GenomeNet

Database: UniProt
Entry: P01375
LinkDB: P01375
Original site: P01375 
ID   TNFA_HUMAN              Reviewed;         233 AA.
AC   P01375; O43647; Q9P1Q2; Q9UIV3;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   21-JUL-1986, sequence version 1.
DT   17-JUN-2020, entry version 254.
DE   RecName: Full=Tumor necrosis factor;
DE   AltName: Full=Cachectin;
DE   AltName: Full=TNF-alpha;
DE   AltName: Full=Tumor necrosis factor ligand superfamily member 2;
DE            Short=TNF-a;
DE   Contains:
DE     RecName: Full=Tumor necrosis factor, membrane form;
DE     AltName: Full=N-terminal fragment;
DE              Short=NTF;
DE   Contains:
DE     RecName: Full=Intracellular domain 1;
DE              Short=ICD1;
DE   Contains:
DE     RecName: Full=Intracellular domain 2;
DE              Short=ICD2;
DE   Contains:
DE     RecName: Full=C-domain 1;
DE   Contains:
DE     RecName: Full=C-domain 2;
DE   Contains:
DE     RecName: Full=Tumor necrosis factor, soluble form;
DE   Flags: Precursor;
GN   Name=TNF; Synonyms=TNFA, TNFSF2;
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 [GENOMIC DNA].
RX   PubMed=3555974; DOI=10.1101/sqb.1986.051.01.073;
RA   Nedospasov S.A., Shakhov A.N., Turetskaya R.L., Mett V.A., Azizov M.M.,
RA   Georgiev G.P., Korobko V.G., Dobrynin V.N., Filippov S.A., Bystrov N.S.,
RA   Boldyreva E.F., Chuvpilo S.A., Chumakov A.M., Shingarova L.N.,
RA   Ovchinnikov Y.A.;
RT   "Tandem arrangement of genes coding for tumor necrosis factor (TNF-alpha)
RT   and lymphotoxin (TNF-beta) in the human genome.";
RL   Cold Spring Harb. Symp. Quant. Biol. 51:611-624(1986).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX   PubMed=6392892; DOI=10.1038/312724a0;
RA   Pennica D., Nedwin G.E., Hayflick J.S., Seeburg P.H., Derynck R.,
RA   Palladino M.A., Kohr W.J., Aggarwal B.B., Goeddel D.V.;
RT   "Human tumour necrosis factor: precursor structure, expression and homology
RT   to lymphotoxin.";
RL   Nature 312:724-729(1984).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX   PubMed=3883195; DOI=10.1038/313803a0;
RA   Shirai T., Yamaguchi H., Ito H., Todd C.W., Wallace R.B.;
RT   "Cloning and expression in Escherichia coli of the gene for human tumour
RT   necrosis factor.";
RL   Nature 313:803-806(1985).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX   PubMed=2995927; DOI=10.1093/nar/13.17.6361;
RA   Nedwin G.E., Naylor S.L., Sakaguchi A.Y., Smith D.H., Jarrett-Nedwin J.,
RA   Pennica D., Goeddel D.V., Gray P.W.;
RT   "Human lymphotoxin and tumor necrosis factor genes: structure, homology and
RT   chromosomal localization.";
RL   Nucleic Acids Res. 13:6361-6373(1985).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=3856324; DOI=10.1126/science.3856324;
RA   Wang A.M., Creasey A.A., Ladner M.B., Lin L.S., Strickler J.,
RA   van Arsdell J.N., Yamamoto R., Mark D.F.;
RT   "Molecular cloning of the complementary DNA for human tumor necrosis
RT   factor.";
RL   Science 228:149-154(1985).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=3932069; DOI=10.1111/j.1432-1033.1985.tb09226.x;
RA   Marmenout A., Fransen L., Tavernier J., van der Heyden J., Tizard R.,
RA   Kawashima E., Shaw A., Johnson M.J., Semon D., Mueller R.,
RA   Ruysschaert M.-R., van Vliet A., Fiers W.;
RT   "Molecular cloning and expression of human tumor necrosis factor and
RT   comparison with mouse tumor necrosis factor.";
RL   Eur. J. Biochem. 152:515-522(1985).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=8499947; DOI=10.1038/ng0293-137;
RA   Iris F.J.M., Bougueleret L., Prieur S., Caterina D., Primas G., Perrot V.,
RA   Jurka J., Rodriguez-Tome P., Claverie J.-M., Dausset J., Cohen D.;
RT   "Dense Alu clustering and a potential new member of the NF kappa B family
RT   within a 90 kilobase HLA class III segment.";
RL   Nat. Genet. 3:137-145(1993).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=10202016;
RA   Neville M.J., Campbell R.D.;
RT   "A new member of the Ig superfamily and a V-ATPase G subunit are among the
RT   predicted products of novel genes close to the TNF locus in the human
RT   MHC.";
RL   J. Immunol. 162:4745-4754(1999).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=14656967; DOI=10.1101/gr.1736803;
RA   Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., Campbell R.D.,
RA   Hood L.;
RT   "Analysis of the gene-dense major histocompatibility complex class III
RT   region and its comparison to mouse.";
RL   Genome Res. 13:2621-2636(2003).
