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Reviewed, UniProtKB/Swiss-Prot O95267 (GRP1_HUMAN)

Last modified November 25, 2008. Version 58. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesRecommended name:
    RAS guanyl-releasing protein 1
Alternative name(s):
    Ras guanyl-releasing protein
    Calcium and DAG-regulated guanine nucleotide exchange factor II
      Short name=CalDAG-GEFII
Gene names
Name: RASGRP1
Synonyms: RASGRP
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length797 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

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General annotation (Comments)

Function

Functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. Activates the Erk/MAP kinase cascade. Couples T-lymphocytes and B-lymphocytes antigen receptors to the activation of Ras. Hence, regulates T-cells and B-cells development, homeostasis and differentiation. Functions also in FcERI-evoked degranulation and cytokine secretion by mast cells, regulating allergic responses. May also function in other cell types differentiation.

Enzyme regulation

Probably regulated by calcium By similarity. Regulated by PLC gamma, DGKA, DGKZ and by F-actin polymerization.

Subunit structure

Forms a signaling complex with DGKZ and HRAS. Interacts with F-actin. Interacts with SKAP1.

Subcellular location

Cytoplasm › cytosol. Cell membrane; Peripheral membrane protein. Golgi apparatus membrane; Peripheral membrane protein. Endoplasmic reticulum membrane; Peripheral membrane protein. Note= Found both in the cytosol and associated with membranes. Relocalization to the cell membrane upon activation is F-actin-dependent. Translocates to the Golgi in response to phorbol ester or nerve growth factor. Localizes to somata and dendrites but not to axons of hippocampal pyramidal cells By similarity.

Tissue specificity

Expressed in brain with higher expression in cerebellum, cerebral cortex and amygdala. Expressed in the hematopoietic system. Expressed in T-cells (at protein level).

Developmental stage

Expressed in fetal brain and kidney.

Domain

The phorbol-ester/DAG-type zinc finger is the principal mediator of the targeting to membranes and is required for functional activation through DAG-binding.

Involvement in disease

Altered expression of the different RASGRP1 isoforms may be a cause of susceptibility to systemic lupus erythematosus (SLE) [MIM:152700]. SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. SLE is thought to represent a failure of the regulatory mechanisms of the autoimmune system.

Sequence similarities

Belongs to the RASGRP family.

Contains 2 EF-hand domains.

Contains 1 N-terminal Ras-GEF domain.

Contains 1 phorbol-ester/DAG-type zinc finger.

Contains 1 Ras-GEF domain.

Sequence caution

The sequence AAH67298.1 differs from that shown. Reason: Miscellaneous discrepancy. Contaminating sequence. Potential poly-A sequence.

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Binary interactions

With

Entry

#Exp.

IntAct

Notes

PPM1BO756881EBI-1054956,EBI-1047039
VHLP403371EBI-1054956,EBI-301246

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Alternative products

This entry describes 5 isoforms produced by alternative splicing. [Align] [Select]

Notes: Additional isoforms seem to exist. Several splicing events may be used independently in a modular way.
Isoform 1 (identifier: O95267-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: O95267-2)

Also known as: A;

The sequence of this isoform differs from the canonical sequence as follows:
     442-476: Missing.
Isoform 3 (identifier: O95267-3)

Also known as: B;

The sequence of this isoform differs from the canonical sequence as follows:
     442-476: Missing.
     625-632: APEEGPFT → GNKYSESR
     633-797: Missing.
Isoform 4 (identifier: O95267-4)

Also known as: C;

The sequence of this isoform differs from the canonical sequence as follows:
     442-476: Missing.
     513-516: REGL → SSGE
     517-797: Missing.
Isoform 5 (identifier: O95267-5)

Also known as: D;

The sequence of this isoform differs from the canonical sequence as follows:
     442-476: Missing.
     574-581: DCGMNCHK → GNKYSESR
     582-797: Missing.
Notes: No experimental confirmation available.

