GRP2_HUMAN
ID GRP2_HUMAN Reviewed; 609 AA.
AC Q7LDG7; A6NDC7; O00538; Q9UL65;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=RAS guanyl-releasing protein 2;
DE AltName: Full=Calcium and DAG-regulated guanine nucleotide exchange factor I;
DE Short=CalDAG-GEFI;
DE AltName: Full=Cdc25-like protein;
DE Short=hCDC25L;
DE AltName: Full=F25B3.3 kinase-like protein;
GN Name=RASGRP2; Synonyms=CDC25L, MCG7;
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), AND TISSUE SPECIFICITY.
RX PubMed=9341881; DOI=10.1007/s004390050562;
RA Kedra D., Seroussi E., Fransson I., Trifunovic J., Clark M.,
RA Lagercrantz J., Blennow E., Mehlin H., Dumanski J.;
RT "The germinal centre kinase gene and a novel CDC25-like gene are located in
RT the vicinity of the PYGM gene on 11q13.";
RL Hum. Genet. 100:611-619(1997).
RN [2]
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, ACTIVITY
RP REGULATION, SUBCELLULAR LOCATION, TOPOLOGY, PALMITOYLATION AT CYS-7
RP (ISOFORM 2), MYRISTOYLATION AT GLY-2 (ISOFORM 2), AND TISSUE SPECIFICITY.
RX PubMed=10918068; DOI=10.1074/jbc.m006087200;
RA Clyde-Smith J., Silins G., Gartside M., Grimmond S., Etheridge M.,
RA Apolloni A., Hayward N., Hancock J.F.;
RT "Characterization of RasGRP2, a plasma membrane-targeted, dual specificity
RT Ras/Rap exchange factor.";
RL J. Biol. Chem. 275:32260-32267(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Spleen;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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 [8]
RP ALTERNATIVE SPLICING (ISOFORM 3).
RX PubMed=11278453; DOI=10.1074/jbc.m008970200;
RA Dupuy A.J., Morgan K., von Lintig F.C., Shen H., Acar H., Hasz D.E.,
RA Jenkins N.A., Copeland N.G., Boss G.R., Largaespada D.A.;
RT "Activation of the Rap1 guanine nucleotide exchange gene, CalDAG-GEF I, in
RT BXH-2 murine myeloid leukemia.";
RL J. Biol. Chem. 276:11804-11811(2001).
RN [9]
RP FUNCTION, AND INTERACTION WITH RAP1.
RX PubMed=14702343; DOI=10.1074/jbc.m310717200;
RA Katagiri K., Shimonaka M., Kinashi T.;
RT "Rap1-mediated lymphocyte function-associated antigen-1 activation by the T
RT cell antigen receptor is dependent on phospholipase C-gamma1.";
RL J. Biol. Chem. 279:11875-11881(2004).
RN [10]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH F-ACTIN.
RX PubMed=14988412; DOI=10.1074/jbc.m313013200;
RA Caloca M.J., Zugaza J.L., Vicente-Manzanares M., Sanchez-Madrid F.,
RA Bustelo X.R.;
RT "F-actin-dependent translocation of the Rap1 GDP/GTP exchange factor
RT RasGRP2.";
RL J. Biol. Chem. 279:20435-20446(2004).
RN [11]
RP FUNCTION IN T-LYMPHOCYTES ADHESION, AND TISSUE SPECIFICITY.
RX PubMed=17702895; DOI=10.1182/blood-2007-03-077628;
RA Ghandour H., Cullere X., Alvarez A., Luscinskas F.W., Mayadas T.N.;
RT "Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI
RT in LFA-1 but not VLA-4 integrin mediated human T-cell adhesion.";
RL Blood 110:3682-3690(2007).
RN [12]
RP FUNCTION IN INTEGRIN ACTIVATION, AND TISSUE SPECIFICITY.
RX PubMed=17576779; DOI=10.1084/jem.20070058;
RA Pasvolsky R., Feigelson S.W., Kilic S.S., Simon A.J., Tal-Lapidot G.,
RA Grabovsky V., Crittenden J.R., Amariglio N., Safran M., Graybiel A.M.,
RA Rechavi G., Ben-Dor S., Etzioni A., Alon R.;
RT "A LAD-III syndrome is associated with defective expression of the Rap-1
RT activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets.";
RL J. Exp. Med. 204:1571-1582(2007).
RN [13]
RP LACK OF INVOLVEMENT IN LAD3.
