NGEF_HUMAN
ID NGEF_HUMAN Reviewed; 710 AA.
AC Q8N5V2; B4DMB8; B9A045; E9PC42; Q53QQ4; Q53ST7; Q6GMQ5; Q9NQD6;
DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2006, sequence version 2.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=Ephexin-1;
DE AltName: Full=Eph-interacting exchange protein;
DE AltName: Full=Neuronal guanine nucleotide exchange factor;
GN Name=NGEF;
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 [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP THR-111.
RC TISSUE=Leiomyosarcoma;
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 147-583 (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Fetal brain;
RX PubMed=10777665; DOI=10.1006/geno.2000.6138;
RA Rodrigues N.R., Theodosiou A.M., Nesbit M.A., Campbell L., Tandle A.T.,
RA Saranath D., Davies K.E.;
RT "Characterization of Ngef, a novel member of the Dbl family of genes
RT expressed predominantly in the caudate nucleus.";
RL Genomics 65:53-61(2000).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
CC -!- FUNCTION: Acts as a guanine nucleotide exchange factor (GEF) which
CC differentially activates the GTPases RHOA, RAC1 and CDC42. Plays a role
CC in axon guidance regulating ephrin-induced growth cone collapse and
CC dendritic spine morphogenesis. Upon activation by ephrin through EPHA4,
CC the GEF activity switches toward RHOA resulting in its activation.
CC Activated RHOA promotes cone retraction at the expense of RAC1- and
CC CDC42-stimulated growth cone extension (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Interacts with CDK5R1 and EPHA4; activated by EPHA4 through
CC the CDK5 kinase. {ECO:0000250}.
CC -!- INTERACTION:
CC Q8N5V2; P22607: FGFR3; NbExp=3; IntAct=EBI-718372, EBI-348399;
CC Q8N5V2; P28799: GRN; NbExp=3; IntAct=EBI-718372, EBI-747754;
CC Q8N5V2; P06396: GSN; NbExp=3; IntAct=EBI-718372, EBI-351506;
CC Q8N5V2; P01112: HRAS; NbExp=3; IntAct=EBI-718372, EBI-350145;
CC Q8N5V2; P04792: HSPB1; NbExp=3; IntAct=EBI-718372, EBI-352682;
CC Q8N5V2; P42858: HTT; NbExp=3; IntAct=EBI-718372, EBI-466029;
CC Q8N5V2; O60333-2: KIF1B; NbExp=3; IntAct=EBI-718372, EBI-10975473;
CC Q8N5V2; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-718372, EBI-396669;
CC Q8N5V2; O76024: WFS1; NbExp=3; IntAct=EBI-718372, EBI-720609;
CC Q8N5V2; Q9Y649; NbExp=3; IntAct=EBI-718372, EBI-25900580;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Membrane {ECO:0000250}.
CC Cell projection, growth cone {ECO:0000250}. Note=Associated with
CC membranes. Localizes to axonal growth cones (By similarity).
CC {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q8N5V2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8N5V2-2; Sequence=VSP_020259, VSP_020260, VSP_020261;
CC Name=3;
CC IsoId=Q8N5V2-3; Sequence=VSP_020259, VSP_020260;
CC -!- TISSUE SPECIFICITY: Highly expressed in brain specifically in caudate
CC nucleus and to a lower extent in amygdala and hippocampus. Also
CC detected in lung. {ECO:0000269|PubMed:10777665}.
CC -!- DOMAIN: The DH domain and the PH domain are both required to mediate
CC interaction with EPHA4. {ECO:0000250}.
CC -!- PTM: Src-dependent phosphorylation at Tyr-179 upon EPHA4 activation
CC increases the guanine exchange factor activity toward RHOA.
CC Phosphorylation by CDK5 upon EPHA4 activation by EFNA1 may regulate
CC dendritic spine morphogenesis (By similarity). {ECO:0000250}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH73962.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=AAX93288.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=CAC00686.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK297390; BAG59830.1; -; mRNA.
DR EMBL; AC016692; AAX93288.1; ALT_INIT; Genomic_DNA.
DR EMBL; AC106876; AAY24359.1; -; Genomic_DNA.
DR EMBL; BC031573; AAH31573.1; -; mRNA.
DR EMBL; BC073962; AAH73962.1; ALT_INIT; mRNA.
DR EMBL; AJ238899; CAC00686.1; ALT_FRAME; mRNA.