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 797797RAS guanyl-releasing protein 1
PRO_0000316978

Regions

Domain53 – 176124N-terminal Ras-GEF
Domain205 – 436232Ras-GEF
Domain470 – 50536EF-hand 1
Domain497 – 53236EF-hand 2
Calcium binding483 – 494121 Potential
Calcium binding510 – 521122 Potential
Zinc finger541 – 59151Phorbol-ester/DAG-type
Region57 – 11054Ras exchanger motif region; required for transforming activity By similarity
Region686 – 6949Suppress the PT region-mediated translocation to plasma membrane By similarity
Region718 – 79780PT region; mediates the BCR-dependent translocation to plasma membrane By similarity
Coiled coil746 – 78641 Potential

Amino acid modifications

Modified residue1841Phosphothreonine; by PKC

Natural variations

Alternative sequence442 – 47635Missing in isoform 2, isoform 3, isoform 4 and isoform 5.
VSP_030836
Alternative sequence513 – 5164REGL → SSGE in isoform 4.
VSP_030837
Alternative sequence517 – 797281Missing in isoform 4.
VSP_030838
Alternative sequence574 – 5818DCGMNCHK → GNKYSESR in isoform 5.
VSP_030839
Alternative sequence582 – 797216Missing in isoform 5.
VSP_030840
Alternative sequence625 – 6328APEEGPFT → GNKYSESR in isoform 3.
VSP_030841
Alternative sequence633 – 797165Missing in isoform 3.
VSP_030842

Experimental info

Mutagenesis2711R → E: Loss of function; prevents Ras activation
Mutagenesis5491Y → F: Loss of localization to the endoplasmic reticulum and the Golgi apparatus
Sequence conflict3741E → G in AAC79699 and AAF21898. Ref.1

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Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified February 5, 2008. Version 2.
Checksum: 8ACDCF0F715ABAA9

FASTA79790,402
        10         20         30         40         50         60 
MGTLGKAREA PRKPSHGCRA ASKARLEAKP ANSPFPSHPS LAHITQFRMM VSLGHLAKGA 

        70         80         90        100        110        120 
SLDDLIDSCI QSFDADGNLC RSNQLLQVML TMHRIVISSA ELLQKVITLY KDALAKNSPG 

       130        140        150        160        170        180 
LCLKICYFVR YWITEFWVMF KMDASLTDTM EEFQELVKAK GEELHCRLID TTQINARDWS 

       190        200        210        220        230        240 
RKLTQRIKSN TSKKRKVSLL FDHLEPEELS EHLTYLEFKS FRRISFSDYQ NYLVNSCVKE 

       250        260        270        280        290        300 
NPTMERSIAL CNGISQWVQL MVLSRPTPQL RAEVFIKFIQ VAQKLHQLQN FNTLMAVIGG 

       310        320        330        340        350        360 
LCHSSISRLK ETSSHVPHEI NKVLGEMTEL LSSSRNYDNY RRAYGECTDF KIPILGVHLK 

       370        380        390        400        410        420 
DLISLYEAMP DYLEDGKVNV HKLLALYNHI SELVQLQEVA PPLEANKDLV HLLTLSLDLY 

       430        440        450        460        470        480 
YTEDEIYELS YAREPRNHRA PPLTPSKPPV VVDWASGVSP KPDPKTISKH VQRMVDSVFK 

       490        500        510        520        530        540 
NYDHDQDGYI SQEEFEKIAA SFPFSFCVMD KDREGLISRD EITAYFMRAS SIYSKLGLGF 

       550        560        570        580        590        600 
PHNFQETTYL KPTFCDNCAG FLWGVIKQGY RCKDCGMNCH KQCKDLVVFE CKKRAKNPVA 

       610        620        630        640        650        660 
PTENNTSVGP VSNLCSLGAK DLLHAPEEGP FTFPNGEAVE HGEESKDRTI MLMGVSSQKI 

       670        680        690        700        710        720 
SLRLKRAVAH KATQTESQPW IGSEGPSGPF VLSSPRKTAQ DTLYVLPSPT SPCPSPVLVR 

       730        740        750        760        770        780 
KRAFVKWENK DSLIKSKEEL RHLRLPTYQE LEQEINTLKA DNDALKIQLK YAQKKIESLQ 

       790 
LEKSNHVLAQ MEQGDCS

« Hide

Isoform 2 (A) [UniParc].

