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   24-JAN-2024, entry version 142.
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 hours of fasting with an
CC       improvement of 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   GlyGen; Q8BU11; 4 sites, 1 O-linked glycan (4 sites).
DR   iPTMnet; Q8BU11; -.
DR   PhosphoSitePlus; Q8BU11; -.
DR   EPD; Q8BU11; -.
DR   jPOST; Q8BU11; -.
DR   MaxQB; Q8BU11; -.
DR   PaxDb; 10090-ENSMUSP00000022766; -.
DR   ProteomicsDB; 258816; -.
DR   Pumba; Q8BU11; -.
DR   Antibodypedia; 7517; 144 antibodies from 18 providers.
DR   DNASU; 268741; -.
DR   Ensembl; ENSMUST00000022766.8; ENSMUSP00000022766.7; ENSMUSG00000016831.13.
DR   GeneID; 268741; -.
DR   KEGG; mmu:268741; -.
DR   UCSC; uc007tpa.2; mouse.
DR   AGR; MGI:1915389; -.
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; AVDSEDW; -.
DR   OrthoDB; 4252846at2759; -.
DR   PhylomeDB; Q8BU11; -.
DR   TreeFam; TF106481; -.
DR   BioGRID-ORCS; 268741; 8 hits in 78 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 276 other cell types or tissues.
DR   GO; GO:0000785; C:chromatin; ISS:UniProtKB.
DR   GO; GO:0000781; C:chromosome, telomeric region; IEA:Ensembl.
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   CDD; cd21995; HMG-box_TOX-like; 1.
DR   Gene3D; 1.10.30.10; High mobility group box domain; 1.
DR   InterPro; IPR009071; HMG_box_dom.
DR   InterPro; IPR036910; HMG_box_dom_sf.
DR   PANTHER; PTHR45781; AGAP000281-PA; 1.
DR   PANTHER; PTHR45781:SF2; TOX HIGH MOBILITY GROUP BOX FAMILY MEMBER 4; 1.
DR   Pfam; PF00505; HMG_box; 1.
DR   PRINTS; PR00886; HIGHMOBLTY12.
DR   SMART; SM00398; HMG; 1.
DR   SUPFAM; SSF47095; HMG-box; 1.
DR   PROSITE; PS50118; HMG_BOX_2; 1.
DR   Genevisible; Q8BU11; MM.
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
//