RX PubMed=19064721; DOI=10.1182/blood-2008-10-182154;
RA Kuijpers T.W., van de Vijver E., Weterman M.A.J., de Boer M., Tool A.T.J.,
RA van den Berg T.K., Moser M., Jakobs M.E., Seeger K., Sanal O., Uenal S.,
RA Cetin M., Roos D., Verhoeven A.J., Baas F.;
RT "LAD-1/variant syndrome is caused by mutations in FERMT3.";
RL Blood 113:4740-4746(2009).
RN [14]
RP LACK OF INVOLVEMENT IN LAD3.
RX PubMed=19234463; DOI=10.1038/nm.1931;
RA Svensson L., Howarth K., McDowall A., Patzak I., Evans R., Ussar S.,
RA Moser M., Metin A., Fried M., Tomlinson I., Hogg N.;
RT "Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3
RT affecting integrin activation.";
RL Nat. Med. 15:306-312(2009).
RN [15]
RP LACK OF INVOLVEMENT IN LAD3.
RX PubMed=19234460; DOI=10.1038/nm.1917;
RA Malinin N.L., Zhang L., Choi J., Ciocea A., Razorenova O., Ma Y.-Q.,
RA Podrez E.A., Tosi M., Lennon D.P., Caplan A.I., Shurin S.B., Plow E.F.,
RA Byzova T.V.;
RT "A point mutation in KINDLIN3 ablates activation of three integrin
RT subfamilies in humans.";
RL Nat. Med. 15:313-318(2009).
RN [16]
RP FUNCTION, INVOLVEMENT IN BDPLT18, VARIANT BDPLT18 TRP-248, AND
RP CHARACTERIZATION OF VARIANT BDPLT18 TRP-248.
RX PubMed=24958846; DOI=10.1084/jem.20130477;
RA Canault M., Ghalloussi D., Grosdidier C., Guinier M., Perret C.,
RA Chelghoum N., Germain M., Raslova H., Peiretti F., Morange P.E., Saut N.,
RA Pillois X., Nurden A.T., Cambien F., Pierres A., van den Berg T.K.,
RA Kuijpers T.W., Alessi M.C., Tregouet D.A.;
RT "Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and
RT causes severe bleeding.";
RL J. Exp. Med. 211:1349-1362(2014).
RN [17]
RP FUNCTION, VARIANTS BDPLT18 113-ARG--LEU-609 DEL AND PHE-381, AND
RP CHARACTERIZATION OF VARIANTS BDPLT18 113-ARG--LEU-609 DEL AND PHE-381.
RX PubMed=27235135; DOI=10.1182/blood-2015-11-683102;
RA Lozano M.L., Cook A., Bastida J.M., Paul D.S., Iruin G., Cid A.R.,
RA Adan-Pedroso R., Ramon Gonzalez-Porras J., Hernandez-Rivas J.M.,
RA Fletcher S.J., Johnson B., Morgan N., Ferrer-Marin F., Vicente V.,
RA Sondek J., Watson S.P., Bergmeier W., Rivera J.;
RT "Novel mutations in RASGRP2, which encodes CalDAG-GEFI, abrogate Rap1
RT activation, causing platelet dysfunction.";
RL Blood 128:1282-1289(2016).
RN [18]
RP STRUCTURE BY NMR OF 417-497 IN COMPLEX WITH CALCIUM.
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 [19]
RP VARIANT BDPLT18 ASP-305.
RX PubMed=28726538; DOI=10.1080/09537104.2017.1332759;
RA Bermejo E., Alberto M.F., Paul D.S., Cook A.A., Nurden P.,
RA Sanchez Luceros A., Nurden A.T., Bergmeier W.;
RT "Marked bleeding diathesis in patients with platelet dysfunction due to a
RT novel mutation in RASGRP2, encoding CalDAG-GEFI (p.Gly305Asp).";
RL Platelets 2017:1-3(2017).
RN [20]
RP VARIANTS BDPLT18 236-GLN--LEU-609 DEL AND TYR-296, AND CHARACTERIZATION OF
RP VARIANTS BDPLT18 236-GLN--LEU-609 DEL AND TYR-296.