RN   [10]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Shiina S., Tamiya G., Oka A., Inoko H.;
RT   "Homo sapiens 2,229,817bp genomic DNA of 6p21.3 HLA class I region.";
RL   Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN   [11]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Shiina T., Ota M., Katsuyama Y., Hashimoto N., Inoko H.;
RT   "Genome diversity in HLA: a new strategy for detection of genetic
RT   polymorphisms in expressed genes within the HLA class III and class I
RT   regions.";
RL   Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN   [12]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG   SeattleSNPs variation discovery resource;
RL   Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases.
RN   [13]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LEU-84.
RG   NIEHS SNPs program;
RL   Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN   [14]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Blood;
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   [15]
RP   PROTEIN SEQUENCE OF 77-99, AND GLYCOSYLATION AT SER-80.
RX   PubMed=8631363; DOI=10.1111/j.1432-1033.1996.00431.x;
RA   Takakura-Yamamoto R., Yamamoto S., Fukuda S., Kurimoto M.;
RT   "O-glycosylated species of natural human tumor-necrosis factor-alpha.";
RL   Eur. J. Biochem. 235:431-437(1996).
RN   [16]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 77-233.
RA   Jang J.S., Kim B.E.;
RL   Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases.
RN   [17]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 84-214.
RC   TISSUE=Prostatic carcinoma;
RA   Shao C., Yan W., Zhu F., Yue W., Chai Y., Zhao Z., Wang C.;
RL   Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases.
RN   [18]
RP   PHOSPHORYLATION (MEMBRANE FORM).
RX   PubMed=8597870;
RA   Pocsik E., Duda E., Wallach D.;
RT   "Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in
RT   transfected HeLa cells.";
RL   J. Inflamm. 45:152-160(1995).
RN   [19]
RP   PHOSPHORYLATION BY CK1, AND DEPHOSPHORYLATION.
RX   PubMed=10205166; DOI=10.1093/emboj/18.8.2119;
RA   Watts A.D., Hunt N.H., Wanigasekara Y., Bloomfield G., Wallach D.,
RA   Roufogalis B.D., Chaudhri G.;
RT   "A casein kinase I motif present in the cytoplasmic domain of members of
RT   the tumour necrosis factor ligand family is implicated in 'reverse
RT   signalling'.";
RL   EMBO J. 18:2119-2126(1999).
RN   [20]
RP   MUTAGENESIS.
RX   PubMed=2009860;
RA   Ostade X.V., Tavernier J., Prange T., Fiers W.;
RT   "Localization of the active site of human tumour necrosis factor (hTNF) by
RT   mutational analysis.";
RL   EMBO J. 10:827-836(1991).
RN   [21]
RP   MYRISTOYLATION AT LYS-19 AND LYS-20.
RX   PubMed=1402651; DOI=10.1084/jem.176.4.1053;
RA   Stevenson F.T., Bursten S.L., Locksley R.M., Lovett D.H.;
RT   "Myristyl acylation of the tumor necrosis factor alpha precursor on
RT   specific lysine residues.";
RL   J. Exp. Med. 176:1053-1062(1992).
RN   [22]
RP   CLEAVAGE BY ADAM17.
RX   PubMed=9034191; DOI=10.1038/385733a0;
RA   Moss M.L., Jin S.-L.C., Milla M.E., Burkhart W., Carter H.L., Chen W.-J.,
RA   Clay W.C., Didsbury J.R., Hassler D., Hoffman C.R., Kost T.A.,
RA   Lambert M.H., Leesnitzer M.A., McCauley P., McGeehan G., Mitchell J.,
RA   Moyer M., Pahel G., Rocque W., Overton L.K., Schoenen F., Seaton T.,
RA   Su J.-L., Warner J., Willard D., Becherer J.D.;
RT   "Cloning of a disintegrin metalloproteinase that processes precursor
RT   tumour-necrosis factor-alpha.";
RL   Nature 385:733-736(1997).
RN   [23]
RP   POLYMORPHISM, AND INVOLVEMENT IN SUSCEPTIBILITY TO MALARIA.
RX   PubMed=10369255; DOI=10.1038/9649;
RA   Knight J.C., Udalova I., Hill A.V., Greenwood B.M., Peshu N., Marsh K.,
RA   Kwiatkowski D.;
RT   "A polymorphism that affects OCT-1 binding to the TNF promoter region is
RT   associated with severe malaria.";
RL   Nat. Genet. 22:145-150(1999).
RN   [24]
RP   FUNCTION OF TNF INTRACELLULAR DOMAIN, CLEAVAGE BY SPPL2A AND SPPL2B, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=16829952; DOI=10.1038/ncb1440;
RA   Friedmann E., Hauben E., Maylandt K., Schleeger S., Vreugde S.,
RA   Lichtenthaler S.F., Kuhn P.H., Stauffer D., Rovelli G., Martoglio B.;
RT   "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in
RT   activated dendritic cells to trigger IL-12 production.";
RL   Nat. Cell Biol. 8:843-848(2006).
