GRP1_HUMAN
ID GRP1_HUMAN Reviewed; 797 AA.
AC O95267; Q56CZ0; Q58G75; Q59HB1; Q5I3A8; Q6GV31; Q6NX39; Q7LDG6; Q9UI94;
AC Q9UNN9;
DT 05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-FEB-2008, sequence version 2.
DT 03-AUG-2022, entry version 177.
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 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] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP DEVELOPMENTAL STAGE.
RC TISSUE=Frontal cortex;
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] (ISOFORM 1).
RC TISSUE=T-cell;
RX PubMed=10087292; DOI=10.1007/s003359901001;
RA Bottorff D.A., Ebinu J.O., Stone J.C.;
RT "RasGRP, a Ras activator: mouse and human cDNA sequences and chromosomal
RT positions.";
RL Mamm. Genome 10:358-361(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4 AND 5), INVOLVEMENT IN
RP SYSTEMIC LUPUS ERYTHEMATOSUS, AND TISSUE SPECIFICITY.
RC TISSUE=Peripheral blood;
RX PubMed=17878389; DOI=10.4049/jimmunol.179.7.4890;
RA Yasuda S., Stevens R.L., Terada T., Takeda M., Hashimoto T., Fukae J.,
RA Horita T., Kataoka H., Atsumi T., Koike T.;
RT "Defective expression of ras guanyl nucleotide-releasing protein 1 in a
RT subset of patients with systemic lupus erythematosus.";
RL J. Immunol. 179:4890-4900(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 233-797 (ISOFORM 2).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP FUNCTION IN T-CELL RECEPTOR SIGNALING, TOPOLOGY, AND TISSUE SPECIFICITY.
RX PubMed=10807788;
RA Ebinu J.O., Stang S.L., Teixeira C., Bottorff D.A., Hooton J.,
RA Blumberg P.M., Barry M., Bleakley R.C., Ostergaard H.L., Stone J.C.;
RT "RasGRP links T-cell receptor signaling to Ras.";
RL Blood 95:3199-3203(2000).
RN [7]
RP IDENTIFICATION IN A COMPLEX WITH DGKZ AND HRAS, AND ACTIVITY REGULATION.
RX PubMed=11257115; DOI=10.1083/jcb.152.6.1135;
RA Topham M.K., Prescott S.M.;
RT "Diacylglycerol kinase zeta regulates Ras activation by a novel
RT mechanism.";
RL J. Cell Biol. 152:1135-1143(2001).
RN [8]
RP ACTIVITY REGULATION.
RX PubMed=11919165; DOI=10.1096/fj.01-0762fje;
RA Jones D.R., Sanjuan M.A., Stone J.C., Merida I.;
RT "Expression of a catalytically inactive form of diacylglycerol kinase alpha
RT induces sustained signaling through RasGRP.";
RL FASEB J. 16:595-597(2002).
RN [9]
RP FUNCTION IN B-CELLS, SUBCELLULAR LOCATION, INTERACTION WITH F-ACTIN, AND
RP ACTIVITY REGULATION.
RX PubMed=12839994; DOI=10.1093/emboj/cdg316;
RA Caloca M.J., Zugaza J.L., Matallanas D., Crespo P., Bustelo X.R.;
RT "Vav mediates Ras stimulation by direct activation of the GDP/GTP exchange
RT factor Ras GRP1.";
RL EMBO J. 22:3326-3336(2003).
RN [10]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-549.
RX PubMed=12782630; DOI=10.1074/jbc.m302807200;
RA Caloca M.J., Zugaza J.L., Bustelo X.R.;
RT "Exchange factors of the RasGRP family mediate Ras activation in the
RT Golgi.";
RL J. Biol. Chem. 278:33465-33473(2003).
RN [11]
RP FUNCTION, AND MUTAGENESIS OF ARG-271.