RX PubMed=28762304; DOI=10.1080/09537104.2017.1336214;
RA Sevivas T., Bastida J.M., Paul D.S., Caparros E., Palma-Barqueros V.,
RA Coucelo M., Marques D., Ferrer-Marin F., Gonzalez-Porras J.R., Vicente V.,
RA Hernandez-Rivas J.M., Watson S.P., Lozano M.L., Bergmeier W., Rivera J.;
RT "Identification of two novel mutations in RASGRP2 affecting platelet
RT CalDAG-GEFI expression and function in patients with bleeding diathesis.";
RL Platelets 2017:1-4(2017).
CC -!- FUNCTION: Functions as a calcium- and DAG-regulated nucleotide exchange
CC factor specifically activating Rap through the exchange of bound GDP
CC for GTP. May also activate other GTPases such as RRAS, RRAS2, NRAS,
CC KRAS but not HRAS. Functions in aggregation of platelets and adhesion
CC of T-lymphocytes and neutrophils probably through inside-out integrin
CC activation. May function in the muscarinic acetylcholine receptor
CC M1/CHRM1 signaling pathway. {ECO:0000269|PubMed:10918068,
CC ECO:0000269|PubMed:14702343, ECO:0000269|PubMed:17576779,
CC ECO:0000269|PubMed:17702895, ECO:0000269|PubMed:24958846,
CC ECO:0000269|PubMed:27235135}.
CC -!- ACTIVITY REGULATION: Isoform 1 and isoform 2 are differently regulated
CC by calcium and DAG. {ECO:0000269|PubMed:10918068}.
CC -!- SUBUNIT: Forms a signaling complex with RAP1 and BRAF (By similarity).
CC Interacts with RAP1. Interacts with F-actin. {ECO:0000250,
CC ECO:0000269|PubMed:14702343, ECO:0000269|PubMed:14988412}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Cell membrane; Peripheral
CC membrane protein. Synapse, synaptosome {ECO:0000305}. Cell projection,
CC ruffle membrane {ECO:0000305}; Peripheral membrane protein
CC {ECO:0000305}. Note=Found both in the cytosol and associated with
CC membranes. Isoform 2 mainly localizes to the cell membrane. Enriched at
CC juxtamembrane areas and membrane ruffles through association with F-
CC actin. Localizes to the cell bodies and axons of striatal neurons (By
CC similarity). {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=CalDAG-GEFI, CalDAG-GEFIa;
CC IsoId=Q7LDG7-1; Sequence=Displayed;
CC Name=2; Synonyms=RasGRP2;
CC IsoId=Q7LDG7-2; Sequence=VSP_030574;
CC Name=3; Synonyms=CalDAG-GEFIb;
CC IsoId=Q7LDG7-3; Sequence=VSP_030575, VSP_030576;
CC Name=4;
CC IsoId=Q7LDG7-4; Sequence=VSP_054132;
CC -!- TISSUE SPECIFICITY: Detected in platelets, neutrophils and T
CC lymphocytes (at protein level). Expressed in brain where it is enriched
CC in the striatum. Also expressed in the hematopoietic system. Detected
CC in heart, brain, lung, placenta, liver, skeletal muscle and kidney.
CC {ECO:0000269|PubMed:10918068, ECO:0000269|PubMed:17576779,
CC ECO:0000269|PubMed:17702895, ECO:0000269|PubMed:9341881,
CC ECO:0000269|PubMed:9789079}.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal brain, lung, liver and kidney.
CC {ECO:0000269|PubMed:9789079}.
CC -!- DOMAIN: The N-terminal Ras-GEF domain mediates association with F-
CC actin.
CC -!- PTM: Isoform 2 is palmitoylated and myristoylated.
CC {ECO:0000269|PubMed:10918068}.
CC -!- DISEASE: Bleeding disorder, platelet-type, 18 (BDPLT18) [MIM:615888]: A
CC disorder characterized by increased bleeding tendency due to platelet
CC dysfunction. Clinical features include epistaxis, hematomas, bleeding
CC after tooth extraction, and menorrhagia. {ECO:0000269|PubMed:24958846,
CC ECO:0000269|PubMed:27235135, ECO:0000269|PubMed:28726538,
CC ECO:0000269|PubMed:28762304}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 3]: The corresponding protein is not
CC undetectable. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the RASGRP family. {ECO:0000305}.
CC -!- CAUTION: Defects in RASGRP2 were initially thought (PubMed:17576779) to
CC be the cause of leukocyte adhesion deficiency type 3 (LAD3), a syndrome
CC characterized by recurrent bacterial infections and major bleeding
CC disorders. However, it was later shown (PubMed:19064721,
CC PubMed:19234463 and PubMed:19234460) that it is not the case and that
CC LAD3 is caused by defects in FERMT3 gene.