RN   [25]
RP   CLEAVAGE BY SPPL2A AND SPPL2B, CLEAVAGE SITE, INTERACTION WITH SPPL2B, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=16829951; DOI=10.1038/ncb1450;
RA   Fluhrer R., Grammer G., Israel L., Condron M.M., Haffner C., Friedmann E.,
RA   Bohland C., Imhof A., Martoglio B., Teplow D.B., Haass C.;
RT   "A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD
RT   aspartyl protease SPPL2b.";
RL   Nat. Cell Biol. 8:894-896(2006).
RN   [26]
RP   FUNCTION.
RX   PubMed=22517918; DOI=10.1189/jlb.1211623;
RA   Jinesh G.G., Chunduru S., Kamat A.M.;
RT   "Smac mimetic enables the anticancer action of BCG-stimulated neutrophils
RT   through TNF-alpha but not through TRAIL and FasL.";
RL   J. Leukoc. Biol. 92:233-244(2012).
RN   [27]
RP   FUNCTION.
RX   PubMed=23396208; DOI=10.1038/nm.3085;
RA   Nie H., Zheng Y., Li R., Guo T.B., He D., Fang L., Liu X., Xiao L.,
RA   Chen X., Wan B., Chin Y.E., Zhang J.Z.;
RT   "Phosphorylation of FOXP3 controls regulatory T cell function and is
RT   inhibited by TNF-alpha in rheumatoid arthritis.";
RL   Nat. Med. 19:322-328(2013).
RN   [28]
RP   X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
RX   PubMed=2922050; DOI=10.1038/338225a0;
RA   Jones E.Y., Stuart D.I., Walker N.P.;
RT   "Structure of tumour necrosis factor.";
RL   Nature 338:225-228(1989).
RN   [29]
RP   X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
RX   PubMed=1964681; DOI=10.1242/jcs.1990.supplement_13.3;
RA   Jones E.Y., Stuart D.I., Walker N.P.;
RT   "The structure of tumour necrosis factor -- implications for biological
RT   function.";
RL   J. Cell Sci. Suppl. 13:11-18(1990).
RN   [30]
RP   X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX   PubMed=2551905; DOI=10.2210/pdb1tnf/pdb;
RA   Eck M.J., Sprang S.R.;
RT   "The structure of tumor necrosis factor-alpha at 2.6-A resolution.
RT   Implications for receptor binding.";
RL   J. Biol. Chem. 264:17595-17605(1989).
RN   [31]
RP   X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF MUTANT ARG-107.
RX   PubMed=9488135; DOI=10.1093/protein/10.10.1101;
RA   Reed C., Fu Z.Q., Wu J., Xue Y.N., Harrison R.W., Chen M.J., Weber I.T.;
RT   "Crystal structure of TNF-alpha mutant R31D with greater affinity for
RT   receptor R1 compared with R2.";
RL   Protein Eng. 10:1101-1107(1997).
RN   [32]
RP   X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF MUTANT SER-3.
RX   PubMed=9442056; DOI=10.1074/jbc.273.4.2153;
RA   Cha S.S., Kim J.S., Cho H.S., Shin N.K., Jeong W., Shin H.C., Kim Y.J.,
RA   Hahn J.H., Oh B.H.;
RT   "High resolution crystal structure of a human tumor necrosis factor-alpha
RT   mutant with low systemic toxicity.";
RL   J. Biol. Chem. 273:2153-2160(1998).
RN   [33]
RP   INVOLVEMENT IN PSORIATIC ARTHRITIS SUSCEPTIBILITY.
RX   PubMed=12746914; DOI=10.1002/art.10935;
RA   Balding J., Kane D., Livingstone W., Mynett-Johnson L., Bresnihan B.,
RA   Smith O., FitzGerald O.;
RT   "Cytokine gene polymorphisms: association with psoriatic arthritis
RT   susceptibility and severity.";
RL   Arthritis Rheum. 48:1408-1413(2003).
RN   [34]
RP   INVOLVEMENT IN SUSCEPTIBILITY TO HBV INFECTION.
RX   PubMed=12915457; DOI=10.1093/hmg/ddg262;
RA   Kim Y.J., Lee H.-S., Yoon J.-H., Kim C.Y., Park M.H., Kim L.H., Park B.L.,
RA   Shin H.D.;
RT   "Association of TNF-alpha promoter polymorphisms with the clearance of
RT   hepatitis B virus infection.";
RL   Hum. Mol. Genet. 12:2541-2546(2003).