RX PubMed=12845332; DOI=10.1038/nature01806;
RA Bivona T.G., Perez De Castro I., Ahearn I.M., Grana T.M., Chiu V.K.,
RA Lockyer P.J., Cullen P.J., Pellicer A., Cox A.D., Philips M.R.;
RT "Phospholipase Cgamma activates Ras on the Golgi apparatus by means of
RT RasGRP1.";
RL Nature 424:694-698(2003).
RN [12]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15060167; DOI=10.1128/mcb.24.8.3485-3496.2004;
RA Perez de Castro I., Bivona T.G., Philips M.R., Pellicer A.;
RT "Ras activation in Jurkat T cells following low-grade stimulation of the T-
RT cell receptor is specific to N-Ras and occurs only on the Golgi
RT apparatus.";
RL Mol. Cell. Biol. 24:3485-3496(2004).
RN [13]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15184873; DOI=10.1038/sj.onc.1207768;
RA Zugaza J.L., Caloca M.J., Bustelo X.R.;
RT "Inverted signaling hierarchy between RAS and RAC in T-lymphocytes.";
RL Oncogene 23:5823-5833(2004).
RN [14]
RP PHOSPHORYLATION AT THR-184 BY PKC.
RX PubMed=15657177; DOI=10.1182/blood-2004-10-3916;
RA Zheng Y., Liu H., Coughlin J.J., Zheng J., Li L., Stone J.C.;
RT "Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link
RT between PKC and Ras signaling systems in B cells.";
RL Blood 105:3648-3654(2005).
RN [15]
RP FUNCTION, AND PHOSPHORYLATION AT THR-184.
RX PubMed=15899849; DOI=10.1128/mcb.25.11.4426-4441.2005;
RA Roose J.P., Mollenauer M., Gupta V.A., Stone J.C., Weiss A.;
RT "A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation
RT upon antigen receptor stimulation of T cells.";
RL Mol. Cell. Biol. 25:4426-4441(2005).
RN [16]
RP INTERACTION WITH SKAP1.
RX PubMed=17658605; DOI=10.1016/j.molimm.2007.05.024;
RA Kosco K.A., Cerignoli F., Williams S., Abraham R.T., Mustelin T.;
RT "SKAP55 modulates T cell antigen receptor-induced activation of the Ras-
RT Erk-AP1 pathway by binding RasGRP1.";
RL Mol. Immunol. 45:510-522(2008).
RN [17]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=19933860; DOI=10.4049/jimmunol.0902012;
RA Lee S.H., Yun S., Lee J., Kim M.J., Piao Z.H., Jeong M., Chung J.W.,
RA Kim T.D., Yoon S.R., Greenberg P.D., Choi I.;
RT "RasGRP1 is required for human NK cell function.";
RL J. Immunol. 183:7931-7938(2009).
RN [18]
RP INVOLVEMENT IN IMD64, VARIANT IMD64 246-ARG--SER-797 DEL, CHARACTERIZATION
RP OF VARIANT IMD64 246-ARG--SER-797 DEL, AND FUNCTION.
RX PubMed=27776107; DOI=10.1038/ni.3575;
RA Salzer E., Cagdas D., Hons M., Mace E.M., Garncarz W., Petronczki O.Y.,
RA Platzer R., Pfajfer L., Bilic I., Ban S.A., Willmann K.L., Mukherjee M.,
RA Supper V., Hsu H.T., Banerjee P.P., Sinha P., McClanahan F.,
RA Zlabinger G.J., Pickl W.F., Gribben J.G., Stockinger H., Bennett K.L.,
RA Huppa J.B., Dupre L., Sanal O., Jaeger U., Sixt M., Tezcan I., Orange J.S.,
RA Boztug K.;
RT "RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal
RT dynamics.";
RL Nat. Immunol. 17:1352-1360(2016).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 50-607 AND 739-793, FUNCTION,
RP ACTIVITY REGULATION, SUBUNIT, DOMAIN, AND MUTAGENESIS OF ARG-271;
RP 483-ASP--ASP-487; GLU-494; PHE-506 AND VAL-508.