DR CCDS; CCDS2500.1; -. [Q8N5V2-1]
DR CCDS; CCDS46544.1; -. [Q8N5V2-3]
DR RefSeq; NP_001107562.1; NM_001114090.1. [Q8N5V2-3]
DR RefSeq; NP_062824.2; NM_019850.2. [Q8N5V2-1]
DR RefSeq; XP_011509225.1; XM_011510923.2. [Q8N5V2-1]
DR AlphaFoldDB; Q8N5V2; -.
DR SMR; Q8N5V2; -.
DR BioGRID; 117324; 70.
DR IntAct; Q8N5V2; 38.
DR MINT; Q8N5V2; -.
DR STRING; 9606.ENSP00000264051; -.
DR iPTMnet; Q8N5V2; -.
DR PhosphoSitePlus; Q8N5V2; -.
DR BioMuta; NGEF; -.
DR DMDM; 114152090; -.
DR EPD; Q8N5V2; -.
DR jPOST; Q8N5V2; -.
DR MassIVE; Q8N5V2; -.
DR MaxQB; Q8N5V2; -.
DR PaxDb; Q8N5V2; -.
DR PeptideAtlas; Q8N5V2; -.
DR PRIDE; Q8N5V2; -.
DR ProteomicsDB; 19359; -.
DR ProteomicsDB; 72101; -. [Q8N5V2-1]
DR ProteomicsDB; 72102; -. [Q8N5V2-2]
DR Antibodypedia; 2119; 143 antibodies from 21 providers.
DR DNASU; 25791; -.
DR Ensembl; ENST00000264051.8; ENSP00000264051.3; ENSG00000066248.15. [Q8N5V2-1]
DR Ensembl; ENST00000373552.8; ENSP00000362653.4; ENSG00000066248.15. [Q8N5V2-3]
DR Ensembl; ENST00000409079.1; ENSP00000387033.1; ENSG00000066248.15. [Q8N5V2-2]
DR GeneID; 25791; -.
DR KEGG; hsa:25791; -.
DR MANE-Select; ENST00000264051.8; ENSP00000264051.3; NM_019850.3; NP_062824.2.
DR UCSC; uc002vts.3; human. [Q8N5V2-1]
DR CTD; 25791; -.
DR DisGeNET; 25791; -.
DR GeneCards; NGEF; -.
DR HGNC; HGNC:7807; NGEF.
DR HPA; ENSG00000066248; Group enriched (adrenal gland, brain, intestine, liver, skin).
DR MIM; 605991; gene.
DR neXtProt; NX_Q8N5V2; -.
DR OpenTargets; ENSG00000066248; -.
DR PharmGKB; PA31613; -.
DR VEuPathDB; HostDB:ENSG00000066248; -.
DR eggNOG; KOG3523; Eukaryota.
DR GeneTree; ENSGT01030000234571; -.
DR HOGENOM; CLU_012820_5_1_1; -.
DR InParanoid; Q8N5V2; -.
DR OMA; IDSCTRA; -.
DR OrthoDB; 1176939at2759; -.
DR PhylomeDB; Q8N5V2; -.
DR TreeFam; TF316357; -.
DR PathwayCommons; Q8N5V2; -.
DR Reactome; R-HSA-193648; NRAGE signals death through JNK.
DR Reactome; R-HSA-3928663; EPHA-mediated growth cone collapse.
DR Reactome; R-HSA-416482; G alpha (12/13) signalling events.
DR Reactome; R-HSA-8980692; RHOA GTPase cycle.
DR Reactome; R-HSA-9013148; CDC42 GTPase cycle.
DR Reactome; R-HSA-9013149; RAC1 GTPase cycle.
DR SignaLink; Q8N5V2; -.
DR SIGNOR; Q8N5V2; -.
DR BioGRID-ORCS; 25791; 9 hits in 1066 CRISPR screens.
DR ChiTaRS; NGEF; human.
DR GenomeRNAi; 25791; -.
DR Pharos; Q8N5V2; Tbio.
DR PRO; PR:Q8N5V2; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q8N5V2; protein.
DR Bgee; ENSG00000066248; Expressed in prefrontal cortex and 156 other tissues.
DR ExpressionAtlas; Q8N5V2; baseline and differential.
DR Genevisible; Q8N5V2; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030426; C:growth cone; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; EXP:Reactome.
DR GO; GO:0090630; P:activation of GTPase activity; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0048013; P:ephrin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0061002; P:negative regulation of dendritic spine morphogenesis; ISS:UniProtKB.