CC   -!- FUNCTION: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It
CC       is mainly secreted by macrophages and can induce cell death of certain
CC       tumor cell lines. It is potent pyrogen causing fever by direct action
CC       or by stimulation of interleukin-1 secretion and is implicated in the
CC       induction of cachexia, Under certain conditions it can stimulate cell
CC       proliferation and induce cell differentiation. Impairs regulatory T-
CC       cells (Treg) function in individuals with rheumatoid arthritis via
CC       FOXP3 dephosphorylation. Upregulates the expression of protein
CC       phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue
CC       of FOXP3, thereby inactivating FOXP3 and rendering Treg cells
CC       functionally defective (PubMed:23396208). Key mediator of cell death in
CC       the anticancer action of BCG-stimulated neutrophils in combination with
CC       DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line
CC       (PubMed:22517918, PubMed:16829952, PubMed:23396208). Induces insulin
CC       resistance in adipocytes via inhibition of insulin-induced IRS1
CC       tyrosine phosphorylation and insulin-induced glucose uptake. Induces
CC       GKAP42 protein degradation in adipocytes which is partially responsible
CC       for TNF-induced insulin resistance (By similarity).
CC       {ECO:0000250|UniProtKB:P06804, ECO:0000269|PubMed:16829952,
CC       ECO:0000269|PubMed:22517918, ECO:0000269|PubMed:23396208}.
CC   -!- FUNCTION: The TNF intracellular domain (ICD) form induces IL12
CC       production in dendritic cells. {ECO:0000269|PubMed:16829952}.
CC   -!- SUBUNIT: Homotrimer. Interacts with SPPL2B.
CC       {ECO:0000269|PubMed:16829951}.
CC   -!- INTERACTION:
CC       P01375; Q92482: AQP3; NbExp=3; IntAct=EBI-359977, EBI-2808854;
CC       P01375; Q9BXK5: BCL2L13; NbExp=3; IntAct=EBI-359977, EBI-747430;
CC       P01375; Q6UXG8-3: BTNL9; NbExp=3; IntAct=EBI-359977, EBI-17953245;
CC       P01375; Q8IYJ2-2: C10orf67; NbExp=3; IntAct=EBI-359977, EBI-13381098;
CC       P01375; Q8WV48: CCDC107; NbExp=3; IntAct=EBI-359977, EBI-947033;
CC       P01375; Q8N6L0: CCDC155; NbExp=3; IntAct=EBI-359977, EBI-749265;
CC       P01375; Q6NSX1: CCDC70; NbExp=3; IntAct=EBI-359977, EBI-6873045;
CC       P01375; O95471: CLDN7; NbExp=3; IntAct=EBI-359977, EBI-740744;
CC       P01375; Q8IUN9: CLEC10A; NbExp=3; IntAct=EBI-359977, EBI-2873246;
CC       P01375; Q96BA8: CREB3L1; NbExp=3; IntAct=EBI-359977, EBI-6942903;
CC       P01375; P00387: CYB5R3; NbExp=3; IntAct=EBI-359977, EBI-1046040;
CC       P01375; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-359977, EBI-18304435;
CC       P01375; O15552: FFAR2; NbExp=3; IntAct=EBI-359977, EBI-2833872;
CC       P01375; Q8TBE3: FNDC9; NbExp=3; IntAct=EBI-359977, EBI-12142257;
CC       P01375; Q9Y6K9: IKBKG; NbExp=3; IntAct=EBI-359977, EBI-81279;
CC       P01375; Q8N386: LRRC25; NbExp=3; IntAct=EBI-359977, EBI-11304917;
CC       P01375; O43300: LRRTM2; NbExp=3; IntAct=EBI-359977, EBI-18096461;
CC       P01375; Q9HC36: MRM3; NbExp=3; IntAct=EBI-359977, EBI-1045440;
CC       P01375; O75459: PAGE1; NbExp=3; IntAct=EBI-359977, EBI-2559100;
CC       P01375; Q96RD7: PANX1; NbExp=3; IntAct=EBI-359977, EBI-7037612;
CC       P01375; Q8N4L2: PIP4P2; NbExp=3; IntAct=EBI-359977, EBI-2820617;
CC       P01375; Q53GL0: PLEKHO1; NbExp=3; IntAct=EBI-359977, EBI-949945;
CC       P01375; Q6ZMZ0: RNF19B; NbExp=3; IntAct=EBI-359977, EBI-2466594;
CC       P01375; Q16585: SGCB; NbExp=3; IntAct=EBI-359977, EBI-5663627;
CC       P01375; Q15849: SLC14A2; NbExp=3; IntAct=EBI-359977, EBI-1573290;
CC       P01375; O14863: SLC30A4; NbExp=3; IntAct=EBI-359977, EBI-13918058;
CC       P01375; Q8WWF3: SSMEM1; NbExp=3; IntAct=EBI-359977, EBI-17280858;
CC       P01375; P27105: STOM; NbExp=3; IntAct=EBI-359977, EBI-1211440;
CC       P01375; Q16623: STX1A; NbExp=4; IntAct=EBI-359977, EBI-712466;
CC       P01375; O15393-2: TMPRSS2; NbExp=3; IntAct=EBI-359977, EBI-12345267;
CC       P01375; P01375: TNF; NbExp=3; IntAct=EBI-359977, EBI-359977;
CC       P01375; P19438: TNFRSF1A; NbExp=15; IntAct=EBI-359977, EBI-299451;
CC       P01375; P20333: TNFRSF1B; NbExp=2; IntAct=EBI-359977, EBI-358983;
CC       P01375; Q9H7M9: VSIR; NbExp=3; IntAct=EBI-359977, EBI-744988;