RX PubMed=23908768; DOI=10.7554/elife.00813;
RA Iwig J.S., Vercoulen Y., Das R., Barros T., Limnander A., Che Y.,
RA Pelton J.G., Wemmer D.E., Roose J.P., Kuriyan J.;
RT "Structural analysis of autoinhibition in the Ras-specific exchange factor
RT RasGRP1.";
RL Elife 2:E00813-E00813(2013).
RN [20]
RP VARIANT IMD64 257-TRP--SER-797 DEL.
RX PubMed=28822832; DOI=10.1016/j.clim.2017.08.007;
RA Platt C.D., Fried A.J., Hoyos-Bachiloglu R., Usmani G.N., Schmidt B.,
RA Whangbo J., Chiarle R., Chou J., Geha R.S.;
RT "Combined immunodeficiency with EBV positive B cell lymphoma and
RT epidermodysplasia verruciformis due to a novel homozygous mutation in
RT RASGRP1.";
RL Clin. Immunol. 183:142-144(2017).
RN [21]
RP VARIANTS IMD64 ILE-214 AND 322-LYS--SER-797 DEL, CHARACTERIZATION OF
RP VARIANTS IMD64 ILE-214 AND 322-LYS--SER-797 DEL, AND FUNCTION.
RX PubMed=29155103; DOI=10.1016/j.jaci.2017.10.026;
RA Mao H., Yang W., Latour S., Yang J., Winter S., Zheng J., Ni K., Lv M.,
RA Liu C., Huang H., Chan K.W., Pui-Wah Lee P., Tu W., Fischer A., Lau Y.L.;
RT "RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like
RT disease.";
RL J. Allergy Clin. Immunol. 142:595-604(2018).
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:15899849, PubMed:23908768,
CC PubMed:27776107, PubMed:29155103). Activates the Erk/MAP kinase cascade
CC (PubMed:15899849). Regulates T-cell/B-cell development, homeostasis and
CC differentiation by coupling T-lymphocyte/B-lymphocyte antigen receptors
CC to Ras (PubMed:10807788, PubMed:12839994, PubMed:27776107,
CC PubMed:29155103). Regulates NK cell cytotoxicity and ITAM-dependent
CC cytokine production by activation of Ras-mediated ERK and JNK pathways
CC (PubMed:19933860). Functions in mast cell degranulation and cytokine
CC secretion, regulating FcERI-evoked allergic responses. May also
CC function in differentiation of other cell types (PubMed:12845332).
CC {ECO:0000250|UniProtKB:Q9Z1S3, ECO:0000269|PubMed:10807788,
CC ECO:0000269|PubMed:12782630, ECO:0000269|PubMed:12839994,
CC ECO:0000269|PubMed:12845332, ECO:0000269|PubMed:15060167,
CC ECO:0000269|PubMed:15184873, ECO:0000269|PubMed:15899849,
CC ECO:0000269|PubMed:19933860, ECO:0000269|PubMed:23908768,
CC ECO:0000269|PubMed:27776107, ECO:0000269|PubMed:29155103}.
CC -!- ACTIVITY REGULATION: Autoinhibited. Activated by diacylglycerol and
CC calcium binding, which induces a conformational change releasing the
CC autoinhibitory state (PubMed:23908768). Regulated by DGKA
CC (PubMed:11919165). Regulated by DGKZ (PubMed:11257115). Regulated by
CC PLC gamma and F-actin polymerization (PubMed:12839994).
CC {ECO:0000269|PubMed:11257115, ECO:0000269|PubMed:11919165,
CC ECO:0000269|PubMed:12839994, ECO:0000269|PubMed:23908768}.
