ARHG8_MOUSE
ID ARHG8_MOUSE Reviewed; 595 AA.
AC Q9Z206; Q8C4I0; Q9Z1L7;
DT 27-SEP-2004, integrated into UniProtKB/Swiss-Prot.
DT 27-SEP-2004, sequence version 2.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Neuroepithelial cell-transforming gene 1 protein;
DE AltName: Full=Rho guanine nucleotide exchange factor 8;
GN Name=Net1; Synonyms=Arhgef8;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND MUTAGENESIS OF
RP LEU-321 AND TRP-492.
RX PubMed=9670022; DOI=10.1093/emboj/17.14.4075;
RA Alberts A.S., Treisman R.;
RT "Activation of RhoA and SAPK/JNK signalling pathways by the RhoA-specific
RT exchange factor mNET1.";
RL EMBO J. 17:4075-4085(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Wempe F., Nigro S., Melchner H.;
RT "NET1A: a new transforming splice-varriant of the Rho guanine nucleotide-
RT exchange factor NET1.";
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6J, and NOD; TISSUE=Cerebellum, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=FVB/N; TISSUE=Mammary tumor;
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 [5]
RP INTERACTION WITH RHOA AND CDC42.
RX PubMed=9535835; DOI=10.1074/jbc.273.15.8616;
RA Alberts A.S., Bouquin N., Johnston L.H., Treisman R.;
RT "Analysis of RhoA-binding proteins reveals an interaction domain conserved
RT in heterotrimeric G protein beta subunits and the yeast response regulator
RT protein Skn7.";
RL J. Biol. Chem. 273:8616-8622(1998).
RN [6]
RP INTERACTION WITH BAIAP1.
RX PubMed=11350080; DOI=10.1006/bbrc.2001.4880;
RA Dobrosotskaya I.Y.;
RT "Identification of mNET1 as a candidate ligand for the first PDZ domain of
RT MAGI-1.";
RL Biochem. Biophys. Res. Commun. 283:969-975(2001).
RN [7]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 12-ARG--ARG-16 AND 67-ARG--ARG-70.
RX PubMed=11839749; DOI=10.1074/jbc.m111108200;
RA Schmidt A., Hall A.;
RT "The Rho exchange factor Net1 is regulated by nuclear sequestration.";
RL J. Biol. Chem. 277:14581-14588(2002).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-508, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
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:9670022}.
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
CC BAIAP1. {ECO:0000269|PubMed:11350080, ECO:0000269|PubMed:9535835}.
CC -!- INTERACTION:
CC Q9Z206; Q6RHR9: Magi1; NbExp=6; IntAct=EBI-7840997, EBI-7440897;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11839749}. Nucleus
CC {ECO:0000269|PubMed:11839749}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9Z206-1; Sequence=Displayed;
CC Name=2; Synonyms=Net1a;
CC IsoId=Q9Z206-2; Sequence=VSP_011622, VSP_011623;
CC -!- DOMAIN: The PH domain is sufficient for the nuclear export of the
CC oncogenic N-terminal truncated form. The relocalization is not affected
CC by the Leu-492 mutation.
CC -!- MISCELLANEOUS: Can be converted to an oncogenic protein by N-terminal
CC deletion that leads to nuclear export and cytoplasmic localization.
CC Transformation seems to require the activity of multiple signaling
CC pathways. The physiological conditions for cytoplasmic relocalization
CC are not known yet.
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DR EMBL; AF094520; AAC71772.1; -; mRNA.
DR EMBL; AJ010045; CAA08973.1; -; mRNA.
DR EMBL; AK082128; BAC38417.1; -; mRNA.
DR EMBL; AK088632; BAC40466.1; -; mRNA.
DR EMBL; BC004699; AAH04699.1; -; mRNA.
DR CCDS; CCDS26216.1; -. [Q9Z206-1]
DR CCDS; CCDS36583.1; -. [Q9Z206-2]
DR RefSeq; NP_001040624.1; NM_001047159.2. [Q9Z206-2]
DR RefSeq; NP_062645.2; NM_019671.3. [Q9Z206-1]
DR AlphaFoldDB; Q9Z206; -.
DR SMR; Q9Z206; -.
DR BioGRID; 207915; 17.
DR IntAct; Q9Z206; 1.
DR MINT; Q9Z206; -.
DR STRING; 10090.ENSMUSP00000089464; -.
DR iPTMnet; Q9Z206; -.
DR PhosphoSitePlus; Q9Z206; -.
DR EPD; Q9Z206; -.
DR jPOST; Q9Z206; -.
DR MaxQB; Q9Z206; -.
DR PaxDb; Q9Z206; -.
DR PRIDE; Q9Z206; -.
DR ProteomicsDB; 283264; -. [Q9Z206-1]
DR ProteomicsDB; 283265; -. [Q9Z206-2]
DR Antibodypedia; 10610; 419 antibodies from 36 providers.
DR DNASU; 56349; -.
DR Ensembl; ENSMUST00000091853; ENSMUSP00000089464; ENSMUSG00000021215. [Q9Z206-1]
DR Ensembl; ENSMUST00000099946; ENSMUSP00000097529; ENSMUSG00000021215. [Q9Z206-2]
DR GeneID; 56349; -.
DR KEGG; mmu:56349; -.
DR UCSC; uc007pje.3; mouse. [Q9Z206-1]
DR CTD; 10276; -.
DR MGI; MGI:1927138; Net1.
DR VEuPathDB; HostDB:ENSMUSG00000021215; -.
DR eggNOG; KOG4305; Eukaryota.