CC       P01375; Q6PEW1: ZCCHC12; NbExp=3; IntAct=EBI-359977, EBI-748373;
CC       P01375; Q9DHW0: 2L; Xeno; NbExp=2; IntAct=EBI-359977, EBI-15810797;
CC       P01375; O89110: Casp8; Xeno; NbExp=2; IntAct=EBI-359977, EBI-851690;
CC       P01375; Q8UYL3: crmE; Xeno; NbExp=3; IntAct=EBI-359977, EBI-7539950;
CC       P01375; O88351: Ikbkb; Xeno; NbExp=3; IntAct=EBI-359977, EBI-447960;
CC       P01375; Q60855: Ripk1; Xeno; NbExp=3; IntAct=EBI-359977, EBI-529119;
CC       P01375; Q60769: Tnfaip3; Xeno; NbExp=2; IntAct=EBI-359977, EBI-646595;
CC       P01375; P25118: Tnfrsf1a; Xeno; NbExp=3; IntAct=EBI-359977, EBI-518014;
CC       P01375; Q3U0V2: Tradd; Xeno; NbExp=2; IntAct=EBI-359977, EBI-1544032;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16829952};
CC       Single-pass type II membrane protein {ECO:0000269|PubMed:16829952}.
CC   -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, membrane form]: Membrane;
CC       Single-pass type II membrane protein.
CC   -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, soluble form]: Secreted.
CC   -!- SUBCELLULAR LOCATION: [C-domain 1]: Secreted.
CC   -!- SUBCELLULAR LOCATION: [C-domain 2]: Secreted.
CC   -!- PTM: The soluble form derives from the membrane form by proteolytic
CC       processing. The membrane-bound form is further proteolytically
CC       processed by SPPL2A or SPPL2B through regulated intramembrane
CC       proteolysis producing TNF intracellular domains (ICD1 and ICD2)
CC       released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into
CC       the extracellular space. {ECO:0000269|PubMed:16829951,
CC       ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:9034191}.
CC   -!- PTM: The membrane form, but not the soluble form, is phosphorylated on
CC       serine residues. Dephosphorylation of the membrane form occurs by
CC       binding to soluble TNFRSF1A/TNFR1. {ECO:0000269|PubMed:10205166,
CC       ECO:0000269|PubMed:8597870}.
CC   -!- PTM: O-glycosylated; glycans contain galactose, N-acetylgalactosamine
CC       and N-acetylneuraminic acid. {ECO:0000269|PubMed:8631363}.
CC   -!- POLYMORPHISM: Genetic variations in TNF influence susceptibility to
CC       hepatitis B virus (HBV) infection [MIM:610424].
CC   -!- POLYMORPHISM: Genetic variations in TNF are involved in susceptibility
CC       to malaria [MIM:611162].
CC   -!- DISEASE: Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory,
CC       seronegative arthritis associated with psoriasis. It is a heterogeneous
CC       disorder ranging from a mild, non-destructive disease to a severe,
CC       progressive, erosive arthropathy. Five types of psoriatic arthritis
CC       have been defined: asymmetrical oligoarthritis characterized by primary
CC       involvement of the small joints of the fingers or toes; asymmetrical
CC       arthritis which involves the joints of the extremities; symmetrical
CC       polyarthritis characterized by a rheumatoid like pattern that can
CC       involve hands, wrists, ankles, and feet; arthritis mutilans, which is a
CC       rare but deforming and destructive condition; arthritis of the
CC       sacroiliac joints and spine (psoriatic spondylitis).
CC       {ECO:0000269|PubMed:12746914}. Note=Disease susceptibility is
CC       associated with variations affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAF71992.1; Type=Frameshift; Evidence={ECO:0000305};
CC       Sequence=CAA75070.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=Tumor necrosis factor alpha entry;
CC       URL="https://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha";
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/TNFaID319.html";
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/tnf/";
CC   -!- WEB RESOURCE: Name=SeattleSNPs;
CC       URL="http://pga.gs.washington.edu/data/tnf/";
CC   -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC       polymorphism database;
CC       URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=TNF";
DR   EMBL; M16441; AAA61200.1; -; Genomic_DNA.
DR   EMBL; X02910; CAA26669.1; -; Genomic_DNA.
DR   EMBL; X01394; CAA25650.1; -; mRNA.
DR   EMBL; M10988; AAA61198.1; -; mRNA.
DR   EMBL; M26331; AAA36758.1; -; Genomic_DNA.
DR   EMBL; Z15026; CAA78745.1; -; Genomic_DNA.