CC -!- SUBUNIT: Homodimer (PubMed:23908768). Forms a signaling complex with
CC DGKZ and HRAS (PubMed:11257115). Interacts with F-actin
CC (PubMed:12839994). Interacts with SKAP1 (PubMed:17658605).
CC {ECO:0000269|PubMed:11257115, ECO:0000269|PubMed:12839994,
CC ECO:0000269|PubMed:17658605, ECO:0000269|PubMed:23908768}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Cell membrane; Peripheral
CC membrane protein. Golgi apparatus membrane; Peripheral membrane
CC protein. Endoplasmic reticulum membrane; Peripheral membrane protein.
CC Note=Found both in the cytosol and associated with membranes.
CC Relocalization to the cell membrane upon activation is F-actin-
CC dependent. Translocates to the Golgi in response to phorbol ester or
CC nerve growth factor. Localizes to somata and dendrites but not to axons
CC of hippocampal pyramidal cells (By similarity). {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Comment=Additional isoforms seem to exist. Several splicing events
CC may be used independently in a modular way.;
CC Name=1;
CC IsoId=O95267-1; Sequence=Displayed;
CC Name=2; Synonyms=A;
CC IsoId=O95267-2; Sequence=VSP_030836;
CC Name=3; Synonyms=B;
CC IsoId=O95267-3; Sequence=VSP_030836, VSP_030841, VSP_030842;
CC Name=4; Synonyms=C;
CC IsoId=O95267-4; Sequence=VSP_030836, VSP_030837, VSP_030838;
CC Name=5; Synonyms=D;
CC IsoId=O95267-5; Sequence=VSP_030836, VSP_030839, VSP_030840;
CC -!- TISSUE SPECIFICITY: Expressed in brain with higher expression in
CC cerebellum, cerebral cortex and amygdala. Expressed in the
CC hematopoietic system. Expressed in T-cells (at protein level).
CC Expressed in NK cells (at protein level) (PubMed:19933860).
CC {ECO:0000269|PubMed:10807788, ECO:0000269|PubMed:17878389,
CC ECO:0000269|PubMed:19933860, ECO:0000269|PubMed:9789079}.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal brain and kidney.
CC {ECO:0000269|PubMed:9789079}.
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:0000269|PubMed:23908768}.
CC -!- DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic,
CC relapsing, inflammatory, and often febrile multisystemic disorder of
CC connective tissue, characterized principally by involvement of the
CC skin, joints, kidneys and serosal membranes. It is of unknown etiology,
CC but is thought to represent a failure of the regulatory mechanisms of
CC the autoimmune system. The disease is marked by a wide range of system
CC dysfunctions, an elevated erythrocyte sedimentation rate, and the
CC formation of LE cells in the blood or bone marrow.
CC {ECO:0000269|PubMed:17878389}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC Aberrantly spliced isoforms and/or diminished levels of RASGRP1 are
CC found in a cohort of SLE patients raising the possibility that
CC dysregulation of this signaling protein contributes to the development
CC of autoimmunity in a subset of SLE patients.
CC -!- DISEASE: Immunodeficiency 64 (IMD64) [MIM:618534]: An autosomal
CC recessive primary immunodeficiency characterized by recurrent
CC bacterial, viral and fungal infections, variably decreased numbers of T
CC cells, deficiencies of B and NK cells, and increased susceptibility to
CC Epstein-Barr virus (EBV) infection. Patients may develop
CC lymphoproliferation or EBV-associated lymphoma. Some patients may
CC develop features of autoimmunity. {ECO:0000269|PubMed:27776107,
CC ECO:0000269|PubMed:28822832, ECO:0000269|PubMed:29155103}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the RASGRP family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH67298.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
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DR EMBL; AF081195; AAC79699.1; -; mRNA.
DR EMBL; AF081197; AAF21898.1; -; mRNA.
DR EMBL; AF106071; AAC97349.1; -; mRNA.
DR EMBL; AY634315; AAT47482.2; -; mRNA.
