -!- DOMAIN: Two EF-hand domains are present. However, only EF-hand 1 (and
CC not EF-hand 2) binds calcium. {ECO:0000250|UniProtKB:O95267}.
CC -!- SIMILARITY: Belongs to the RASGRP family. {ECO:0000305}.
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DR EMBL; AF081196; AAC79700.1; -; mRNA.
DR EMBL; AF060819; AAC40137.1; -; mRNA.
DR RefSeq; NP_062084.2; NM_019211.2.
DR AlphaFoldDB; Q9R1K8; -.
DR SMR; Q9R1K8; -.
DR STRING; 10116.ENSRNOP00000007687; -.
DR BindingDB; Q9R1K8; -.
DR ChEMBL; CHEMBL3109; -.
DR iPTMnet; Q9R1K8; -.
DR PhosphoSitePlus; Q9R1K8; -.
DR PaxDb; Q9R1K8; -.
DR PRIDE; Q9R1K8; -.
DR GeneID; 29434; -.
DR KEGG; rno:29434; -.
DR UCSC; RGD:3539; rat.
DR CTD; 10125; -.
DR RGD; 3539; Rasgrp1.
DR VEuPathDB; HostDB:ENSRNOG00000005404; -.
DR eggNOG; KOG3417; Eukaryota.
DR HOGENOM; CLU_019261_0_0_1; -.
DR InParanoid; Q9R1K8; -.
DR OMA; HVPNEVT; -.
DR OrthoDB; 355412at2759; -.
DR PhylomeDB; Q9R1K8; -.
DR TreeFam; TF312918; -.
DR Reactome; R-RNO-1169092; Activation of RAS in B cells.
DR Reactome; R-RNO-354192; Integrin signaling.
DR Reactome; R-RNO-392517; Rap1 signalling.
DR Reactome; R-RNO-5673001; RAF/MAP kinase cascade.
DR PRO; PR:Q9R1K8; -.
DR Proteomes; UP000002494; Chromosome 3.
DR Bgee; ENSRNOG00000005404; Expressed in frontal cortex and 19 other tissues.
DR Genevisible; Q9R1K8; RN.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; ISO:RGD.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005509; F:calcium ion binding; ISO:RGD.
DR GO; GO:0019992; F:diacylglycerol binding; ISO:RGD.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0031210; F:phosphatidylcholine binding; ISO:RGD.
DR GO; GO:0008270; F:zinc ion binding; ISO:RGD.
DR GO; GO:0090630; P:activation of GTPase activity; ISO:RGD.
DR GO; GO:0042113; P:B cell activation; ISO:RGD.
DR GO; GO:0042100; P:B cell proliferation; ISO:RGD.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0002437; P:inflammatory response to antigenic stimulus; ISO:RGD.
DR GO; GO:0043303; P:mast cell degranulation; ISO:RGD.
DR GO; GO:0030101; P:natural killer cell activation; ISO:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISO:RGD.
DR GO; GO:0032725; P:positive regulation of granulocyte macrophage colony-stimulating factor production; ISO:RGD.
DR GO; GO:0043547; P:positive regulation of GTPase activity; ISO:RGD.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; ISO:RGD.
DR GO; GO:0046330; P:positive regulation of JNK cascade; ISO:RGD.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; ISO:RGD.
DR GO; GO:0032816; P:positive regulation of natural killer cell activation; ISO:RGD.
DR GO; GO:0032825; P:positive regulation of natural killer cell differentiation; ISO:RGD.
DR GO; GO:0045954; P:positive regulation of natural killer cell mediated cytotoxicity; ISO:RGD.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0046579; P:positive regulation of Ras protein signal transduction; ISO:RGD.
DR GO; GO:0033089; P:positive regulation of T cell differentiation in thymus; ISO:RGD.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISO:RGD.
DR GO; GO:0007265; P:Ras protein signal transduction; IBA:GO_Central.
DR GO; GO:0070372; P:regulation of ERK1 and ERK2 cascade; ISO:RGD.
DR GO; GO:0014066; P:regulation of phosphatidylinositol 3-kinase signaling; ISO:RGD.
DR GO; GO:0032252; P:secretory granule localization; ISO:RGD.
DR GO; GO:0042110; P:T cell activation; ISO:RGD.
DR GO; GO:0042098; P:T cell proliferation; ISO:RGD.
DR GO; GO:0047496; P:vesicle transport along microtubule; ISO:RGD.
DR CDD; cd00029; C1; 1.
DR CDD; cd00051; EFh; 1.
DR CDD; cd00155; RasGEF; 1.
DR CDD; cd06224; REM; 1.
DR Gene3D; 1.10.840.10; -; 1.
DR InterPro; IPR046349; C1-like_sf.
DR InterPro; IPR020454; DAG/PE-bd.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR002219; PE/DAG-bd.
DR InterPro; IPR008937; Ras-like_GEF.
DR InterPro; IPR000651; Ras-like_Gua-exchang_fac_N.
DR InterPro; IPR023578; Ras_GEF_dom_sf.
DR InterPro; IPR001895; RASGEF_cat_dom.
