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Q7LDG7 (GRP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 97. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
RAS guanyl-releasing protein 2
Alternative name(s):
Calcium and DAG-regulated guanine nucleotide exchange factor I
Short name=CalDAG-GEFI
Cdc25-like protein
Short name=hCDC25L
F25B3.3 kinase-like protein
Gene names
Name:RASGRP2
Synonyms:CDC25L, MCG7
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length609 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. May also activates other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. Functions in aggregation of platelets and adhesion of T-lymphocytes and neutrophils probably through inside-out integrin activation. May function in the muscarinic acetylcholine receptor M1/CHRM1 signaling pathway. Ref.3 Ref.7 Ref.9 Ref.10

Enzyme regulation

Isoform 1 and isoform 2 are differently regulated by calcium and DAG. Ref.3

Subunit structure

Forms a signaling complex with RAP1 and BRAF By similarity. Interacts with RAP1. Interacts with F-actin. Ref.7 Ref.8

Subcellular location

Cytoplasmcytosol. Cell membrane; Peripheral membrane protein. Cell junctionsynapsesynaptosome Potential. Cell projectionruffle membrane; Peripheral membrane protein Potential. Note: Found both in the cytosol and associated with membranes. Isoform 2 mainly localizes to the cell membrane. Enriched at juxtamembrane areas and membrane ruffles through association with F-actin. Localizes to the cell bodies and axons of striatal neurons By similarity. Ref.3 Ref.8

Tissue specificity

Detected in platelets, neutrophils and T lymphocytes (at protein level). Expressed in brain where it is enriched in the striatum. Also expressed in the hematopoietic system. Detected in heart, brain, lung, placenta, liver, skeletal muscle and kidney. Ref.1 Ref.2 Ref.3 Ref.9 Ref.10

Developmental stage

Expressed in fetal brain, lung, liver and kidney. Ref.2

Domain

The N-terminal Ras-GEF domain mediates association with F-actin.

Post-translational modification

Isoform 2 is palmitoylated and myristoylated while isoform 1. Ref.3

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.

Caution

Defects in RASGRP2 were initially thought (Ref.10) to be the cause of leukocyte adhesion deficiency type 3 (LAD3), a syndrome characterized by recurrent bacterial infections and major bleeding disorders. However, it was later shown (Ref.11, Ref.12 and Ref.13) that it is not the case and that LAD3 is caused by defects in FERMT3 gene.

Ontologies

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q7LDG7-1)

Also known as: CalDAG-GEFI; CalDAG-GEFIa;

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: Q7LDG7-2)

Also known as: RasGRP2;

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MGTQRLCGRGTQGWPGSSEQHVQEATSSAGLHSGVDELGVRSEPGGRLPERSLGPAHPAPAAM
Isoform 3 (identifier: Q7LDG7-3)

Also known as: CalDAG-GEFIb;

The sequence of this isoform differs from the canonical sequence as follows:
     125-125: P → CVGAEHRGLGGHSVSYTICA
     126-609: Missing.
Note: The corresponding protein is not undetectable.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 609609RAS guanyl-releasing protein 2
PRO_0000315608

Regions

Domain4 – 126123N-terminal Ras-GEF
Domain154 – 387234Ras-GEF
Domain426 – 46136EF-hand 1
Domain455 – 49036EF-hand 2
Calcium binding439 – 450121 Potential
Calcium binding468 – 479122 Potential
Zinc finger498 – 54851Phorbol-ester/DAG-type

Amino acid modifications

Modified residue1161Phosphoserine By similarity
Modified residue1171Phosphoserine By similarity

Natural variations

Alternative sequence11M → MGTQRLCGRGTQGWPGSSEQ HVQEATSSAGLHSGVDELGV RSEPGGRLPERSLGPAHPAP AAM in isoform 2.
VSP_030574
Alternative sequence1251P → CVGAEHRGLGGHSVSYTICA in isoform 3.
VSP_030575
Alternative sequence126 – 609484Missing in isoform 3.
VSP_030576
Natural variant4931G → A.
Corresponds to variant rs2301562 [ dbSNP | Ensembl ].
VAR_038257

Secondary structure

............ 609
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (CalDAG-GEFI) (CalDAG-GEFIa) [UniParc].