DR EMBL; AY858556; AAW32406.2; -; mRNA.
DR EMBL; AY954625; AAX54699.4; -; mRNA.
DR EMBL; AY966005; AAX76907.1; -; mRNA.
DR EMBL; BC067298; AAH67298.1; ALT_SEQ; mRNA.
DR EMBL; BC109296; AAI09297.1; -; mRNA.
DR EMBL; BC109297; AAI09298.1; -; mRNA.
DR EMBL; AB208848; BAD92085.1; -; mRNA.
DR CCDS; CCDS45221.1; -. [O95267-2]
DR CCDS; CCDS45222.1; -. [O95267-1]
DR CCDS; CCDS76733.1; -. [O95267-3]
DR RefSeq; NP_001122074.1; NM_001128602.1. [O95267-2]
DR RefSeq; NP_001293015.1; NM_001306086.1. [O95267-3]
DR RefSeq; NP_005730.2; NM_005739.3. [O95267-1]
DR PDB; 4L9M; X-ray; 3.00 A; A=50-607.
DR PDB; 4L9U; X-ray; 1.60 A; A/B=739-793.
DR PDBsum; 4L9M; -.
DR PDBsum; 4L9U; -.
DR AlphaFoldDB; O95267; -.
DR SMR; O95267; -.
DR BioGRID; 115429; 5.
DR CORUM; O95267; -.
DR IntAct; O95267; 2.
DR MINT; O95267; -.
DR STRING; 9606.ENSP00000310244; -.
DR BindingDB; O95267; -.
DR ChEMBL; CHEMBL5953; -.
DR GuidetoPHARMACOLOGY; 3016; -.
DR iPTMnet; O95267; -.
DR PhosphoSitePlus; O95267; -.
DR BioMuta; RASGRP1; -.
DR MassIVE; O95267; -.
DR MaxQB; O95267; -.
DR PaxDb; O95267; -.
DR PeptideAtlas; O95267; -.
DR PRIDE; O95267; -.
DR ProteomicsDB; 50767; -. [O95267-1]
DR ProteomicsDB; 50768; -. [O95267-2]
DR ProteomicsDB; 50769; -. [O95267-3]
DR ProteomicsDB; 50770; -. [O95267-4]
DR ProteomicsDB; 50771; -. [O95267-5]
DR Antibodypedia; 53148; 152 antibodies from 22 providers.
DR DNASU; 10125; -.
DR Ensembl; ENST00000310803.10; ENSP00000310244.5; ENSG00000172575.13. [O95267-1]
DR Ensembl; ENST00000414708.6; ENSP00000413105.2; ENSG00000172575.13. [O95267-4]
DR Ensembl; ENST00000450598.6; ENSP00000388540.2; ENSG00000172575.13. [O95267-2]
DR Ensembl; ENST00000558164.5; ENSP00000454164.1; ENSG00000172575.13. [O95267-5]
DR Ensembl; ENST00000559830.5; ENSP00000452721.1; ENSG00000172575.13. [O95267-3]
DR GeneID; 10125; -.
DR KEGG; hsa:10125; -.
DR MANE-Select; ENST00000310803.10; ENSP00000310244.5; NM_005739.4; NP_005730.2.
DR UCSC; uc001zkd.5; human. [O95267-1]
DR CTD; 10125; -.
DR DisGeNET; 10125; -.
DR GeneCards; RASGRP1; -.
DR HGNC; HGNC:9878; RASGRP1.
DR HPA; ENSG00000172575; Tissue enhanced (brain, lymphoid tissue, retina).
DR MalaCards; RASGRP1; -.
DR MIM; 152700; phenotype.
DR MIM; 603962; gene.
DR MIM; 618534; phenotype.
DR neXtProt; NX_O95267; -.
DR OpenTargets; ENSG00000172575; -.