CC {ECO:0000305|PubMed:17576779}.
CC -!- WEB RESOURCE: Name=RASGRP2base; Note=RASGRP2 mutation db;
CC URL="http://structure.bmc.lu.se/idbase/RASGRP2base/";
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DR EMBL; Y12336; CAA73005.1; -; mRNA.
DR EMBL; AF081194; AAC79698.1; -; mRNA.
DR EMBL; U78170; AAD12741.1; -; mRNA.
DR EMBL; AF043722; AAF07219.1; -; mRNA.
DR EMBL; AF043723; AAF07220.1; -; mRNA.
DR EMBL; AK092882; BAG52620.1; -; mRNA.
DR EMBL; AP001462; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471076; EAW74281.1; -; Genomic_DNA.
DR EMBL; BC117151; AAI17152.1; -; mRNA.
DR CCDS; CCDS31598.1; -. [Q7LDG7-1]
DR RefSeq; NP_001092140.1; NM_001098670.1. [Q7LDG7-1]
DR RefSeq; NP_001092141.1; NM_001098671.1. [Q7LDG7-1]
DR RefSeq; NP_001305327.1; NM_001318398.1.
DR RefSeq; NP_722541.1; NM_153819.1. [Q7LDG7-1]
DR RefSeq; XP_011543022.1; XM_011544720.1. [Q7LDG7-4]
DR RefSeq; XP_011543023.1; XM_011544721.1. [Q7LDG7-4]
DR RefSeq; XP_011543024.1; XM_011544722.1. [Q7LDG7-4]
DR RefSeq; XP_011543025.1; XM_011544723.2. [Q7LDG7-4]
DR RefSeq; XP_016872573.1; XM_017017084.1. [Q7LDG7-4]
DR PDB; 2MA2; NMR; -; A=417-497.
DR PDB; 6AXF; X-ray; 3.10 A; A/C/E/G/I/K/M/O=1-394.
DR PDBsum; 2MA2; -.
DR PDBsum; 6AXF; -.
DR AlphaFoldDB; Q7LDG7; -.
DR BMRB; Q7LDG7; -.
DR SMR; Q7LDG7; -.
DR BioGRID; 115529; 11.
DR IntAct; Q7LDG7; 3.
DR STRING; 9606.ENSP00000338864; -.
DR iPTMnet; Q7LDG7; -.
DR PhosphoSitePlus; Q7LDG7; -.
DR SwissPalm; Q7LDG7; -.
DR BioMuta; RASGRP2; -.
DR DMDM; 74713056; -.
DR EPD; Q7LDG7; -.
DR jPOST; Q7LDG7; -.
DR MassIVE; Q7LDG7; -.
DR MaxQB; Q7LDG7; -.
DR PaxDb; Q7LDG7; -.
DR PeptideAtlas; Q7LDG7; -.
DR PRIDE; Q7LDG7; -.
DR ProteomicsDB; 68852; -. [Q7LDG7-1]
DR ProteomicsDB; 68853; -. [Q7LDG7-2]
DR ProteomicsDB; 68854; -. [Q7LDG7-3]
DR ProteomicsDB; 899; -.
DR Antibodypedia; 2786; 138 antibodies from 27 providers.
DR DNASU; 10235; -.
DR Ensembl; ENST00000354024.7; ENSP00000338864.3; ENSG00000068831.19. [Q7LDG7-1]
DR Ensembl; ENST00000377494.5; ENSP00000366714.1; ENSG00000068831.19. [Q7LDG7-4]
DR Ensembl; ENST00000377497.7; ENSP00000366717.3; ENSG00000068831.19. [Q7LDG7-1]
DR Ensembl; ENST00000394432.8; ENSP00000377953.3; ENSG00000068831.19. [Q7LDG7-1]
DR GeneID; 10235; -.
DR KEGG; hsa:10235; -.
DR MANE-Select; ENST00000394432.8; ENSP00000377953.3; NM_001098671.2; NP_001092141.1.
DR UCSC; uc001oau.4; human. [Q7LDG7-1]
DR CTD; 10235; -.
DR DisGeNET; 10235; -.
DR GeneCards; RASGRP2; -.
DR HGNC; HGNC:9879; RASGRP2.
DR HPA; ENSG00000068831; Tissue enhanced (bone marrow, lymphoid tissue).
