TOX4_MOUSE
ID TOX4_MOUSE Reviewed; 619 AA.
AC Q8BU11; Q3UGN7; Q80UI2; Q99PN9; Q9CS16;
DT 19-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=TOX high mobility group box family member 4;
DE AltName: Full=Epidermal Langerhans cell protein LCP1;
GN Name=Tox4;
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].
RC STRAIN=BALB/cJ;
RA Luy M.A., Reske K.;
RT "Cloning of a novel gene expressed differentially in maturing epidermal
RT Langerhans cells.";
RL Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Heart, 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Trophoblast;
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-178 AND SER-182, AND
RP IDENTIFICATION BY 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).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-176; SER-178 AND SER-182, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Kidney, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-479, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, and Embryo;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
RN [8]
RP FUNCTION.
RX PubMed=31519808; DOI=10.1242/jcs.232223;
RA Vanheer L., Song J., De Geest N., Janiszewski A., Talon I., Provenzano C.,
RA Oh T., Chappell J., Pasque V.;
RT "Tox4 modulates cell fate reprogramming.";
RL J. Cell Sci. 132:0-0(2019).
RN [9]
RP FUNCTION, INDUCTION BY HFD, INTERACTION WITH FOXO1 AND CREB1, ACTIVITY
RP REGULATION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, DNA-BINDING, AND
RP MUTAGENESIS OF 213-LYS--LYS-218.
RX PubMed=34914893; DOI=10.1016/j.cmet.2021.11.013;
RA Wang L., Yu J., Zhou Q., Wang X., Mukhanova M., Du W., Sun L.,
RA Pajvani U.B., Accili D.;
RT "TOX4, an insulin receptor-independent regulator of hepatic glucose
RT production, is activated in diabetic liver.";
RL Cell Metab. 34:158-170.e5(2022).
CC -!- FUNCTION: Transcription factor that modulates cell fate reprogramming
CC from the somatic state to the pluripotent and neuronal fate
CC (PubMed:31519808). Component of the PTW/PP1 phosphatase complex, which
CC plays a role in the control of chromatin structure and cell cycle
CC progression during the transition from mitosis into interphase (By
CC similarity). In liver, controls the expression of hormone-regulated
CC gluconeogenic genes such as G6PC1 and PCK1. This regulation is
CC independent of the insulin receptor activation (PubMed:34914893).
CC {ECO:0000250|UniProtKB:O94842, ECO:0000269|PubMed:31519808,
CC ECO:0000269|PubMed:34914893}.
CC -!- ACTIVITY REGULATION: In liver, recruited to target gene promoters
CC following treatment with dexamethasone and cAMP. Binding is decreased
CC in presence of insulin. {ECO:0000269|PubMed:34914893}.
CC -!- SUBUNIT: Component of the PTW/PP1 phosphatase complex, composed of
CC PPP1R10/PNUTS, TOX4, WDR82 and PPP1CA or PPP1CB or PPP1CC. Interacts
CC with PPP1R10/PNUTS (By similarity). Interacts with FOXO1 and CREB1
CC (increased by cAMP); FOXO1 and CREB1 are required for full induction of
CC TOX4-dependent activity and the interactions are inhibited by insulin
CC (PubMed:34914893). {ECO:0000250|UniProtKB:O94842,
CC ECO:0000269|PubMed:34914893}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:34914893}.
CC Note=Associated with chromatin. {ECO:0000305|PubMed:34914893}.
CC -!- INDUCTION: In liver, expression is increased upon high fat diet.
CC {ECO:0000269|PubMed:34914893}.
CC -!- DISRUPTION PHENOTYPE: Conditional knockout in liver lead to no 10%
CC reduction of glucose levels after 4 h fasting with an improvement of
CC glucose tolerance and an increased insulin sensitivity.
CC {ECO:0000269|PubMed:34914893}.
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DR EMBL; AF228408; AAK00713.1; -; mRNA.
DR EMBL; AK019980; BAB31949.1; -; mRNA.
DR EMBL; AK088144; BAC40170.1; -; mRNA.
DR EMBL; AK147023; BAE27616.1; -; mRNA.
DR EMBL; AK147834; BAE28170.1; -; mRNA.
DR EMBL; BC050091; AAH50091.1; -; mRNA.
DR CCDS; CCDS36920.1; -.
DR RefSeq; NP_075923.2; NM_023434.3.
DR AlphaFoldDB; Q8BU11; -.
DR SMR; Q8BU11; -.
DR BioGRID; 234546; 13.
DR IntAct; Q8BU11; 15.
DR MINT; Q8BU11; -.
DR STRING; 10090.ENSMUSP00000022766; -.
DR iPTMnet; Q8BU11; -.
DR PhosphoSitePlus; Q8BU11; -.
DR EPD; Q8BU11; -.
DR jPOST; Q8BU11; -.
DR MaxQB; Q8BU11; -.
DR PaxDb; Q8BU11; -.
DR PRIDE; Q8BU11; -.
DR ProteomicsDB; 258816; -.
DR Antibodypedia; 7517; 133 antibodies from 18 providers.
DR DNASU; 268741; -.
DR Ensembl; ENSMUST00000022766; ENSMUSP00000022766; ENSMUSG00000016831.
DR GeneID; 268741; -.
DR KEGG; mmu:268741; -.
DR UCSC; uc007tpa.2; mouse.
