Reviewed, UniProtKB/Swiss-Prot Q9Z1S3 (GRP1_MOUSE)

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	795 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

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. Proto-oncogene which promotes T-cell lymphomagenesis when its expression is deregulated. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.17 Ref.18
Enzyme regulation	Probably regulated by calcium. Regulated by PLC gamma, DGKA, DGKZ and by F-actin polymerization By similarity.
Subunit structure	Forms a signaling complex with DGKZ and HRAS. Interacts with F-actin. Interacts with SKAP1 By similarity.
Subcellular location	Cytoplasm › cytosol By similarity. Cell membrane; Peripheral membrane protein By similarity. Golgi apparatus membrane; Peripheral membrane protein. Endoplasmic reticulum membrane; Peripheral membrane protein By similarity. Note: Found both in the cytosol and associated with membranes. Relocalization to the cell membrane upon activation is F-actin-dependent By similarity. 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. Ref.5 Ref.9 Ref.11 Ref.16 Ref.20
Tissue specificity	Detected in spleen and thymus. Expressed by mature thymocytes and to a lower extent by bone marrow-derived mast cells (at protein level). Detected in B-cells and keratinocytes (at protein level). Ref.5 Ref.6 Ref.7 Ref.9 Ref.12 Ref.18
Induction	Up-regulated at the double-negative to double-positive transition during thymocyte development. Down-regulated by 12-O-tetradecanoylphorbol-13-acetate (TPA). Ref.9 Ref.10
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.
Disruption phenotype	Mice fail to mount anaphylactic allergic reactions and display chronic T-cell immunodeficiencies. Lag (lymphoproliferation-autoimmunity-glomerulonephritis) mice do not express Rasgrp1 and display a systemic lupus erythematosus-like phenotype. Ref.6 Ref.15 Ref.19
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.