DR   EMBL; Y14768; CAA75070.1; ALT_SEQ; Genomic_DNA.
DR   EMBL; AF129756; AAD18091.1; -; Genomic_DNA.
DR   EMBL; BA000025; BAB63396.1; -; Genomic_DNA.
DR   EMBL; AB088112; BAC54944.1; -; Genomic_DNA.
DR   EMBL; AY066019; AAL47581.1; -; Genomic_DNA.
DR   EMBL; AY214167; AAO21132.1; -; Genomic_DNA.
DR   EMBL; BC028148; AAH28148.1; -; mRNA.
DR   EMBL; AF043342; AAC03542.1; -; mRNA.
DR   EMBL; AF098751; AAF71992.1; ALT_FRAME; mRNA.
DR   CCDS; CCDS4702.1; -.
DR   PIR; A93585; QWHUN.
DR   RefSeq; NP_000585.2; NM_000594.3.
DR   PDB; 1A8M; X-ray; 2.30 A; A/B/C=77-233.
DR   PDB; 1TNF; X-ray; 2.60 A; A/B/C=77-233.
DR   PDB; 2AZ5; X-ray; 2.10 A; A/B/C/D=86-233.
DR   PDB; 2E7A; X-ray; 1.80 A; A/B/C=77-233.
DR   PDB; 2TUN; X-ray; 3.10 A; A/B/C/D/E/F=77-233.
DR   PDB; 2ZJC; X-ray; 2.50 A; A/B/C=77-233.
DR   PDB; 2ZPX; X-ray; 2.83 A; A/B/C=77-233.
DR   PDB; 3ALQ; X-ray; 3.00 A; A/B/C/D/E/F=77-233.
DR   PDB; 3IT8; X-ray; 2.80 A; A/B/C/G/H/I=82-233.
DR   PDB; 3L9J; X-ray; 2.10 A; T=85-233.
DR   PDB; 3WD5; X-ray; 3.10 A; A=77-233.
DR   PDB; 4G3Y; X-ray; 2.60 A; C=77-233.
DR   PDB; 4TSV; X-ray; 1.80 A; A=84-233.
DR   PDB; 4TWT; X-ray; 2.85 A; A/B/C/D=77-233.
DR   PDB; 4Y6O; X-ray; 1.60 A; C/D=17-23.
DR   PDB; 5M2I; X-ray; 2.15 A; A/B/C/D/E/F=77-233.
DR   PDB; 5M2J; X-ray; 1.90 A; A=77-233.
DR   PDB; 5M2M; X-ray; 2.30 A; A/B/C/G/I/M=77-233.
DR   PDB; 5MU8; X-ray; 3.00 A; A/B/C/D/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b/c/d/e=77-233.
DR   PDB; 5TSW; X-ray; 2.50 A; A/B/C/D/E/F=84-233.
DR   PDB; 5UUI; X-ray; 1.40 A; A=77-233.
DR   PDB; 5WUX; X-ray; 2.90 A; E/F/G=77-233.
DR   PDB; 5YOY; X-ray; 2.73 A; A/B/C/J/K/L=76-233.
DR   PDB; 6OOY; X-ray; 2.50 A; A/B/C=77-233.
DR   PDB; 6OOZ; X-ray; 2.80 A; A/B/C=77-233.
DR   PDB; 6OP0; X-ray; 2.55 A; A/B/C=77-233.
DR   PDB; 6RMJ; X-ray; 2.65 A; A/B/C=77-233.
DR   PDBsum; 1A8M; -.
DR   PDBsum; 1TNF; -.
DR   PDBsum; 2AZ5; -.
DR   PDBsum; 2E7A; -.
DR   PDBsum; 2TUN; -.
DR   PDBsum; 2ZJC; -.
DR   PDBsum; 2ZPX; -.
DR   PDBsum; 3ALQ; -.
DR   PDBsum; 3IT8; -.
DR   PDBsum; 3L9J; -.
DR   PDBsum; 3WD5; -.
DR   PDBsum; 4G3Y; -.
DR   PDBsum; 4TSV; -.
DR   PDBsum; 4TWT; -.
DR   PDBsum; 4Y6O; -.
DR   PDBsum; 5M2I; -.
DR   PDBsum; 5M2J; -.
DR   PDBsum; 5M2M; -.
DR   PDBsum; 5MU8; -.
DR   PDBsum; 5TSW; -.
DR   PDBsum; 5UUI; -.
DR   PDBsum; 5WUX; -.
DR   PDBsum; 5YOY; -.
DR   PDBsum; 6OOY; -.
DR   PDBsum; 6OOZ; -.
DR   PDBsum; 6OP0; -.
DR   PDBsum; 6RMJ; -.
DR   SMR; P01375; -.
DR   BioGRID; 112979; 272.
DR   CORUM; P01375; -.
DR   DIP; DIP-2895N; -.
DR   IntAct; P01375; 112.
DR   MINT; P01375; -.
