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ARHG8_HUMAN
ID   ARHG8_HUMAN             Reviewed;         596 AA.
AC   Q7Z628; Q12773; Q96D82; Q99903; Q9UEN6;
DT   27-SEP-2004, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-2003, sequence version 1.
DT   03-AUG-2022, entry version 160.
DE   RecName: Full=Neuroepithelial cell-transforming gene 1 protein;
DE   AltName: Full=Proto-oncogene p65 Net1;
DE   AltName: Full=Rho guanine nucleotide exchange factor 8;
GN   Name=NET1; Synonyms=ARHGEF8;
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 2), AND TISSUE SPECIFICITY.
RC   TISSUE=Neuroepithelium;
RX   PubMed=8649828;
RA   Chan A.M.-L., Takai S., Yamada K., Miki T.;
RT   "Isolation of a novel oncogene, NET1, from neuroepithelioma cells by
RT   expression cDNA cloning.";
RL   Oncogene 12:1259-1266(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Eye, and Placenta;
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   [3]
RP   INDUCTION BY TGFB1.
RX   PubMed=11278519; DOI=10.1074/jbc.m009534200;
RA   Shen X., Li J., Hu P.P.-C., Waddell D., Zhang J., Wang X.-F.;
RT   "The activity of guanine exchange factor NET1 is essential for transforming
RT   growth factor-beta-mediated stress fiber formation.";
RL   J. Biol. Chem. 276:15362-15368(2001).
RN   [4]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-106, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [5]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21; SER-32 AND SER-106, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [6]
RP   FUNCTION, AND INDUCTION.
RX   PubMed=21373644; DOI=10.1371/journal.pone.0017108;
RA   Srougi M.C., Burridge K.;
RT   "The nuclear guanine nucleotide exchange factors Ect2 and Net1 regulate
RT   RhoB-mediated cell death after DNA damage.";
RL   PLoS ONE 6:E17108-E17108(2011).
RN   [7]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA   Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-terminal
RT   acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [8]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21; SER-100; SER-106 AND
RP   SER-122, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma, and Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [9]
RP   X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 161-373.
RG   Structural genomics consortium (SGC);
RT   "Crystal structure of the RhoGEF domain of human neuroepithelial cell-
RT   transforming gene 1 protein.";
RL   Submitted (FEB-2009) to the PDB data bank.
RN   [10]
RP   VARIANT [LARGE SCALE ANALYSIS] ASN-202.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA   Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA   Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA   Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA   Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal cancers.";
RL   Science 314:268-274(2006).
CC   -!- FUNCTION: Acts as guanine nucleotide exchange factor (GEF) for RhoA
CC       GTPase. May be involved in activation of the SAPK/JNK pathway
CC       Stimulates genotoxic stress-induced RHOB activity in breast cancer
CC       cells leading to their cell death. {ECO:0000269|PubMed:21373644}.
CC   -!- SUBUNIT: Interacts with RHOA in its GTP- and GDP-bound states, and with
CC       CDC42 in its GTP-bound state. Interacts with the PDZ 1 domain of BAIAP1
CC       (By similarity). {ECO:0000250}.
CC   -!- INTERACTION:
CC       Q7Z628; Q12959: DLG1; NbExp=5; IntAct=EBI-2511306, EBI-357481;
CC       Q7Z628; O43639: NCK2; NbExp=3; IntAct=EBI-2511306, EBI-713635;
CC       Q7Z628; Q14160: SCRIB; NbExp=2; IntAct=EBI-2511306, EBI-357345;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q7Z628-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q7Z628-2; Sequence=VSP_011619, VSP_011620;
CC   -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:8649828}.
CC   -!- INDUCTION: By TGFB1. Up-regulated by DNA damaging agents like H(2)O(2)
CC       or ionizing radiation (IR). {ECO:0000269|PubMed:11278519,
CC       ECO:0000269|PubMed:21373644}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAB08847.1; Type=Frameshift; Evidence={ECO:0000305};
CC       Sequence=AAB37683.1; Type=Frameshift; Evidence={ECO:0000305};
CC       Sequence=CAA08974.1; Type=Frameshift; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/NET1ID41526ch10p15.html";
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DR   EMBL; S82401; AAB37683.1; ALT_FRAME; mRNA.
DR   EMBL; U02081; AAB08847.1; ALT_FRAME; mRNA.
DR   EMBL; AJ010046; CAA08974.1; ALT_FRAME; mRNA.
DR   EMBL; BC010285; AAH10285.1; -; mRNA.
DR   EMBL; BC053553; AAH53553.1; -; mRNA.
DR   CCDS; CCDS41483.1; -. [Q7Z628-1]
DR   CCDS; CCDS7067.1; -. [Q7Z628-2]
DR   PIR; G01210; G01210.