Checksum: C3ACFFF5888E3236
Show »

76286,625
Isoform 3 (B) [UniParc].

Checksum: 979AEA31D0FBE5DC
Show »

59768,170
Isoform 4 (C) [UniParc].

Checksum: 11408850F4E84118
Show »

48155,100
Isoform 5 (D) [UniParc].

Checksum: 54018A113532AF92
Show »

54662,674

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References

« Hide 'large scale' references
[1]"A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia."
Kawasaki H., Springett G.M., Toki S., Canales J.J., Harlan P., Blumenstiel J.P., Chen E.J., Bany I.A., Mochizuki N., Ashbacher A., Matsuda M., Housman D.E., Graybiel A.M.
Proc. Natl. Acad. Sci. U.S.A. 95:13278-13283(1998) [PubMed: 9789079] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
Tissue: Frontal cortex.
[2]"RasGRP, a Ras activator: mouse and human cDNA sequences and chromosomal positions."
Bottorff D.A., Ebinu J.O., Stone J.C.
Mamm. Genome 10:358-361(1999) [PubMed: 10087292] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: T-cell.
[3]"Defective expression of ras guanyl nucleotide-releasing protein 1 in a subset of patients with systemic lupus erythematosus."
Yasuda S., Stevens R.L., Terada T., Takeda M., Hashimoto T., Fukae J., Horita T., Kataoka H., Atsumi T., Koike T.
J. Immunol. 179:4890-4900(2007) [PubMed: 17878389] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4 AND 5), INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS, TISSUE SPECIFICITY.
Tissue: Peripheral blood.
[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: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Testis.
[5]Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno F.R.
Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 233-797 (ISOFORM 2).
Tissue: Brain.
[6]"RasGRP links T-cell receptor signaling to Ras."
Ebinu J.O., Stang S.L., Teixeira C., Bottorff D.A., Hooton J., Blumberg P.M., Barry M., Bleakley R.C., Ostergaard H.L., Stone J.C.
Blood 95:3199-3203(2000) [PubMed: 10807788] [Abstract]
Cited for: FUNCTION IN T-CELL RECEPTOR SIGNALING, TOPOLOGY, TISSUE SPECIFICITY.
[7]"Diacylglycerol kinase zeta regulates Ras activation by a novel mechanism."
Topham M.K., Prescott S.M.
J. Cell Biol. 152:1135-1143(2001) [PubMed: 11257115] [Abstract]
Cited for: IDENTIFICATION IN A COMPLEX WITH DGKZ AND HRAS, ENZYME REGULATION.
[8]"Expression of a catalytically inactive form of diacylglycerol kinase alpha induces sustained signaling through RasGRP."
Jones D.R., Sanjuan M.A., Stone J.C., Merida I.
FASEB J. 16:595-597(2002) [PubMed: 11919165] [Abstract]
Cited for: ENZYME REGULATION.
[9]"Vav mediates Ras stimulation by direct activation of the GDP/GTP exchange factor Ras GRP1."
Caloca M.J., Zugaza J.L., Matallanas D., Crespo P., Bustelo X.R.
EMBO J. 22:3326-3336(2003) [PubMed: 12839994] [Abstract]
Cited for: FUNCTION IN B-CELLS, SUBCELLULAR LOCATION, INTERACTION WITH F-ACTIN, ENZYME REGULATION.
[10]"Exchange factors of the RasGRP family mediate Ras activation in the Golgi."
Caloca M.J., Zugaza J.L., Bustelo X.R.
J. Biol. Chem. 278:33465-33473(2003) [PubMed: 12782630] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF TYR-549.
[11]"Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1."
Bivona T.G., Perez De Castro I., Ahearn I.M., Grana T.M., Chiu V.K., Lockyer P.J., Cullen P.J., Pellicer A., Cox A.D., Philips M.R.
Nature 424:694-698(2003) [PubMed: 12845332] [Abstract]
Cited for: FUNCTION, MUTAGENESIS OF ARG-271.
[12]"Ras activation in Jurkat T cells following low-grade stimulation of the T-cell receptor is specific to N-Ras and occurs only on the Golgi apparatus."
Perez de Castro I., Bivona T.G., Philips M.R., Pellicer A.
Mol. Cell. Biol. 24:3485-3496(2004) [PubMed: 15060167] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[13]"Inverted signaling hierarchy between RAS and RAC in T-lymphocytes."
Zugaza J.L., Caloca M.J., Bustelo X.R.
Oncogene 23:5823-5833(2004) [PubMed: 15184873] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[14]"Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells."
Zheng Y., Liu H., Coughlin J.J., Zheng J., Li L., Stone J.C.
Blood 105:3648-3654(2005) [PubMed: 15657177] [Abstract]
Cited for: PHOSPHORYLATION AT THR-184 BY PKC.
[15]"A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells."
Roose J.P., Mollenauer M., Gupta V.A., Stone J.C., Weiss A.
Mol. Cell. Biol. 25:4426-4441(2005) [PubMed: 15899849] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT THR-184.
[16]"SKAP55 modulates T cell antigen receptor-induced activation of the Ras-Erk-AP1 pathway by binding RasGRP1."
Kosco K.A., Cerignoli F., Williams S., Abraham R.T., Mustelin T.
Mol. Immunol. 45:510-522(2008) [PubMed: 17658605] [Abstract]
Cited for: INTERACTION WITH SKAP1.
+Additional computationally mapped references.