DR   STRING; 9606.ENSP00000398698; -.
DR   BindingDB; P01375; -.
DR   ChEMBL; CHEMBL1825; -.
DR   DrugBank; DB00051; Adalimumab.
DR   DrugBank; DB04956; Afelimomab.
DR   DrugBank; DB05879; AME-527.
DR   DrugBank; DB01427; Amrinone.
DR   DrugBank; DB05767; Andrographolide.
DR   DrugBank; DB05513; Atiprimod.
DR   DrugBank; DB11967; Binimetinib.
DR   DrugBank; DB08904; Certolizumab pegol.
DR   DrugBank; DB00608; Chloroquine.
DR   DrugBank; DB01407; Clenbuterol.
DR   DrugBank; DB05744; CRx-139.
DR   DrugBank; DB05758; CYT007-TNFQb.
DR   DrugBank; DB06444; Dexanabinol.
DR   DrugBank; DB12140; Dilmapimod.
DR   DrugBank; DB00668; Epinephrine.
DR   DrugBank; DB00005; Etanercept.
DR   DrugBank; DB05869; Ethyl pyruvate.
DR   DrugBank; DB10770; Foreskin fibroblast (neonatal).
DR   DrugBank; DB10772; Foreskin keratinocyte (neonatal).
DR   DrugBank; DB01296; Glucosamine.
DR   DrugBank; DB13751; Glycyrrhizic acid.
DR   DrugBank; DB06674; Golimumab.
DR   DrugBank; DB00065; Infliximab.
DR   DrugBank; DB02325; Isopropyl alcohol.
DR   DrugBank; DB05303; OMS-103HP.
DR   DrugBank; DB06495; Onercept.
DR   DrugBank; DB05992; Plinabulin.
DR   DrugBank; DB05218; PN0621.
DR   DrugBank; DB09221; Polaprezinc.
DR   DrugBank; DB08910; Pomalidomide.
DR   DrugBank; DB05968; PR-104.
DR   DrugBank; DB01411; Pranlukast.
DR   DrugBank; DB00852; Pseudoephedrine.
DR   DrugBank; DB05207; SD118.
DR   DrugBank; DB05412; Talmapimod.
DR   DrugBank; DB01041; Thalidomide.
DR   DrugBank; DB05470; VX-702.
DR   DrugBank; DB05017; YSIL6.
DR   DrugCentral; P01375; -.
DR   GlyConnect; 609; -.
DR   iPTMnet; P01375; -.
DR   PhosphoSitePlus; P01375; -.
DR   SwissPalm; P01375; -.
DR   UniCarbKB; P01375; -.
DR   BioMuta; TNF; -.
DR   DMDM; 135934; -.
DR   MassIVE; P01375; -.
DR   PaxDb; P01375; -.
DR   PeptideAtlas; P01375; -.
DR   PRIDE; P01375; -.
DR   ProteomicsDB; 12707; -.
DR   ProteomicsDB; 51379; -.
DR   ABCD; P01375; 27 sequenced antibodies.
DR   Antibodypedia; 27196; 4596 antibodies.
DR   DNASU; 7124; -.
DR   Ensembl; ENST00000376122; ENSP00000365290; ENSG00000204490.
DR   Ensembl; ENST00000383496; ENSP00000372988; ENSG00000206439.
DR   Ensembl; ENST00000412275; ENSP00000392858; ENSG00000228321.
DR   Ensembl; ENST00000420425; ENSP00000410668; ENSG00000228849.
DR   Ensembl; ENST00000443707; ENSP00000389492; ENSG00000230108.
DR   Ensembl; ENST00000448781; ENSP00000389490; ENSG00000223952.
DR   Ensembl; ENST00000449264; ENSP00000398698; ENSG00000232810.
DR   GeneID; 7124; -.
DR   KEGG; hsa:7124; -.
DR   CTD; 7124; -.
DR   DisGeNET; 7124; -.
DR   EuPathDB; HostDB:ENSG00000232810.3; -.
DR   GeneCards; TNF; -.
DR   HGNC; HGNC:11892; TNF.
DR   HPA; ENSG00000232810; Tissue enhanced (bone marrow, lymphoid tissue).
DR   MalaCards; TNF; -.
DR   MIM; 191160; gene.
DR   MIM; 607507; phenotype.
DR   MIM; 610424; phenotype.
DR   MIM; 611162; phenotype.
DR   neXtProt; NX_P01375; -.
DR   OpenTargets; ENSG00000232810; -.
DR   Orphanet; 40050; NON RARE IN EUROPE: Psoriatic arthritis.
DR   PharmGKB; PA435; -.
DR   eggNOG; ENOG410ISAN; Eukaryota.
DR   eggNOG; ENOG410YQC4; LUCA.
DR   GeneTree; ENSGT00970000193380; -.
DR   HOGENOM; CLU_070352_3_1_1; -.
DR   InParanoid; P01375; -.
DR   KO; K03156; -.
DR   OMA; GATMLFC; -.