Last modified July 5, 2004. Version 1.
Checksum: 8B1321F864D24BC7

FASTA60969,248
        10         20         30         40         50         60 
MAGTLDLDKG CTVEELLRGC IEAFDDSGKV RDPQLVRMFL MMHPWYIPSS QLAAKLLHIY 

        70         80         90        100        110        120 
QQSRKDNSNS LQVKTCHLVR YWISAFPAEF DLNPELAEQI KELKALLDQE GNRRHSSLID 

       130        140        150        160        170        180 
IDSVPTYKWK RQVTQRNPVG QKKRKMSLLF DHLEPMELAE HLTYLEYRSF CKILFQDYHS 

       190        200        210        220        230        240 
FVTHGCTVDN PVLERFISLF NSVSQWVQLM ILSKPTAPQR ALVITHFVHV AEKLLQLQNF 

       250        260        270        280        290        300 
NTLMAVVGGL SHSSISRLKE THSHVSPETI KLWEGLTELV TATGNYGNYR RRLAACVGFR 

       310        320        330        340        350        360 
FPILGVHLKD LVALQLALPD WLDPARTRLN GAKMKQLFSI LEELAMVTSL RPPVQANPDL 

       370        380        390        400        410        420 
LSLLTVSLDQ YQTEDELYQL SLQREPRSKS SPTSPTSCTP PPRPPVLEEW TSAAKPKLDQ 

       430        440        450        460        470        480 
ALVVEHIEKM VESVFRNFDV DGDGHISQEE FQIIRGNFPY LSAFGDLDQN QDGCISREEM 

       490        500        510        520        530        540 
VSYFLRSSSV LGGRMGFVHN FQESNSLRPV ACRHCKALIL GIYKQGLKCR ACGVNCHKQC 

       550        560        570        580        590        600 
KDRLSVECRR RAQSVSLEGS APSPSPMHSH HHRAFSFSLP RPGRRGSRPP EIREEEVQTV 


EDGVFDIHL 

« Hide

Isoform 2 (RasGRP2) [UniParc].

Checksum: 67B7BD2B4F4AED4D
Show »

FASTA67175,547
Isoform 3 (CalDAG-GEFIb) [UniParc].

Checksum: 23E5F426383B4F9A
Show »

FASTA14416,203

References

« Hide 'large scale' references
[1]"The germinal centre kinase gene and a novel CDC25-like gene are located in the vicinity of the PYGM gene on 11q13."
Kedra D., Seroussi E., Fransson I., Trifunovic J., Clark M., Lagercrantz J., Blennow E., Mehlin H., Dumanski J.
Hum. Genet. 100:611-619(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
[2]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
Tissue: Frontal cortex.
[3]"Characterization of RasGRP2, a plasma membrane-targeted, dual specificity Ras/Rap exchange factor."
Clyde-Smith J., Silins G., Gartside M., Grimmond S., Etheridge M., Apolloni A., Hayward N., Hancock J.F.
J. Biol. Chem. 275:32260-32267(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, TOPOLOGY, PALMITOYLATION, MYRISTOYLATION, TISSUE SPECIFICITY.
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Brain.
[6]"Activation of the Rap1 guanine nucleotide exchange gene, CalDAG-GEF I, in BXH-2 murine myeloid leukemia."
Dupuy A.J., Morgan K., von Lintig F.C., Shen H., Acar H., Hasz D.E., Jenkins N.A., Copeland N.G., Boss G.R., Largaespada D.A.
J. Biol. Chem. 276:11804-11811(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: ALTERNATIVE SPLICING (ISOFORM 3).
[7]"Rap1-mediated lymphocyte function-associated antigen-1 activation by the T cell antigen receptor is dependent on phospholipase C-gamma1."
Katagiri K., Shimonaka M., Kinashi T.
J. Biol. Chem. 279:11875-11881(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH RAP1.
[8]"F-actin-dependent translocation of the Rap1 GDP/GTP exchange factor RasGRP2."
Caloca M.J., Zugaza J.L., Vicente-Manzanares M., Sanchez-Madrid F., Bustelo X.R.
J. Biol. Chem. 279:20435-20446(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH F-ACTIN.
[9]"Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin mediated human T-cell adhesion."
Ghandour H., Cullere X., Alvarez A., Luscinskas F.W., Mayadas T.N.
Blood 110:3682-3690(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN T-LYMPHOCYTES ADHESION, TISSUE SPECIFICITY.
[10]"A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets."
Pasvolsky R., Feigelson S.W., Kilic S.S., Simon A.J., Tal-Lapidot G., Grabovsky V., Crittenden J.R., Amariglio N., Safran M., Graybiel A.M., Rechavi G., Ben-Dor S., Etzioni A., Alon R.
J. Exp. Med. 204:1571-1582(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INTEGRIN ACTIVATION, TISSUE SPECIFICITY.
[11]"LAD-1/variant syndrome is caused by mutations in FERMT3."
Kuijpers T.W., van de Vijver E., Weterman M.A.J., de Boer M., Tool A.T.J., van den Berg T.K., Moser M., Jakobs M.E., Seeger K., Sanal O., Uenal S., Cetin M., Roos D., Verhoeven A.J., Baas F.
Blood 113:4740-4746(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: LACK OF INVOLVEMENT IN LAD3.
[12]"Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation."
Svensson L., Howarth K., McDowall A., Patzak I., Evans R., Ussar S., Moser M., Metin A., Fried M., Tomlinson I., Hogg N.
Nat. Med. 15:306-312(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: LACK OF INVOLVEMENT IN LAD3.
[13]"A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans."
Malinin N.L., Zhang L., Choi J., Ciocea A., Razorenova O., Ma Y.-Q., Podrez E.A., Tosi M., Lennon D.P., Caplan A.I., Shurin S.B., Plow E.F., Byzova T.V.
Nat. Med. 15:313-318(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: LACK OF INVOLVEMENT IN LAD3.
+Additional computationally mapped references.