DR   RefSeq; NP_001040625.1; NM_001047160.2. [Q7Z628-1]
DR   RefSeq; NP_005854.2; NM_005863.4. [Q7Z628-2]
DR   PDB; 3EO2; X-ray; 2.60 A; A=161-373.
DR   PDB; 4XH9; X-ray; 2.00 A; A/D=149-501.
DR   PDBsum; 3EO2; -.
DR   PDBsum; 4XH9; -.
DR   AlphaFoldDB; Q7Z628; -.
DR   SMR; Q7Z628; -.
DR   BioGRID; 115565; 35.
DR   IntAct; Q7Z628; 18.
DR   MINT; Q7Z628; -.
DR   STRING; 9606.ENSP00000347134; -.
DR   BindingDB; Q7Z628; -.
DR   ChEMBL; CHEMBL4295880; -.
DR   iPTMnet; Q7Z628; -.
DR   PhosphoSitePlus; Q7Z628; -.
DR   BioMuta; NET1; -.
DR   DMDM; 52782735; -.
DR   EPD; Q7Z628; -.
DR   jPOST; Q7Z628; -.
DR   MassIVE; Q7Z628; -.
DR   MaxQB; Q7Z628; -.
DR   PaxDb; Q7Z628; -.
DR   PeptideAtlas; Q7Z628; -.
DR   PRIDE; Q7Z628; -.
DR   ProteomicsDB; 69371; -. [Q7Z628-1]
DR   ProteomicsDB; 69372; -. [Q7Z628-2]
DR   Antibodypedia; 10610; 419 antibodies from 36 providers.
DR   DNASU; 10276; -.
DR   Ensembl; ENST00000355029.9; ENSP00000347134.4; ENSG00000173848.19. [Q7Z628-1]
DR   Ensembl; ENST00000380359.3; ENSP00000369717.3; ENSG00000173848.19. [Q7Z628-2]
DR   GeneID; 10276; -.
DR   KEGG; hsa:10276; -.
DR   MANE-Select; ENST00000355029.9; ENSP00000347134.4; NM_001047160.3; NP_001040625.1.
DR   UCSC; uc001iia.5; human. [Q7Z628-1]
DR   CTD; 10276; -.
DR   DisGeNET; 10276; -.
DR   GeneCards; NET1; -.
DR   HGNC; HGNC:14592; NET1.
DR   HPA; ENSG00000173848; Low tissue specificity.
DR   MIM; 606450; gene.
DR   neXtProt; NX_Q7Z628; -.
DR   OpenTargets; ENSG00000173848; -.
DR   PharmGKB; PA164742175; -.
DR   VEuPathDB; HostDB:ENSG00000173848; -.
DR   eggNOG; KOG4305; Eukaryota.
DR   GeneTree; ENSGT00940000155849; -.
DR   HOGENOM; CLU_027428_2_0_1; -.
DR   InParanoid; Q7Z628; -.
DR   OMA; KTHRTQS; -.
DR   PhylomeDB; Q7Z628; -.
DR   TreeFam; TF328974; -.
DR   PathwayCommons; Q7Z628; -.
DR   Reactome; R-HSA-193648; NRAGE signals death through JNK.
DR   Reactome; R-HSA-416482; G alpha (12/13) signalling events.
DR   Reactome; R-HSA-8980692; RHOA GTPase cycle.
DR   Reactome; R-HSA-9013026; RHOB GTPase cycle.
DR   SignaLink; Q7Z628; -.
DR   SIGNOR; Q7Z628; -.
DR   BioGRID-ORCS; 10276; 8 hits in 1083 CRISPR screens.
DR   ChiTaRS; NET1; human.
DR   EvolutionaryTrace; Q7Z628; -.
DR   GeneWiki; NET1; -.
DR   GenomeRNAi; 10276; -.
DR   Pharos; Q7Z628; Tbio.
DR   PRO; PR:Q7Z628; -.
DR   Proteomes; UP000005640; Chromosome 10.
DR   RNAct; Q7Z628; protein.
DR   Bgee; ENSG00000173848; Expressed in tendon of biceps brachii and 210 other tissues.
DR   ExpressionAtlas; Q7Z628; baseline and differential.
DR   Genevisible; Q7Z628; HS.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; TAS:Reactome.
DR   GO; GO:0070301; P:cellular response to hydrogen peroxide; IDA:UniProtKB.
DR   GO; GO:0071479; P:cellular response to ionizing radiation; IDA:UniProtKB.
DR   GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR   GO; GO:0051451; P:myoblast migration; IEA:Ensembl.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR   GO; GO:0043547; P:positive regulation of GTPase activity; IMP:UniProtKB.
DR   GO; GO:0035025; P:positive regulation of Rho protein signal transduction; IBA:GO_Central.
DR   GO; GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
DR   GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR   CDD; cd13224; PH_Net1; 1.
DR   CDD; cd00160; RhoGEF; 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; IPR001331; GDS_CDC24_CS.
DR   InterPro; IPR037853; Net1_PH.