Ontologies

Keywords
Biological process	Differentiation
Cellular component	Cell membrane Cytoplasm Endoplasmic reticulum Golgi apparatus Membrane
Disease	Proto-oncogene
Domain	Coiled coil Repeat Zinc-finger
Ligand	Calcium Metal-binding Zinc
Molecular function	Guanine-nucleotide releasing factor
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW regulation of small GTPase mediated signal transduction Inferred from electronic annotation. Source: InterPro small GTPase mediated signal transduction Inferred from electronic annotation. Source: InterPro
Cellular component	Golgi apparatus Inferred from electronic annotation. Source: UniProtKB-KW cytosol Inferred from electronic annotation. Source: UniProtKB-SubCell endoplasmic reticulum Inferred from electronic annotation. Source: UniProtKB-KW extrinsic to membrane Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	calcium ion binding Inferred from electronic annotation. Source: UniProtKB-KW guanyl-nucleotide exchange factor activity Inferred from electronic annotation. Source: UniProtKB-KW zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 795	795	RAS guanyl-releasing protein 1		PRO_0000316979
Regions
	Domain	53 – 176	124	N-terminal Ras-GEF
	Domain	205 – 436	232	Ras-GEF
	Domain	470 – 505	36	EF-hand 1
	Domain	497 – 532	36	EF-hand 2
	Calcium binding	483 – 494	12	1 Potential
	Calcium binding	510 – 521	12	2 Potential
	Zinc finger	541 – 591	51	Phorbol-ester/DAG-type
	Region	57 – 110	54	Ras exchanger motif region; required for transforming activity
	Region	686 – 694	9	Suppress the PT region-mediated translocation to plasma membrane
	Region	717 – 795	79	PT region; mediates the BCR-dependent translocation to plasma membrane
	Coiled coil	738 – 779	42	Potential
Amino acid modifications
	Modified residue	184	1	Phosphothreonine; by PKC By similarity
	Modified residue	694	1	Phosphoserine By similarity
Experimental info
	Mutagenesis	271	1	R → E: Loss of function and transforming activity. Ref.5 Ref.12
	Sequence conflict	171	1	T → R in BAE24718. Ref.2
	Sequence conflict	472	1	Q → K in BAE20439. Ref.2
	Sequence conflict	485	1	D → E in BAE20439. Ref.2
	Sequence conflict	501	1	S → T in BAE20439. Ref.2
	Sequence conflict	520	1	D → H in BAE20439. Ref.2
	Sequence conflict	768	1	K → R in BAC33100. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q9Z1S3-1 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: E2096D985DFB79A0	FASTA	795	90,304
	10 20 30 40 50 60 MGTLGKAREA PRKPCHGSRA GPKARLEAKS TNSPLPAQPS LAQITQFRMM VSLGHLAKGA 70 80 90 100 110 120 SLDDLIDSCI QSFDADGNLC RNNQLLQVML TMHRIIISSA ELLQKVMNLY KDALEKNSPG 130 140 150 160 170 180 VCLKICYFVR YWITEFWIMF KMDASLTSTM EEFQDLVKAN GEETHCHLID TTQINSRDWS 190 200 210 220 230 240 RKLTQRIKSN TSKKRKVSLL FDHLEPEELS EHLTYLEFKS FRRISFSDYQ NYLVNSCVKE 250 260 270 280 290 300 NPTMERSIAL CNGISQWVQL MVLSRPTPQL RAEVFIKFIH VAQKLHQLQN FNTLMAVIGG 310 320 330 340 350 360 LCHSSISRLK ETSSHVPHEI NKVLGEMTEL LSSCRNYDNY RRAYGECTHF KIPILGVHLK 370 380 390 400 410 420 DLISLYEAMP DYLEDGKVNV QKLLALYNHI NELVQLQEMA PPLDANKDLV HLLTLSLDLY 430 440 450 460 470 480 YTEDEIYELS YAREPRNHRA PPLTPSKPPV VVDWASGVSP KPDPKTISKH VQRMVDSVFK 490 500 510 520 530 540 NYDLDQDGYI SQEEFEKIAA SFPFSFCVMD KDREGLISRD EITAYFMRAS SIYSKLGLGF 550 560 570 580 590 600 PHNFQETTYL KPTFCDNCAG FLWGVIKQGY RCKDCGMNCH KQCKDLVVFE CKKRIKSPAI 610 620 630 640 650 660 STENISSVVP MSTLCPLGTK DLLHAPEEGS FIFQNGEIVD HSEESKDRTI MLLGVSSQKI 670 680 690 700 710 720 SVRLKRTVAH KSTQTESFPW VGGETTPGHF VLSSPRKSAQ GALYVHSPAS PCPSPALVRK 730 740 750 760 770 780 RAFVKWENKE SLIKPKPELH LRLRTYQELE QEINTLKADN DALKIQLKYA QKKIESLQLG 790 KSNHVLAQMD HGDSA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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]. Strain: C57BL/6 X C3H. Tissue: Brain.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Brain, Corpus striatum and Hippocampus.