DR CTD; 9878; -.
DR MGI; MGI:1915389; Tox4.
DR VEuPathDB; HostDB:ENSMUSG00000016831; -.
DR eggNOG; KOG0381; Eukaryota.
DR GeneTree; ENSGT00940000154888; -.
DR HOGENOM; CLU_030650_0_0_1; -.
DR InParanoid; Q8BU11; -.
DR OMA; WCSIKNQ; -.
DR OrthoDB; 1465513at2759; -.
DR PhylomeDB; Q8BU11; -.
DR TreeFam; TF106481; -.
DR BioGRID-ORCS; 268741; 7 hits in 73 CRISPR screens.
DR ChiTaRS; Tox4; mouse.
DR PRO; PR:Q8BU11; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; Q8BU11; protein.
DR Bgee; ENSMUSG00000016831; Expressed in spermatocyte and 272 other tissues.
DR Genevisible; Q8BU11; MM.
DR GO; GO:0000785; C:chromatin; ISS:UniProtKB.
DR GO; GO:0000781; C:chromosome, telomeric region; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0072357; C:PTW/PP1 phosphatase complex; ISS:UniProtKB.
DR GO; GO:0031490; F:chromatin DNA binding; IBA:GO_Central.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR Gene3D; 1.10.30.10; -; 1.
DR InterPro; IPR009071; HMG_box_dom.
DR InterPro; IPR036910; HMG_box_dom_sf.
DR InterPro; IPR037985; TOX4.
DR PANTHER; PTHR45781:SF2; PTHR45781:SF2; 1.
DR Pfam; PF00505; HMG_box; 1.
DR SMART; SM00398; HMG; 1.
DR SUPFAM; SSF47095; SSF47095; 1.
DR PROSITE; PS50118; HMG_BOX_2; 1.
PE 1: Evidence at protein level;
KW DNA-binding; Methylation; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation.
FT CHAIN 1..619
FT /note="TOX high mobility group box family member 4"
FT /id="PRO_0000048569"
FT DNA_BIND 223..291
FT /note="HMG box"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00267"
FT REGION 155..227
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 306..335
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 213..218
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:34914893"
FT COMPBIAS 168..183
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 310..324
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 176
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 178
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19144319,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 182
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19144319,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 313
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O94842"
FT MOD_RES 315
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O94842"
FT MOD_RES 479
FT /note="Asymmetric dimethylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 531
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O94842"
FT MOD_RES 548
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O94842"
FT MOD_RES 550
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O94842"
FT MOD_RES 558
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O94842"
FT MOD_RES 560
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O94842"
FT MOD_RES 565
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O94842"
FT MUTAGEN 213..218
FT /note="Missing: Loss of transcriptional regulation of
FT gluconeogenic genes expression."
FT /evidence="ECO:0000269|PubMed:34914893"
FT CONFLICT 3
FT /note="F -> S (in Ref. 1; AAK00713)"
FT /evidence="ECO:0000305"
FT CONFLICT 243
FT /note="G -> R (in Ref. 2; BAC40170)"
FT /evidence="ECO:0000305"
FT CONFLICT 321
FT /note="A -> T (in Ref. 1; AAK00713, 2; BAC40170 and 3;
FT AAH50091)"
FT /evidence="ECO:0000305"
FT CONFLICT 365
FT /note="I -> T (in Ref. 3; AAH50091)"
FT /evidence="ECO:0000305"
FT CONFLICT 425
FT /note="Q -> R (in Ref. 3; AAH50091)"
FT /evidence="ECO:0000305"
FT CONFLICT 446
FT /note="L -> S (in Ref. 1; AAK00713)"
FT /evidence="ECO:0000305"
FT CONFLICT 453
FT /note="P -> T (in Ref. 2; BAB31949)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 619 AA; 65961 MW; 232AAF5171000D92 CRC64;
MEFPGGNDNY LTITGPSHPF LSGAETFHTP SLGDEEFEIP PISLDSDPSL AVSDVVGHFD
DLADPSSSQD GSFSAQYGVQ TLDMPVGMTH GLMEQGGGLL SGGLTMDLDH SIGTQYSANP
PVTIDVPMTD MTSGLMGHSQ LTTIDQSELS SQLGLSLGGG TILPPAQSPE DRLSTTPSPT
NSLHEDGVDD FRRQLPAQKT VVVETGKKQK APKKRKKKDP NEPQKPVSAY ALFFRDTQAA
IKGQNPNATF GEVSKIVASM WDSLGEEQKQ VYKRKTEAAK KEYLKALAAY KDNQECQATV
ETVELDPVPQ SQTPSPPPVT AADPASPAPA STESPALPPC IIVNSTLSSY VANQASSGPG
GQPNITKLII TKQMLPSSIT MSQGGMVTVI PATVVTSRGL QVGQTSTATI QPSQQAQIVT
RSVLQAAAAA AASMQLPPPR LQPPPLQQMP QPPTQQQVTI LQQPPPLQAM QQPPPQKVRI
NLQQQPPPLQ SKIVPPPTLK IQTTVVPPTV ESSPEQPMNS SPEAHTVEAT SPETICEMIA
DVVPEVESPS QMDVELVSGS PVALSPQPRC VRSGCENPPV VSKDWDNEYC SNECVVKHCR
DVFLAWVASR NPNSVVFVK