DR MalaCards; RASGRP2; -.
DR MIM; 605577; gene.
DR MIM; 615888; phenotype.
DR neXtProt; NX_Q7LDG7; -.
DR OpenTargets; ENSG00000068831; -.
DR Orphanet; 420566; Bleeding disorder due to CalDAG-GEFI deficiency.
DR PharmGKB; PA34241; -.
DR VEuPathDB; HostDB:ENSG00000068831; -.
DR eggNOG; KOG3417; Eukaryota.
DR GeneTree; ENSGT00940000160483; -.
DR HOGENOM; CLU_019261_1_0_1; -.
DR InParanoid; Q7LDG7; -.
DR OMA; PPVLDEW; -.
DR OrthoDB; 355412at2759; -.
DR PhylomeDB; Q7LDG7; -.
DR TreeFam; TF312918; -.
DR PathwayCommons; Q7LDG7; -.
DR Reactome; R-HSA-114508; Effects of PIP2 hydrolysis.
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 SignaLink; Q7LDG7; -.
DR BioGRID-ORCS; 10235; 42 hits in 1081 CRISPR screens.
DR GeneWiki; RASGRP2; -.
DR GenomeRNAi; 10235; -.
DR Pharos; Q7LDG7; Tbio.
DR PRO; PR:Q7LDG7; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q7LDG7; protein.
DR Bgee; ENSG00000068831; Expressed in granulocyte and 175 other tissues.
DR ExpressionAtlas; Q7LDG7; baseline and differential.
DR Genevisible; Q7LDG7; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0043005; C:neuron projection; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; TAS:UniProtKB.
DR GO; GO:0019992; F:diacylglycerol binding; NAS:UniProtKB.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0008289; F:lipid binding; TAS:UniProtKB.
DR GO; GO:0071277; P:cellular response to calcium ion; IDA:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IDA:UniProtKB.
DR GO; GO:0007265; P:Ras protein signal transduction; IBA:GO_Central.
DR GO; GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:UniProtKB.
DR CDD; cd00029; C1; 1.
DR CDD; cd00051; EFh; 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; 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; PF13499; EF-hand_7; 1.
DR Pfam; PF00617; RasGEF; 1.
DR Pfam; PF00618; RasGEF_N; 1.
DR SMART; SM00109; C1; 1.
DR SMART; SM00054; EFh; 2.
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; 2.
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;
KW Cell projection; Cytoplasm; Disease variant;
KW Guanine-nucleotide releasing factor; Membrane; Metal-binding;
KW Phosphoprotein; Reference proteome; Repeat; Synapse; Synaptosome; Zinc;
KW Zinc-finger.
FT CHAIN 1..609
FT /note="RAS guanyl-releasing protein 2"
FT /id="PRO_0000315608"
FT DOMAIN 4..126
FT /note="N-terminal Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00135"
FT DOMAIN 154..387
FT /note="Ras-GEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00168"
FT DOMAIN 426..461
FT /note="EF-hand 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT DOMAIN 455..490
FT /note="EF-hand 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT ZN_FING 498..548
FT /note="Phorbol-ester/DAG-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00226"
FT REGION 382..406
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 557..592
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 439
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT BINDING 441
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT BINDING 443
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT BINDING 445
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT BINDING 450
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT BINDING 468
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT BINDING 470
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT BINDING 472
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT BINDING 474
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT BINDING 479
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448,
FT ECO:0000305|PubMed:23908768"
FT MOD_RES 116
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QUG9"
FT MOD_RES 117
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QUG9"
FT MOD_RES 147
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QUG9"
FT MOD_RES 554
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QUG9"
FT MOD_RES 576
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P0C643"
FT VAR_SEQ 1
FT /note="M -> MGTQRLCGRGTQGWPGSSEQHVQEATSSAGLHSGVDELGVRSEPGGR
FT LPERSLGPAHPAPAAM (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10918068"
FT /id="VSP_030574"
FT VAR_SEQ 125
FT /note="P -> CVGAEHRGLGGHSVSYTICA (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_030575"