[3]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed: 19468303] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[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]. Strain: C57BL/6. Tissue: Fetal brain.
[5]	"Regulation of RasGRP via a phorbol ester-responsive C1 domain." Tognon C.E., Kirk H.E., Passmore L.A., Whitehead I.P., Der C.J., Kay R.J. Mol. Cell. Biol. 18:6995-7008(1998) [PubMed: 9819387] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ARG-271, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[6]	"RasGRP is essential for mouse thymocyte differentiation and TCR signaling." Dower N.A., Stang S.L., Bottorff D.A., Ebinu J.O., Dickie P., Ostergaard H.L., Stone J.C. Nat. Immunol. 1:317-321(2000) [PubMed: 11017103] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION IN T-CELL ACTIVATION, TISSUE SPECIFICITY.
[7]	"RasGRP1 transduces low-grade TCR signals which are critical for T cell development, homeostasis, and differentiation." Priatel J.J., Teh S.-J., Dower N.A., Stone J.C., Teh H.-S. Immunity 17:617-627(2002) [PubMed: 12433368] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[8]	"Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1." Layer K., Lin G., Nencioni A., Hu W., Schmucker A., Antov A.N., Li X., Takamatsu S., Chevassut T., Dower N.A., Stang S.L., Beier D., Buhlmann J., Bronson R.T., Elkon K.B., Stone J.C., Van Parijs L., Lim B. Immunity 19:243-255(2003) [PubMed: 12932358] [Abstract] Cited for: FUNCTION.
[9]	"RasGRP1 represents a novel non-protein kinase C phorbol ester signaling pathway in mouse epidermal keratinocytes." Rambaratsingh R.A., Stone J.C., Blumberg P.M., Lorenzo P.S. J. Biol. Chem. 278:52792-52801(2003) [PubMed: 14532295] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, TOPOLOGY, TISSUE SPECIFICITY, INDUCTION BY TPA.
[10]	"Transgenic expression of RasGRP1 induces the maturation of double-negative thymocytes and enhances the production of CD8 single-positive thymocytes." Norment A.M., Bogatzki L.Y., Klinger M.B., Ojala E.W., Bevan M.J., Kay R.J. J. Immunol. 170:1141-1149(2003) [PubMed: 12538669] [Abstract] Cited for: FUNCTION, INDUCTION.
[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, SUBCELLULAR LOCATION.
[12]	"RasGRP1 sensitizes an immature B cell line to antigen receptor-induced apoptosis." Guilbault B., Kay R.J. J. Biol. Chem. 279:19523-19530(2004) [PubMed: 14970203] [Abstract] Cited for: FUNCTION IN B-CELLS, TISSUE SPECIFICITY, MUTAGENESIS OF ARG-271.
[13]	"RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling." Coughlin J.J., Stang S.L., Dower N.A., Stone J.C. J. Immunol. 175:7179-7184(2005) [PubMed: 16301621] [Abstract] Cited for: FUNCTION.
[14]	"Deregulated expression of RasGRP1 initiates thymic lymphomagenesis independently of T-cell receptors." Klinger M.B., Guilbault B., Goulding R.E., Kay R.J. Oncogene 24:2695-2704(2005) [PubMed: 15829980] [Abstract] Cited for: FUNCTION.
[15]	"RasGRP1 transmits prodifferentiation TCR signaling that is crucial for CD4 T cell development." Priatel J.J., Chen X., Dhanji S., Abraham N., Teh H.-S. J. Immunol. 177:1470-1480(2006) [PubMed: 16849453] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[16]	"Differential membrane binding and diacylglycerol recognition by C1 domains of RasGRPs." Johnson J.E., Goulding R.E., Ding Z., Partovi A., Anthony K.V., Beaulieu N., Tazmini G., Cornell R.B., Kay R.J. Biochem. J. 406:223-236(2007) [PubMed: 17523924] [Abstract] Cited for: DIACYLGLYCEROL-BINDING, SUBCELLULAR LOCATION.
