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 24-JAN-2024, entry version 170. 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, PubMed:19234460) that it is not the case and that LAD3 CC is caused by defects in FERMT3 gene. {ECO:0000305|PubMed:17576779}. CC -!- WEB RESOURCE: Name=RASGRP2base; Note=RASGRP2 mutation db; CC URL="http://structure.bmc.lu.se/idbase/RASGRP2base/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. DR RefSeq; XP_011543025.1; XM_011544723.2. [Q7LDG7-4] DR RefSeq; XP_016872573.1; XM_017017084.1. 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; 9606-ENSP00000338864; -. DR PeptideAtlas; Q7LDG7; -. DR ProteomicsDB; 68852; -. [Q7LDG7-1] DR ProteomicsDB; 68853; -. [Q7LDG7-2] DR ProteomicsDB; 68854; -. [Q7LDG7-3] DR ProteomicsDB; 899; -. DR Antibodypedia; 2786; 150 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 AGR; HGNC:9879; -. 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; HNFHESS; -. DR OrthoDB; 4260488at2759; -. 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 1159 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 177 other cell types or tissues. DR ExpressionAtlas; Q7LDG7; baseline and differential. 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:HPA. 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; cd20861; C1_RASGRP2; 1. DR CDD; cd00051; EFh; 1. DR CDD; cd00155; RasGEF; 1. DR CDD; cd06224; REM; 1. DR Gene3D; 3.30.60.20; -; 1. DR Gene3D; 1.10.238.10; EF-hand; 1. DR Gene3D; 1.10.840.10; Ras guanine-nucleotide exchange factors catalytic domain; 1. DR Gene3D; 1.20.870.10; Son of sevenless (SoS) protein Chain: S domain 1; 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; GUANINE NUCLEOTIDE EXCHANGE FACTOR; 1. DR PANTHER; PTHR23113:SF16; RAS GUANYL-RELEASING PROTEIN 2; 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; SSF57889; Cysteine-rich domain; 1. DR SUPFAM; SSF47473; EF-hand; 1. DR SUPFAM; SSF48366; Ras GEF; 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. DR Genevisible; Q7LDG7; HS. 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 //