DR Orphanet; 3261; Autoimmune lymphoproliferative syndrome.
DR PharmGKB; PA34240; -.
DR VEuPathDB; HostDB:ENSG00000172575; -.
DR eggNOG; KOG3417; Eukaryota.
DR GeneTree; ENSGT00940000158910; -.
DR HOGENOM; CLU_019261_0_0_1; -.
DR InParanoid; O95267; -.
DR OMA; HVPNEVT; -.
DR PhylomeDB; O95267; -.
DR TreeFam; TF312918; -.
DR PathwayCommons; O95267; -.
DR Reactome; R-HSA-114508; Effects of PIP2 hydrolysis.
DR Reactome; R-HSA-1169092; Activation of RAS in B cells.
DR Reactome; R-HSA-2871837; FCERI mediated NF-kB activation.
DR Reactome; R-HSA-354192; Integrin signaling.
DR Reactome; R-HSA-392517; Rap1 signalling.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR SignaLink; O95267; -.
DR SIGNOR; O95267; -.
DR BioGRID-ORCS; 10125; 15 hits in 1069 CRISPR screens.
DR GeneWiki; RASGRP1; -.
DR GenomeRNAi; 10125; -.
DR Pharos; O95267; Tchem.
DR PRO; PR:O95267; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; O95267; protein.
DR Bgee; ENSG00000172575; Expressed in pons and 169 other tissues.
DR ExpressionAtlas; O95267; baseline and differential.
DR Genevisible; O95267; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IDA:CACAO.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005509; F:calcium ion binding; IMP:UniProtKB.
DR GO; GO:0019992; F:diacylglycerol binding; IMP:UniProtKB.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IMP:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
DR GO; GO:0008289; F:lipid binding; TAS:ProtInc.
DR GO; GO:0031210; F:phosphatidylcholine binding; IMP:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IMP:UniProtKB.
DR GO; GO:0090630; P:activation of GTPase activity; IDA:CACAO.
DR GO; GO:0042113; P:B cell activation; IMP:UniProtKB.
DR GO; GO:0042100; P:B cell proliferation; IMP:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0002437; P:inflammatory response to antigenic stimulus; IEA:Ensembl.
DR GO; GO:0043303; P:mast cell degranulation; IEA:Ensembl.
DR GO; GO:0030101; P:natural killer cell activation; IMP:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
DR GO; GO:0032725; P:positive regulation of granulocyte macrophage colony-stimulating factor production; IMP:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IMP:UniProtKB.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IMP:UniProtKB.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:UniProtKB.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IMP:CACAO.
DR GO; GO:0032825; P:positive regulation of natural killer cell differentiation; IEA:Ensembl.
DR GO; GO:0045954; P:positive regulation of natural killer cell mediated cytotoxicity; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:CACAO.
DR GO; GO:0046579; P:positive regulation of Ras protein signal transduction; IMP:UniProtKB.
DR GO; GO:0033089; P:positive regulation of T cell differentiation in thymus; IEA:Ensembl.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IMP:UniProtKB.
DR GO; GO:0007265; P:Ras protein signal transduction; IBA:GO_Central.
DR GO; GO:0070372; P:regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
DR GO; GO:0014066; P:regulation of phosphatidylinositol 3-kinase signaling; IEA:Ensembl.
DR GO; GO:0032252; P:secretory granule localization; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0042110; P:T cell activation; IMP:UniProtKB.
DR GO; GO:0042098; P:T cell proliferation; IMP:UniProtKB.
DR GO; GO:0047496; P:vesicle transport along microtubule; IEA:Ensembl.
DR CDD; cd00029; C1; 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; PF13405; EF-hand_6; 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 3D-structure; Alternative splicing; Calcium; Cell membrane; Coiled coil;
KW Cytoplasm; Differentiation; Disease variant; Endoplasmic reticulum;
KW Golgi apparatus; Guanine-nucleotide releasing factor; Membrane;
KW Metal-binding; Phosphoprotein; Reference proteome; Repeat;
KW Systemic lupus erythematosus; Zinc; Zinc-finger.
