Q7LDG7 (GRP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	609 AA.
Sequence status	Complete.
Protein existence	Evidence 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	Cytoplasm › cytosol. Cell membrane; Peripheral membrane protein. Cell junction › synapse › synaptosome Potential. Cell projection › ruffle 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

Keywords
Cellular component	Cell junction Cell membrane Cell projection Cytoplasm Membrane Synapse Synaptosome
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat Zinc-finger
Ligand	Calcium Metal-binding Zinc
Molecular function	Guanine-nucleotide releasing factor
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Ras protein signal transduction Non-traceable author statement Ref.3. Source: UniProtKB platelet activation Traceable author statement. Source: Reactome regulation of cell growth Non-traceable author statement Ref.3. Source: UniProtKB regulation of small GTPase mediated signal transduction Inferred from electronic annotation. Source: InterPro
Cellular_component	cell junction Inferred from electronic annotation. Source: UniProtKB-KW cytosol Inferred from direct assay Ref.3. Source: UniProtKB neuron projection Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from direct assay Ref.3. Source: UniProtKB ruffle membrane Inferred from electronic annotation. Source: UniProtKB-SubCell synapse Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	calcium ion binding Non-traceable author statement Ref.3. Source: UniProtKB diacylglycerol binding Non-traceable author statement Ref.3. Source: UniProtKB guanyl-nucleotide exchange factor activity Traceable author statement Ref.2. Source: UniProtKB
Complete GO annotation...

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 609	609	RAS guanyl-releasing protein 2		PRO_0000315608
Regions
	Domain	4 – 126	123	N-terminal Ras-GEF
	Domain	154 – 387	234	Ras-GEF
	Domain	426 – 461	36	EF-hand 1
	Domain	455 – 490	36	EF-hand 2
	Calcium binding	439 – 450	12	1 Potential
	Calcium binding	468 – 479	12	2 Potential
	Zinc finger	498 – 548	51	Phorbol-ester/DAG-type
Amino acid modifications
	Modified residue	116	1	Phosphoserine By similarity
	Modified residue	117	1	Phosphoserine By similarity
Natural variations
	Alternative sequence	1	1	M → MGTQRLCGRGTQGWPGSSEQ HVQEATSSAGLHSGVDELGV RSEPGGRLPERSLGPAHPAP AAM in isoform 2.		VSP_030574
	Alternative sequence	125	1	P → CVGAEHRGLGGHSVSYTICA in isoform 3.		VSP_030575
	Alternative sequence	126 – 609	484	Missing in isoform 3.		VSP_030576
	Natural variant	493	1	G → A. Corresponds to variant rs2301562 [ dbSNP | Ensembl ].		VAR_038257

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (CalDAG-GEFI) (CalDAG-GEFIa) [UniParc]. Last modified July 5, 2004. Version 1. Checksum: 8B1321F864D24BC7	FASTA	609	69,248
	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
	Isoform 2 (RasGRP2) [UniParc]. Checksum: 67B7BD2B4F4AED4D	FASTA	671	75,547
	10 20 30 40 50 60 MGTQRLCGRG TQGWPGSSEQ HVQEATSSAG LHSGVDELGV RSEPGGRLPE RSLGPAHPAP 70 80 90 100 110 120 AAMAGTLDLD KGCTVEELLR GCIEAFDDSG KVRDPQLVRM FLMMHPWYIP SSQLAAKLLH 130 140 150 160 170 180 IYQQSRKDNS NSLQVKTCHL VRYWISAFPA EFDLNPELAE QIKELKALLD QEGNRRHSSL 190 200 210 220 230 240 IDIDSVPTYK WKRQVTQRNP VGQKKRKMSL LFDHLEPMEL AEHLTYLEYR SFCKILFQDY 250 260 270 280 290 300 HSFVTHGCTV DNPVLERFIS LFNSVSQWVQ LMILSKPTAP QRALVITHFV HVAEKLLQLQ 310 320 330 340 350 360 NFNTLMAVVG GLSHSSISRL KETHSHVSPE TIKLWEGLTE LVTATGNYGN YRRRLAACVG 370 380 390 400 410 420 FRFPILGVHL KDLVALQLAL PDWLDPARTR LNGAKMKQLF SILEELAMVT SLRPPVQANP 430 440 450 460 470 480 DLLSLLTVSL DQYQTEDELY QLSLQREPRS KSSPTSPTSC TPPPRPPVLE EWTSAAKPKL 490 500 510 520 530 540 DQALVVEHIE KMVESVFRNF DVDGDGHISQ EEFQIIRGNF PYLSAFGDLD QNQDGCISRE 550 560 570 580 590 600 EMVSYFLRSS SVLGGRMGFV HNFQESNSLR PVACRHCKAL ILGIYKQGLK CRACGVNCHK 610 620 630 640 650 660 QCKDRLSVEC RRRAQSVSLE GSAPSPSPMH SHHHRAFSFS LPRPGRRGSR PPEIREEEVQ 670 TVEDGVFDIH L
	Isoform 3 (CalDAG-GEFIb) [UniParc]. Checksum: 23E5F426383B4F9A	FASTA	144	16,203
	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 IDSVCVGAEH RGLGGHSVSY TICA