DR GeneTree; ENSGT00940000155849; -.
DR HOGENOM; CLU_027428_2_0_1; -.
DR InParanoid; Q9Z206; -.
DR OMA; KTHRTQS; -.
DR PhylomeDB; Q9Z206; -.
DR TreeFam; TF328974; -.
DR Reactome; R-MMU-193648; NRAGE signals death through JNK.
DR Reactome; R-MMU-416482; G alpha (12/13) signalling events.
DR Reactome; R-MMU-8980692; RHOA GTPase cycle.
DR Reactome; R-MMU-9013026; RHOB GTPase cycle.
DR BioGRID-ORCS; 56349; 2 hits in 70 CRISPR screens.
DR ChiTaRS; Net1; mouse.
DR PRO; PR:Q9Z206; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; Q9Z206; protein.
DR Bgee; ENSMUSG00000021215; Expressed in epithelium of small intestine and 191 other tissues.
DR ExpressionAtlas; Q9Z206; baseline and differential.
DR Genevisible; Q9Z206; MM.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IEA:UniProtKB-KW.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISS:UniProtKB.
DR GO; GO:0071479; P:cellular response to ionizing radiation; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0051451; P:myoblast migration; IGI:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; ISS:UniProtKB.
DR GO; GO:0035025; P:positive regulation of Rho protein signal transduction; IBA:GO_Central.
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; PF16652; PH_13; 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 Acetylation; Alternative splicing; Cytoplasm;
KW Guanine-nucleotide releasing factor; Nucleus; Phosphoprotein;
KW Proto-oncogene; Reference proteome.
FT CHAIN 1..595
FT /note="Neuroepithelial cell-transforming gene 1 protein"
FT /id="PRO_0000080925"
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 REGION 1..42
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 127..151
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 555..595
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 12..19
FT /note="Nuclear localization signal"
FT MOTIF 66..72
FT /note="Nuclear localization signal"
FT COMPBIAS 575..595
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q7Z628"
FT MOD_RES 21
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7Z628"
FT MOD_RES 100
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7Z628"
FT MOD_RES 106
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7Z628"
FT MOD_RES 122
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q7Z628"
FT MOD_RES 508
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19144319"
FT VAR_SEQ 1..54
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072, ECO:0000303|Ref.2"
FT /id="VSP_011622"
FT VAR_SEQ 55..85
FT /note="LTPGPHWDFTLKRKRREKDDDAVSLSSLDLK -> MVAHDEIGGLLPIKRTI
FT RVLDVNNQPFREQE (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072, ECO:0000303|Ref.2"
FT /id="VSP_011623"
FT MUTAGEN 12..16
FT /note="RPRRR->APAAA: Leads to cytoplasmic relocalization;
FT when associated with 67-A--A-70."
FT /evidence="ECO:0000269|PubMed:11839749"
FT MUTAGEN 67..70
FT /note="RKRR->AAAA: Leads to cytoplasmic relocalization;
FT when associated with 12-A--A-16."
FT /evidence="ECO:0000269|PubMed:11839749"
FT MUTAGEN 321
FT /note="L->E: Inhibits transformation by N-terminal
FT truncated form."
FT /evidence="ECO:0000269|PubMed:9670022"
FT MUTAGEN 492
FT /note="W->L: Inhibits transformation by N-terminal
FT truncated form."
FT /evidence="ECO:0000269|PubMed:9670022"
FT CONFLICT 116
FT /note="F -> S (in Ref. 3; BAC38417)"
FT /evidence="ECO:0000305"
FT CONFLICT 412
FT /note="L -> W (in Ref. 1; AAC71772)"
FT /evidence="ECO:0000305"
FT CONFLICT 418
FT /note="R -> G (in Ref. 1; AAC71772)"
FT /evidence="ECO:0000305"
FT CONFLICT 473
FT /note="P -> L (in Ref. 1; AAC71772)"
FT /evidence="ECO:0000305"
FT CONFLICT 581..582
FT /note="RD -> SH (in Ref. 1; AAC71772)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 595 AA; 67734 MW; 95614632A87EA4F3 CRC64;
MEPEPAAQKQ PRPRRRSRRV SMLSEEPAAG LPADTPGPAA NERCSLRRGS SFTFLTPGPH
WDFTLKRKRR EKDDDAVSLS SLDLKEPSNK RVRPLARVTS LANLISPVRN GAVRRFGQTI
QSFTLRGDHR SPASAQKSFS RSTVPTPTKR RSSALWSEML DINMKESLTT REIKRQEAIY
ELSRGEQDLI EDLKLARKAY HDPMLKLSIM SEEELTHIFG DLDAYIPLHE DLLARIGEAT
KPDGTVEQIG HILVNWLPGL NAYRGYCSNQ LAAKALLDQK KQDPRVQDFL QRCLESPFSR
KLDLWSFLDI PRSRLVKYPL LLKEILRHTP KDHRDVQLLE EAILIIQGVL SDINLKKGES
ECQYYINKLE YLDEKQKDPR IEASKVLLCH GELKNKSGHK LYIFLFQDIL VLTRPVTRNE
RHLYQVYRQP IPVQELVLED LQDGDVRMGG SFRGAFGNSD KAKNIFRVRF QDPSPGHSHT
LQANDVFHKQ QWFNCIRAAI APFQRAASPL ELQGLPDLHE ECEENNPSAG NLRAQRRSCV
VPGVMQIDEE SALDCGSSVQ TVEDTRNMKA QRPQPGLRRA RDKAQSGGKK KETLV