DR GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
DR GO; GO:0043087; P:regulation of GTPase activity; ISS:UniProtKB.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR CDD; cd00160; RhoGEF; 1.
DR CDD; cd11939; SH3_ephexin1; 1.
DR Gene3D; 1.20.900.10; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR035899; DBL_dom_sf.
DR InterPro; IPR000219; DH-domain.
DR InterPro; IPR035635; Ephexin-1_SH3.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00621; RhoGEF; 1.
DR Pfam; PF00018; SH3_1; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00325; RhoGEF; 1.
DR SMART; SM00326; SH3; 1.
DR SUPFAM; SSF48065; SSF48065; 1.
DR SUPFAM; SSF50044; SSF50044; 1.
DR PROSITE; PS50010; DH_2; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell projection; Cytoplasm; Developmental protein;
KW Differentiation; Guanine-nucleotide releasing factor; Membrane;
KW Neurogenesis; Phosphoprotein; Reference proteome; SH3 domain.
FT CHAIN 1..710
FT /note="Ephexin-1"
FT /id="PRO_0000248388"
FT DOMAIN 273..457
FT /note="DH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00062"
FT DOMAIN 489..601
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 612..673
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT REGION 1..273
FT /note="Regulatory region; modulates activity toward RHOA,
FT RAC1 and CDC42"
FT /evidence="ECO:0000250"
FT REGION 1..143
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 194..236
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 687..710
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..20
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 30..58
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 85..104
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 121..138
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 212..227
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 687..703
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 179
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q5BKC9"
FT VAR_SEQ 1..92
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_020259"
FT VAR_SEQ 93..127
FT /note="DNGKSVNEPLTLNIPWSRMPPCRTAMQTDPGAQEM -> MELLAAAFSAACA
FT VDHDSSTSESDARDSAAGHLPG (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_020260"
FT VAR_SEQ 331..710
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_020261"
FT VARIANT 78
FT /note="R -> G (in dbSNP:rs2271703)"
FT /id="VAR_027289"
FT VARIANT 111
FT /note="M -> T (in dbSNP:rs4973588)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_027290"
FT CONFLICT 147
FT /note="A -> T (in Ref. 4; CAC00686)"
FT /evidence="ECO:0000305"
FT CONFLICT 543
FT /note="A -> R (in Ref. 4; CAC00686)"
FT /evidence="ECO:0000305"
FT CONFLICT 578
FT /note="T -> I (in Ref. 4; CAC00686)"
FT /evidence="ECO:0000305"
FT CONFLICT 604
FT /note="F -> S (in Ref. 1; BAG59830)"
FT /evidence="ECO:0000305"
FT CONFLICT 702
FT /note="R -> M (in Ref. 1; BAG59830)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 710 AA; 82496 MW; 82A4CA71D4E7AE6E CRC64;
METRESEDLE KTRRKSASDQ WNTDNEPAKV KPELLPEKEE TSQADQDIQD KEPHCHIPIK
RNSIFNRSIR RKSKAKARDN PERNASCLAD SQDNGKSVNE PLTLNIPWSR MPPCRTAMQT
DPGAQEMSES SSTPGNGATP EEWPALADSP TTLTEALRMI HPIPADSWRN LIEQIGLLYQ
EYRDKSTLQE IETRRQQDAE IEDNTNGSPA SEDTPEEEEE EEEEEEPASP PERKTLPQIC
LLSNPHSRFN LWQDLPEIRS SGVLEILQPE EIKLQEAMFE LVTSEASYYK SLNLLVSHFM
ENERIRKILH PSEAHILFSN VLDVLAVSER FLLELEHRME ENIVISDVCD IVYRYAADHF
SVYITYVSNQ TYQERTYKQL LQEKAAFREL IAQLELDPKC RGLPFSSFLI LPFQRITRLK
LLVQNILKRV EERSERECTA LDAHKELEMV VKACNEGVRK MSRTEQMISI QKKMEFKIKS
VPIISHSRWL LKQGELQQMS GPKTSRTLRT KKLFHEIYLF LFNDLLVICR QIPGDKYQVF
DSAPRGLLRV EELEDQGQTL ANVFILRLLE NADDREATYM LKASSQSEMK RWMTSLAPNR
RTKFVSFTSR LLDCPQVQCV HPYVAQQPDE LTLELADILN ILDKTDDGWI FGERLHDQER
GWFPSSMTEE ILNPKIRSQN LKECFRVHKM DDPQRSQNKD RRKLGSRNRQ