FT CHAIN 1..797
FT /note="RAS guanyl-releasing protein 1"
FT /id="PRO_0000316978"
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..23
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 673..694
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 686..694
FT /note="Suppress the PT region-mediated translocation to
FT plasma membrane"
FT /evidence="ECO:0000250"
FT REGION 718..797
FT /note="PT region; mediates the BCR-dependent translocation
FT to plasma membrane"
FT /evidence="ECO:0000250"
FT COILED 746..786
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 /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT MOD_RES 184
FT /note="Phosphothreonine; by PKC"
FT /evidence="ECO:0000269|PubMed:15657177,
FT ECO:0000269|PubMed:15899849"
FT VAR_SEQ 442..476
FT /note="Missing (in isoform 2, isoform 3, isoform 4 and
FT isoform 5)"
FT /evidence="ECO:0000303|PubMed:17878389, ECO:0000303|Ref.5"
FT /id="VSP_030836"
FT VAR_SEQ 513..516
FT /note="REGL -> SSGE (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:17878389"
FT /id="VSP_030837"
FT VAR_SEQ 517..797
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:17878389"
FT /id="VSP_030838"
FT VAR_SEQ 574..581
FT /note="DCGMNCHK -> GNKYSESR (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:17878389"
FT /id="VSP_030839"
FT VAR_SEQ 582..797
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:17878389"
FT /id="VSP_030840"
FT VAR_SEQ 625..632
FT /note="APEEGPFT -> GNKYSESR (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:17878389"
FT /id="VSP_030841"
FT VAR_SEQ 633..797
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:17878389"
FT /id="VSP_030842"
FT VARIANT 214
FT /note="T -> I (in IMD64; no effect on protein expression;
FT decreased T cell activation; dbSNP:rs1595848141)"
FT /evidence="ECO:0000269|PubMed:29155103"
FT /id="VAR_083338"
FT VARIANT 246..797
FT /note="Missing (in IMD64; loss of protein expression)"
FT /evidence="ECO:0000269|PubMed:27776107"
FT /id="VAR_083339"
FT VARIANT 257..797
FT /note="Missing (in IMD64)"
FT /evidence="ECO:0000269|PubMed:28822832"
FT /id="VAR_083340"
FT VARIANT 322..797
FT /note="Missing (in IMD64; no effect on protein expression;
FT decreased T cell activation)"
FT /evidence="ECO:0000269|PubMed:29155103"
FT /id="VAR_083341"
FT MUTAGEN 271
FT /note="R->E: Loss of function; prevents Ras activation."
FT /evidence="ECO:0000269|PubMed:12845332,
FT ECO:0000269|PubMed:23908768"
FT MUTAGEN 483..487
FT /note="DHDQD->AHAQA: Decrease of Ras activation indicated
FT by decrease of ERK phosphorylation."
FT /evidence="ECO:0000269|PubMed:23908768"
FT MUTAGEN 494
FT /note="E->A: Decrease of Ras activation indicated by
FT decrease of ERK phosphorylation."
FT /evidence="ECO:0000269|PubMed:23908768"
FT MUTAGEN 506
FT /note="F->D: Increase of Ras activation indicated by
FT increase of ERK phosphorylation."
FT /evidence="ECO:0000269|PubMed:23908768"
FT MUTAGEN 508
FT /note="V->D: Increase of Ras activation indicated by
FT increase of ERK phosphorylation."
FT /evidence="ECO:0000269|PubMed:23908768"
FT MUTAGEN 549
FT /note="Y->F: Loss of localization to the endoplasmic
FT reticulum and the Golgi apparatus."