[17]	"Transgenic overexpression of RasGRP1 in mouse epidermis results in spontaneous tumors of the skin." Oki-Idouchi C.E., Lorenzo P.S. Cancer Res. 67:276-280(2007) [PubMed: 17210708] [Abstract] Cited for: FUNCTION.
[18]	"An essential role for RasGRP1 in mast cell function and IgE-mediated allergic response." Liu Y., Zhu M., Nishida K., Hirano T., Zhang W. J. Exp. Med. 204:93-103(2007) [PubMed: 17190838] [Abstract] Cited for: FUNCTION IN MAST CELLS ACTIVATION, TISSUE SPECIFICITY.
[19]	"Chronic immunodeficiency in mice lacking RasGRP1 results in CD4 T cell immune activation and exhaustion." Priatel J.J., Chen X., Zenewicz L.A., Shen H., Harder K.W., Horwitz M.S., Teh H.-S. J. Immunol. 179:2143-2152(2007) [PubMed: 17675473] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[20]	"Regulation of RasGRP1 by B cell antigen receptor requires cooperativity between three domains controlling translocation to the plasma membrane." Beaulieu N., Zahedi B., Goulding R.E., Tazmini G., Anthony K.V., Omeis S.L., de Jong D.R., Kay R.J. Mol. Biol. Cell 18:3156-3168(2007) [PubMed: 17567957] [Abstract] Cited for: SUBCELLULAR LOCATION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF106070 mRNA. Translation: AAC97348.1. AK028308 mRNA. Translation: BAE20439.1. AK047613 mRNA. Translation: BAC33100.1. AK141524 mRNA. Translation: BAE24718.1. AL844579, AL928959 Genomic DNA. Translation: CAM17832.1. AL928959, AL844579 Genomic DNA. Translation: CAM26780.1. BC057120 mRNA. Translation: AAH57120.1. BC057341 mRNA. Translation: AAH57341.1.
IPI	IPI00130414.
RefSeq	NP_035376.1.
UniGene	Mm.42150
3D structure databases
HSSP	HSSP built from PDB template 1PTQ based on UniProtKB P28867.
SMR	Q9Z1S3. Positions 205-436, 359-526, 460-594.
ModBase	Search...
Protein-protein interaction databases
STRING	Q9Z1S3.
PTM databases
PhosphoSite	Q9Z1S3.
Proteomic databases
PRIDE	Q9Z1S3.
Genome annotation databases
Ensembl	ENSMUST00000028823; ENSMUSP00000028823; ENSMUSG00000027347; Mus musculus. [Genome view] ENSMUST00000102534; ENSMUSP00000099593; ENSMUSG00000027347; Mus musculus. [Genome view]
GeneID	19419.
KEGG	mmu:19419.
UCSC	uc008lrl.1. mouse.
Organism-specific databases
CTD	19419.
MGI	MGI:1314635. Rasgrp1.
Phylogenomic databases
eggNOG	roNOG05075.
HOGENOM	HBG403023.
HOVERGEN	Q9Z1S3.
InParanoid	Q9Z1S3.
OMA	AQITQFR.
OrthoDB	EOG9Z91FN.
Gene expression databases
ArrayExpress	Q9Z1S3.
Bgee	Q9Z1S3.
CleanEx	MM_RASGRP1.
Genevestigator	Q9Z1S3.
Family and domain databases
InterPro	IPR020454. DAG/PE_bd. IPR011992. EF-hand-like_dom. IPR018247. EF_Hand_1_Ca_BS. IPR018249. EF_HAND_2. IPR002219. Prot_Kinase_C-like_PE/DAG_bd. IPR000651. Ras-like_Gua-exchang_fac_N. IPR008937. Ras_GEF. IPR001895. RasGRF_CDC25. [Graphical view]
Gene3D	G3DSA:1.10.238.10. EF-Hand_type. 1 hit. G3DSA:1.10.840.10. RasGRF_CDC25. 1 hit.
PANTHER	PTHR23113. Ras_GEF. 1 hit.
Pfam	PF00130. C1_1. 1 hit. PF00617. RasGEF. 1 hit. [Graphical view]
PRINTS	PR00008. DAGPEDOMAIN.
SMART	SM00109. C1. 1 hit. SM00147. RasGEF. 1 hit. SM00229. RasGEFN. 1 hit. [Graphical view]
PROSITE	PS00018. 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]
ProtoNet	Search...
Other Resources
NextBio	296563.
SOURCE	Search...

Entry information

Entry name

GRP1_MOUSE

Accession

Primary (citable) accession number: Q9Z1S3
Secondary accession number(s): Q3URH0, Q3V401, Q8BQP6

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 5, 2008
Last sequence update:	May 1, 1999
Last modified:	January 19, 2010
This is version 80 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)