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Cross-references

Sequence databases

AF081195 mRNA. Translation: AAC79699.1.
AF081197 mRNA. Translation: AAF21898.1.
AF106071 mRNA. Translation: AAC97349.1.
AY634315 mRNA. Translation: AAT47482.2.
AY858556 mRNA. Translation: AAW32406.2.
AY954625 mRNA. Translation: AAX54699.4.
AY966005 mRNA. Translation: AAX76907.1.
BC067298 mRNA. Translation: AAH67298.1. Sequence problems.
BC109296 mRNA. Translation: AAI09297.1.
BC109297 mRNA. Translation: AAI09298.1.
AB208848 mRNA. Translation: BAD92085.1.
RefSeqNP_005730.2.
UniGeneHs.591127

3D structure databases

HSSPHSSP built from PDB template 1PTQ based on UniProtKB P28867.
ModBaseSearch...

Protein-protein interaction databases

IntActO95267.

PTM databases

PhosphoSiteO95267.

Genome annotation databases

EnsemblENSG00000172575. Homo sapiens. [Contig view]
GeneID10125.

Organism-specific databases

HGNCHGNC:9878. RASGRP1.
MIM152700. phenotype.
603962. gene.
PharmGKBPA34240.
GenAtlasSearch...
GeneCardsSearch...

Phylogenomic databases

HOGENOMO95267.
HOVERGENO95267.

Gene expression databases

ArrayExpressO95267.

Family and domain databases

InterProIPR002219. DAG_PE_bd.
IPR011992. EF-Hand_type.
IPR002048. EF_hand_Ca_bd.
IPR008937. Ras_GEF.
IPR000651. RasGef_N.
IPR001895. RasGRF_CDC25.
[Graphical view]
Gene3DG3DSA:1.10.238.10. EF-Hand_type. 1 hit.
G3DSA:1.10.840.10. RasGRF_CDC25. 1 hit.
PANTHERPTHR23113. Ras_GEF. 1 hit.
PfamPF00130. C1_1. 1 hit.
PF00036. efhand. 2 hits.
PF00617. RasGEF. 1 hit.
PF00618. RasGEF_N. 1 hit.
[Graphical view]
PRINTSPR00008. DAGPEDOMAIN.
SMARTSM00109. C1. 1 hit.
SM00147. RasGEF. 1 hit.
SM00229. RasGEFN. 1 hit.
[Graphical view]
PROSITEPS00018. EF_HAND_1. 2 hits.
PS50222. EF_HAND_2. 3 hits.
PS00720. RASGEF. False negative.
PS50009. RASGEF_CAT. 1 hit.
PS50212. RASGEF_NTER. 1 hit.
PS00479. ZF_DAG_PE_1. 1 hit.
PS50081. ZF_DAG_PE_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio38299.
SOURCESearch...

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Entry information

Entry nameGRP1_HUMAN
AccessionPrimary (citable) accession number: O95267
Secondary accession number(s): Q56CZ0