FT /evidence="ECO:0000269|PubMed:12782630"
FT CONFLICT 374
FT /note="E -> G (in Ref. 1; AAC79699/AAF21898)"
FT /evidence="ECO:0000305"
FT HELIX 62..71
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 84..92
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 93..95
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 99..115
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 119..135
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 138..142
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 144..160
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 164..168
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 172..179
FT /evidence="ECO:0007829|PDB:4L9M"
FT STRAND 201..203
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 206..222
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 226..234
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 242..264
FT /evidence="ECO:0007829|PDB:4L9M"
FT TURN 267..269
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 270..287
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 291..301
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 304..307
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 310..315
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 318..331
FT /evidence="ECO:0007829|PDB:4L9M"
FT TURN 335..337
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 338..345
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 355..368
FT /evidence="ECO:0007829|PDB:4L9M"
FT STRAND 376..378
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 380..395
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 396..398
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 407..416
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 423..433
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 464..482
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 492..500
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 519..533
FT /evidence="ECO:0007829|PDB:4L9M"
FT STRAND 544..547
FT /evidence="ECO:0007829|PDB:4L9M"
FT TURN 556..558
FT /evidence="ECO:0007829|PDB:4L9M"
FT STRAND 564..566
FT /evidence="ECO:0007829|PDB:4L9M"
FT STRAND 569..572
FT /evidence="ECO:0007829|PDB:4L9M"
FT TURN 573..575
FT /evidence="ECO:0007829|PDB:4L9M"
FT TURN 581..583
FT /evidence="ECO:0007829|PDB:4L9M"
FT STRAND 584..586
FT /evidence="ECO:0007829|PDB:4L9M"
FT HELIX 748..782
FT /evidence="ECO:0007829|PDB:4L9U"
FT TURN 783..785
FT /evidence="ECO:0007829|PDB:4L9U"
FT HELIX 788..791
FT /evidence="ECO:0007829|PDB:4L9U"
SQ SEQUENCE 797 AA; 90402 MW; 8ACDCF0F715ABAA9 CRC64;
MGTLGKAREA PRKPSHGCRA ASKARLEAKP ANSPFPSHPS LAHITQFRMM VSLGHLAKGA
SLDDLIDSCI QSFDADGNLC RSNQLLQVML TMHRIVISSA ELLQKVITLY KDALAKNSPG
LCLKICYFVR YWITEFWVMF KMDASLTDTM EEFQELVKAK GEELHCRLID TTQINARDWS
RKLTQRIKSN TSKKRKVSLL FDHLEPEELS EHLTYLEFKS FRRISFSDYQ NYLVNSCVKE
NPTMERSIAL CNGISQWVQL MVLSRPTPQL RAEVFIKFIQ VAQKLHQLQN FNTLMAVIGG
LCHSSISRLK ETSSHVPHEI NKVLGEMTEL LSSSRNYDNY RRAYGECTDF KIPILGVHLK
DLISLYEAMP DYLEDGKVNV HKLLALYNHI SELVQLQEVA PPLEANKDLV HLLTLSLDLY
YTEDEIYELS YAREPRNHRA PPLTPSKPPV VVDWASGVSP KPDPKTISKH VQRMVDSVFK
NYDHDQDGYI SQEEFEKIAA SFPFSFCVMD KDREGLISRD EITAYFMRAS SIYSKLGLGF
PHNFQETTYL KPTFCDNCAG FLWGVIKQGY RCKDCGMNCH KQCKDLVVFE CKKRAKNPVA
PTENNTSVGP VSNLCSLGAK DLLHAPEEGP FTFPNGEAVE HGEESKDRTI MLMGVSSQKI
SLRLKRAVAH KATQTESQPW IGSEGPSGPF VLSSPRKTAQ DTLYVLPSPT SPCPSPVLVR
KRAFVKWENK DSLIKSKEEL RHLRLPTYQE LEQEINTLKA DNDALKIQLK YAQKKIESLQ
LEKSNHVLAQ MEQGDCS