References

	« Hide 'large scale' referencesShow '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. , 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.
IPI	IPI00329757. IPI00852607. IPI00854815.
RefSeq	NP_001092140.1. NM_001098670.1. NP_001092141.1. NM_001098671.1. NP_722541.1. NM_153819.1.
UniGene	Hs.99491.
3D structure databases
HSSP	HSSP built from PDB template 1PTQ based on UniProtKB P28867.
ProteinModelPortal	Q7LDG7.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q7LDG7. 3 interactions.
MINT	MINT-1367716.
STRING	9606.ENSP00000338864.
Polymorphism databases
DMDM	74713056.
Proteomic databases
PaxDb	Q7LDG7.
PRIDE	Q7LDG7.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000354024; ENSP00000338864; ENSG00000068831. ENST00000377497; ENSP00000366717; ENSG00000068831. ENST00000394432; ENSP00000377953; ENSG00000068831.
GeneID	10235.
KEGG	hsa:10235.
UCSC	uc009ypu.3. human.
Organism-specific databases
CTD	10235.
GeneCards	GC11M064494.
HGNC	HGNC:9879. RASGRP2.
HPA	HPA015667.
MIM	605577. gene.
neXtProt	NX_Q7LDG7.
PharmGKB	PA34241.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG256085.
HOGENOM	HOG000293171.
HOVERGEN	HBG007513.
InParanoid	Q7LDG7.
KO	K12361.
OrthoDB	EOG4TB49W.
Enzyme and pathway databases
Pathway_Interaction_DB	tcrpathway. TCR signaling in naive CD4+ T cells. cd8tcrpathway. TCR signaling in naive CD8+ T cells.
Reactome	REACT_111102. Signal Transduction. REACT_604. Hemostasis. REACT_6900. Immune System.
Gene expression databases
ArrayExpress	Q7LDG7.
Bgee	Q7LDG7.
CleanEx	HS_RASGRP2.
Genevestigator	Q7LDG7.
Family and domain databases
Gene3D	1.10.238.10. 1 hit. 1.10.840.10. 1 hit.
InterPro	IPR011992. EF-hand-like_dom. 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]
PANTHER	PTHR23113. PTHR23113. 1 hit.
Pfam	PF00130. C1_1. 1 hit. PF13202. EF_hand_3. 2 hits. PF00617. RasGEF. 1 hit. PF00618. RasGEF_N. 1 hit. [Graphical view]
SMART	SM00109. C1. 1 hit. SM00054. EFh. 2 hits. SM00147. RasGEF. 1 hit. SM00229. RasGEFN. 1 hit. [Graphical view]
SUPFAM	SSF48366. Ras_GEF. 1 hit.
PROSITE	PS00018. EF_HAND_1. 2 hits. PS50222. EF_HAND_2. 2 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]
ProtoNet	Search...
Other
ChiTaRS	RASGRP2. human.
GenomeRNAi	10235.
NextBio	38762.
SOURCE	Search...

Entry information

Entry name

GRP2_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 88 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.