DR   InterPro; IPR011993; PH-like_dom_sf.
DR   InterPro; IPR001849; PH_domain.
DR   Pfam; PF00169; PH; 1.
DR   Pfam; PF00621; RhoGEF; 1.
DR   SMART; SM00233; PH; 1.
DR   SMART; SM00325; RhoGEF; 1.
DR   SUPFAM; SSF48065; SSF48065; 1.
DR   PROSITE; PS00741; DH_1; 1.
DR   PROSITE; PS50010; DH_2; 1.
DR   PROSITE; PS50003; PH_DOMAIN; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; Cytoplasm;
KW   Guanine-nucleotide releasing factor; Nucleus; Phosphoprotein;
KW   Proto-oncogene; Reference proteome.
FT   CHAIN           1..596
FT                   /note="Neuroepithelial cell-transforming gene 1 protein"
FT                   /id="PRO_0000080924"
FT   DOMAIN          174..356
FT                   /note="DH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00062"
FT   DOMAIN          386..501
FT                   /note="PH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT   REGION          1..74
FT                   /note="Necessary for nuclear localization"
FT                   /evidence="ECO:0000250"
FT   REGION          1..44
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          127..146
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          562..596
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           12..19
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250"
FT   MOTIF           66..72
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250"
FT   COMPBIAS        22..39
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        576..596
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0007744|PubMed:22814378"
FT   MOD_RES         21
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19690332,
FT                   ECO:0007744|PubMed:23186163"
FT   MOD_RES         32
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   MOD_RES         100
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         106
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18669648,
FT                   ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"
FT   MOD_RES         122
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         508
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Z206"
FT   VAR_SEQ         1..54
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:8649828"
FT                   /id="VSP_011619"
FT   VAR_SEQ         55..85
FT                   /note="LTPGPNWDFTLKRKRREKDDDVVSLSSLDLK -> MVAHDETGGLLPIKRTI
FT                   RVLDVNNQSFREQE (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334,
FT                   ECO:0000303|PubMed:8649828"
FT                   /id="VSP_011620"
FT   VARIANT         202
FT                   /note="D -> N (in a breast cancer sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:16959974"
FT                   /id="VAR_035972"
FT   VARIANT         417
FT                   /note="T -> I (in dbSNP:rs34658946)"
FT                   /id="VAR_051982"
FT   CONFLICT        39
FT                   /note="E -> R (in Ref. 1; AAB37683)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        61
FT                   /note="W -> C (in Ref. 1; AAB37683)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        143..146
FT                   /note="TVPT -> MDGW (in Ref. 1; AAB08847)"
FT                   /evidence="ECO:0000305"
FT   HELIX           170..199
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           201..206
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           212..219
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   TURN            220..225
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           226..238
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           250..256
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           257..263
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           264..279
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           280..282
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           284..295
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           297..299
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           304..308
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           310..315
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           318..327
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           335..366
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           374..376
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           379..382
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   STRAND          387..395
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   STRAND          400..416
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   STRAND          418..420
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   STRAND          423..426
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           433..435
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   STRAND          436..440
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   STRAND          464..470
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   STRAND          478..482
FT                   /evidence="ECO:0007829|PDB:4XH9"
FT   HELIX           486..501
FT                   /evidence="ECO:0007829|PDB:4XH9"
SQ   SEQUENCE   596 AA;  67740 MW;  E1AD964F14650D2C CRC64;
     MEPELAAQKQ PRPRRRSRRA SGLSTEGATG PSADTSGSEL DGRCSLRRGS SFTFLTPGPN
     WDFTLKRKRR EKDDDVVSLS SLDLKEPSNK RVRPLARVTS LANLISPVRN GAVRRFGQTI
     QSFTLRGDHR SPASAQKFSS RSTVPTPAKR RSSALWSEML DITMKESLTT REIRRQEAIY
     EMSRGEQDLI EDLKLARKAY HDPMLKLSIM SEEELTHIFG DLDSYIPLHE DLLTRIGEAT
     KPDGTVEQIG HILVSWLPRL NAYRGYCSNQ LAAKALLDQK KQDPRVQDFL QRCLESPFSR
     KLDLWSFLDI PRSRLVKYPL LLKEILKHTP KEHPDVQLLE DAILIIQGVL SDINLKKGES
     ECQYYIDKLE YLDEKQRDPR IEASKVLLCH GELRSKSGHK LYIFLFQDIL VLTRPVTRNE
     RHSYQVYRQP IPVQELVLED LQDGDVRMGG SFRGAFSNSE KAKNIFRIRF HDPSPAQSHT
     LQANDVFHKQ QWFNCIRAAI APFQSAGSPP ELQGLPELHE ECEGNHPSAR KLTAQRRAST
     VSSVTQVEVD ENAYRCGSGM QMAEDSKSLK THQTQPGIRR ARDKALSGGK RKETLV
 
 
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