Web resources

RASGRP2base

RASGRP2 mutation db

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
Y12336 mRNA. Translation: CAA73005.1.
AF081194 mRNA. Translation: AAC79698.1.
U78170 mRNA. Translation: AAD12741.1.
AF043722 mRNA. Translation: AAF07219.1.
AF043723 mRNA. Translation: AAF07220.1.
CH471076 Genomic DNA. Translation: EAW74281.1.
BC117151 mRNA. Translation: AAI17152.1.
RefSeqNP_001092140.1. NM_001098670.1.
NP_001092141.1. NM_001098671.1.
NP_722541.1. NM_153819.1.
UniGeneHs.99491.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2MA2NMR-A417-497[»]
ProteinModelPortalQ7LDG7.
SMRQ7LDG7. Positions 7-550.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid115529. 4 interactions.
IntActQ7LDG7. 3 interactions.
MINTMINT-1367716.
STRING9606.ENSP00000338864.

Polymorphism databases

DMDM74713056.

Proteomic databases

PaxDbQ7LDG7.
PRIDEQ7LDG7.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000354024; ENSP00000338864; ENSG00000068831. [Q7LDG7-1]
ENST00000377497; ENSP00000366717; ENSG00000068831. [Q7LDG7-1]
ENST00000394432; ENSP00000377953; ENSG00000068831. [Q7LDG7-1]
GeneID10235.
KEGGhsa:10235.
UCSCuc009ypu.3. human. [Q7LDG7-1]

Organism-specific databases

CTD10235.
GeneCardsGC11M064494.
HGNCHGNC:9879. RASGRP2.
HPAHPA015667.
MIM605577. gene.
neXtProtNX_Q7LDG7.
PharmGKBPA34241.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG256085.
HOGENOMHOG000293171.
HOVERGENHBG007513.
InParanoidQ7LDG7.
KOK12361.
TreeFamTF312918.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.
REACT_604. Hemostasis.
REACT_6900. Immune System.

Gene expression databases

ArrayExpressQ7LDG7.
BgeeQ7LDG7.
CleanExHS_RASGRP2.
GenevestigatorQ7LDG7.

Family and domain databases

Gene3D1.10.238.10. 1 hit.
1.10.840.10. 1 hit.
InterProIPR011992. EF-hand-dom_pair.
IPR018247. EF_Hand_1_Ca_BS.
IPR002048. EF_hand_dom.
IPR002219. Prot_Kinase_C-like_PE/DAG-bd.
IPR000651. Ras-like_Gua-exchang_fac_N.
IPR008937. Ras_GEF.
IPR023578. Ras_GEF_dom.
IPR001895. RasGRF_CDC25.
[Graphical view]
PANTHERPTHR23113. PTHR23113. 1 hit.
PfamPF00130. C1_1. 1 hit.
PF13202. EF-hand_5. 1 hit.
PF00617. RasGEF. 1 hit.
PF00618. RasGEF_N. 1 hit.
[Graphical view]
SMARTSM00109. C1. 1 hit.
SM00054. EFh. 2 hits.
SM00147. RasGEF. 1 hit.
SM00229. RasGEFN. 1 hit.
[Graphical view]
SUPFAMSSF48366. SSF48366. 1 hit.
PROSITEPS00018. EF_HAND_1. 2 hits.
PS50222. EF_HAND_2. 2 hits.
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

ChiTaRSRASGRP2. human.
GeneWikiRASGRP2.
GenomeRNAi10235.
NextBio38762.
PROQ7LDG7.
SOURCESearch...

Entry information

Entry nameGRP2_HUMAN
AccessionPrimary (citable) accession number: Q7LDG7
Secondary accession number(s): O00538, Q9UL65
Entry history
Integrated into UniProtKB/Swiss-Prot: January 15, 2008
Last sequence update: July 5, 2004
Last modified: March 19, 2014
This is version 97 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM