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 27-MAR-2024, entry version 168.
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 a 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="https://atlasgeneticsoncology.org/gene/41526/NET1";
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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; 40.
DR IntAct; Q7Z628; 20.
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; 9606-ENSP00000347134; -.
DR PeptideAtlas; Q7Z628; -.
DR ProteomicsDB; 69371; -. [Q7Z628-1]
DR ProteomicsDB; 69372; -. [Q7Z628-2]
DR Pumba; Q7Z628; -.
DR Antibodypedia; 10610; 479 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 AGR; HGNC:14592; -.
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; ECGENDP; -.
DR OrthoDB; 24012at2759; -.
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; 9 hits in 1161 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 212 other cell types or 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; Dbl homology (DH) domain; 1.
DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 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 PANTHER; PTHR46006:SF4; NEUROEPITHELIAL CELL-TRANSFORMING GENE 1 PROTEIN; 1.
DR PANTHER; PTHR46006; RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR AT 64C, ISOFORM A; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00621; RhoGEF; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00325; RhoGEF; 1.
DR SUPFAM; SSF48065; DBL homology domain (DH-domain); 1.
DR SUPFAM; SSF50729; PH domain-like; 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
//