DR InterPro; IPR036964; RASGEF_cat_dom_sf.
DR PANTHER; PTHR23113; PTHR23113; 1.
DR Pfam; PF00130; C1_1; 1.
DR Pfam; PF13202; EF-hand_5; 1.
DR Pfam; PF00617; RasGEF; 1.
DR Pfam; PF00618; RasGEF_N; 1.
DR PRINTS; PR00008; DAGPEDOMAIN.
DR SMART; SM00109; C1; 1.
DR SMART; SM00054; EFh; 1.
DR SMART; SM00147; RasGEF; 1.
DR SMART; SM00229; RasGEFN; 1.
DR SUPFAM; SSF47473; SSF47473; 1.
DR SUPFAM; SSF48366; SSF48366; 1.
DR SUPFAM; SSF57889; SSF57889; 1.
DR PROSITE; PS00018; EF_HAND_1; 2.
DR PROSITE; PS50222; EF_HAND_2; 3.
DR PROSITE; PS50009; RASGEF_CAT; 1.
DR PROSITE; PS50212; RASGEF_NTER; 1.
DR PROSITE; PS00479; ZF_DAG_PE_1; 1.
DR PROSITE; PS50081; ZF_DAG_PE_2; 1.
PE 1: Evidence at protein level;
KW Calcium; Cell membrane; Coiled coil; Cytoplasm; Differentiation;
KW Endoplasmic reticulum; Golgi apparatus;
KW Guanine-nucleotide releasing factor; Membrane; Metal-binding;
KW Phosphoprotein; Reference proteome; Repeat; Zinc; Zinc-finger.
FT CHAIN 1..795
FT /note="RAS guanyl-releasing protein 1"
FT /id="PRO_0000316980"
FT DOMAIN 53..176
FT /note="N-terminal Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00135"
FT DOMAIN 205..436
FT /note="Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00168"
FT DOMAIN 470..505
FT /note="EF-hand 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT DOMAIN 506..532
FT /note="EF-hand 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT ZN_FING 541..591
FT /note="Phorbol-ester/DAG-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226"
FT REGION 1..37
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 57..110
FT /note="Ras exchanger motif region; required for
FT transforming activity"
FT /evidence="ECO:0000250"
FT REGION 686..694
FT /note="Suppress the PT region-mediated translocation to
FT plasma membrane"
FT /evidence="ECO:0000250"
FT REGION 717..795
FT /note="PT region; mediates the BCR-dependent translocation
FT to plasma membrane"
FT /evidence="ECO:0000250"
FT COILED 738..779
FT /evidence="ECO:0000255"
FT COMPBIAS 9..23
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 483
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 485
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 487
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 489
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 494
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT MOD_RES 184
FT /note="Phosphothreonine; by PKC"
FT /evidence="ECO:0000250|UniProtKB:O95267"
FT MOD_RES 597
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MUTAGEN 510..521
FT /note="DKDREGLISRDE->AKARAGLISRDA: Loss of calcium-
FT binding."
FT /evidence="ECO:0000269|PubMed:9582122"
FT CONFLICT 24
FT /note="G -> A (in Ref. 2; AAC40137)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 795 AA; 90245 MW; 14CC12EBBC967C39 CRC64;
MGTLGKAREA PRKPCHGSRA GPKGRLEAKS TNSPLPAQPS LAQITQFRMM VSLGHLAKGA
SLDDLIDSCI QSFDADGNLC RSNQLLQVML TMHRIIISSA ELLQKLMNLY KDALEKNSPG
ICLKICYFVR YWITEFWIMF KMDASLTSTM EEFQDLVKAN GEESHCHLID TTQINSRDWS
RKLTQRIKSN TSKKRKVSLL FDHLEPEELS EHLTYLEFKS FRRISFSDYQ NYLVNSCVKE
NPTMERSIAL CNGISQWVQL MVLSRPTPQL RAEVFIKFIH VAQKLHQLQN FNTLMAVIGG
LCHSSISRLK ETSSHVPHEI NKVLGEMTEL LSSCRNYDNY RRAYGECTHF KIPILGVHLK
DLISLYEAMP DYLEDGKVNV QKLLALYNHI NELVQLQDVA PPLDANKDLV HLLTLSLDLY
YTEDEIYELS YAREPRNHRA PPLTPSKPPV VVDWASGVSP KPDPKTISKH VQRMVDSVFK
NYDLDQDGYI SQEEFEKIAA SFPFSFCVMD KDREGLISRD EITAYFMRAS SIYSKLGLGF
PHNFQETTYL KPTFCDNCAG FLWGVIKQGY RCKDCGMNCH KQCKDLVVFE CKKRSKSPAV
STENISSVVP MSTLCPLGTK DLLHAPEEGS FIFQNGEVVD HSEESKDRTI MLLGVSSQKI
SVRLKRTVAH KTTQTESFPW VGGEMPPGHF VLTSPRKSAQ GALYVHSPAS PCPSPALVRK
RAFVKWENKE SLIKPKPELH LRLRTYQELE QEVNTLRADN DALKIQLKYA QKQIESLQLG
KSNHVLAQMD HGDGT