FT VAR_SEQ 126..609
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_030576"
FT VAR_SEQ 590
FT /note="P -> PA (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054132"
FT VARIANT 113..609
FT /note="Missing (in BDPLT18)"
FT /evidence="ECO:0000269|PubMed:27235135"
FT /id="VAR_079614"
FT VARIANT 236..609
FT /note="Missing (in BDPLT18; lack of mutant protein in
FT platelets from a patient homozygous for the mutation)"
FT /evidence="ECO:0000269|PubMed:28762304"
FT /id="VAR_079615"
FT VARIANT 248
FT /note="G -> W (in BDPLT18; prevents Rap1 activation upon
FT calcium stimulation; reduces platelet adhesion and
FT spreading; dbSNP:rs587777529)"
FT /evidence="ECO:0000269|PubMed:24958846"
FT /id="VAR_071474"
FT VARIANT 296
FT /note="C -> Y (in BDPLT18; lack of mutant protein in
FT platelets from a patient homozygous for the mutation)"
FT /evidence="ECO:0000269|PubMed:28762304"
FT /id="VAR_079616"
FT VARIANT 305
FT /note="G -> D (in BDPLT18)"
FT /evidence="ECO:0000269|PubMed:28726538"
FT /id="VAR_079617"
FT VARIANT 381
FT /note="S -> F (in BDPLT18; loss of guanyl-nucleotide
FT exchange factor activity; dbSNP:rs767965347)"
FT /evidence="ECO:0000269|PubMed:27235135"
FT /id="VAR_079618"
FT VARIANT 493
FT /note="G -> A (in dbSNP:rs2301562)"
FT /id="VAR_038257"
FT HELIX 13..22
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 33..42
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 43..45
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 49..65
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 69..85
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 87..92
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 94..110
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 116..118
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 129..132
FT /evidence="ECO:0007829|PDB:6AXF"
FT STRAND 137..140
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 145..150
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 155..170
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 175..184
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 191..212
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 217..236
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 240..250
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 253..256
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 259..263
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 267..279
FT /evidence="ECO:0007829|PDB:6AXF"
FT TURN 283..286
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 287..294
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 306..317
FT /evidence="ECO:0007829|PDB:6AXF"
FT STRAND 320..323
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 331..346
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 347..349
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 358..369
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 374..384
FT /evidence="ECO:0007829|PDB:6AXF"
FT HELIX 420..437
FT /evidence="ECO:0007829|PDB:2MA2"
FT HELIX 448..454
FT /evidence="ECO:0007829|PDB:2MA2"
FT TURN 455..457
FT /evidence="ECO:0007829|PDB:2MA2"
FT HELIX 464..467
FT /evidence="ECO:0007829|PDB:2MA2"
FT HELIX 477..486
FT /evidence="ECO:0007829|PDB:2MA2"
FT STRAND 490..492
FT /evidence="ECO:0007829|PDB:2MA2"
FT INIT_MET Q7LDG7-2:1
FT /note="Removed"
FT /evidence="ECO:0000305"
FT LIPID Q7LDG7-2:2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000269|PubMed:10918068"
FT LIPID Q7LDG7-2:7
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:10918068"
SQ SEQUENCE 609 AA; 69248 MW; 8B1321F864D24BC7 CRC64;
MAGTLDLDKG CTVEELLRGC IEAFDDSGKV RDPQLVRMFL MMHPWYIPSS QLAAKLLHIY
QQSRKDNSNS LQVKTCHLVR YWISAFPAEF DLNPELAEQI KELKALLDQE GNRRHSSLID
IDSVPTYKWK RQVTQRNPVG QKKRKMSLLF DHLEPMELAE HLTYLEYRSF CKILFQDYHS
FVTHGCTVDN PVLERFISLF NSVSQWVQLM ILSKPTAPQR ALVITHFVHV AEKLLQLQNF
NTLMAVVGGL SHSSISRLKE THSHVSPETI KLWEGLTELV TATGNYGNYR RRLAACVGFR
FPILGVHLKD LVALQLALPD WLDPARTRLN GAKMKQLFSI LEELAMVTSL RPPVQANPDL
LSLLTVSLDQ YQTEDELYQL SLQREPRSKS SPTSPTSCTP PPRPPVLEEW TSAAKPKLDQ
ALVVEHIEKM VESVFRNFDV DGDGHISQEE FQIIRGNFPY LSAFGDLDQN QDGCISREEM
VSYFLRSSSV LGGRMGFVHN FQESNSLRPV ACRHCKALIL GIYKQGLKCR ACGVNCHKQC
KDRLSVECRR RAQSVSLEGS APSPSPMHSH HHRAFSFSLP RPGRRGSRPP EIREEEVQTV
EDGVFDIHL