DR   OrthoDB; 1124938at2759; -.
DR   PhylomeDB; P01375; -.
DR   TreeFam; TF332169; -.
DR   Reactome; R-HSA-381340; Transcriptional regulation of white adipocyte differentiation.
DR   Reactome; R-HSA-5357786; TNFR1-induced proapoptotic signaling.
DR   Reactome; R-HSA-5357905; Regulation of TNFR1 signaling.
DR   Reactome; R-HSA-5357956; TNFR1-induced NFkappaB signaling pathway.
DR   Reactome; R-HSA-5626978; TNFR1-mediated ceramide production.
DR   Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway.
DR   Reactome; R-HSA-6783783; Interleukin-10 signaling.
DR   Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling.
DR   Reactome; R-HSA-75893; TNF signaling.
DR   SIGNOR; P01375; -.
DR   BioGRID-ORCS; 7124; 0 hits in 786 CRISPR screens.
DR   ChiTaRS; TNF; human.
DR   EvolutionaryTrace; P01375; -.
DR   GeneWiki; Tumor_necrosis_factor-alpha; -.
DR   GenomeRNAi; 7124; -.
DR   Pharos; P01375; Tclin.
DR   PRO; PR:P01375; -.
DR   Proteomes; UP000005640; Chromosome 6.
DR   RNAct; P01375; protein.
DR   Bgee; ENSG00000232810; Expressed in leukocyte and 88 other tissues.
DR   ExpressionAtlas; P01375; baseline and differential.
DR   Genevisible; P01375; HS.
DR   GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR   GO; GO:0009897; C:external side of plasma membrane; ISS:BHF-UCL.
DR   GO; GO:0005576; C:extracellular region; TAS:ARUK-UCL.
DR   GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR   GO; GO:0005887; C:integral component of plasma membrane; IDA:BHF-UCL.
DR   GO; GO:0016020; C:membrane; TAS:ARUK-UCL.
DR   GO; GO:0045121; C:membrane raft; IDA:BHF-UCL.
DR   GO; GO:0001891; C:phagocytic cup; ISS:BHF-UCL.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0032991; C:protein-containing complex; TAS:ARUK-UCL.
DR   GO; GO:0055037; C:recycling endosome; ISS:BHF-UCL.
DR   GO; GO:0005125; F:cytokine activity; IDA:BHF-UCL.
DR   GO; GO:0042802; F:identical protein binding; IDA:BHF-UCL.
DR   GO; GO:0002020; F:protease binding; IPI:BHF-UCL.
DR   GO; GO:0044212; F:transcription regulatory region DNA binding; IDA:UniProtKB.
DR   GO; GO:0005164; F:tumor necrosis factor receptor binding; IDA:BHF-UCL.
DR   GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR   GO; GO:0000187; P:activation of MAPK activity; IDA:BHF-UCL.
DR   GO; GO:0000185; P:activation of MAPKKK activity; IDA:BHF-UCL.
DR   GO; GO:0048143; P:astrocyte activation; NAS:ARUK-UCL.
DR   GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl.
DR   GO; GO:0071316; P:cellular response to nicotine; IDA:UniProtKB.
DR   GO; GO:0071407; P:cellular response to organic cyclic compound; IDA:UniProtKB.
DR   GO; GO:0002439; P:chronic inflammatory response to antigenic stimulus; IMP:BHF-UCL.
DR   GO; GO:0050890; P:cognition; TAS:ARUK-UCL.
DR   GO; GO:0030866; P:cortical actin cytoskeleton organization; IDA:UniProtKB.
DR   GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR   GO; GO:0071550; P:death-inducing signaling complex assembly; TAS:Reactome.
DR   GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR   GO; GO:0048566; P:embryonic digestive tract development; IEP:DFLAT.
DR   GO; GO:0072577; P:endothelial cell apoptotic process; IEA:Ensembl.
DR   GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; IEA:Ensembl.
DR   GO; GO:0030198; P:extracellular matrix organization; IEA:Ensembl.
DR   GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR   GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IDA:UniProtKB.
DR   GO; GO:0006006; P:glucose metabolic process; IEA:Ensembl.
DR   GO; GO:0006959; P:humoral immune response; IEA:Ensembl.
DR   GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; TAS:Reactome.
DR   GO; GO:0006954; P:inflammatory response; IDA:UniProtKB.
DR   GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IEA:Ensembl.
DR   GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR   GO; GO:0050901; P:leukocyte tethering or rolling; IDA:BHF-UCL.
DR   GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IDA:UniProtKB.
DR   GO; GO:0000165; P:MAPK cascade; IMP:UniProtKB.
DR   GO; GO:0001774; P:microglial cell activation; ISS:ARUK-UCL.
DR   GO; GO:0097527; P:necroptotic signaling pathway; IDA:UniProtKB.
DR   GO; GO:0010693; P:negative regulation of alkaline phosphatase activity; IEA:Ensembl.
DR   GO; GO:1900222; P:negative regulation of amyloid-beta clearance; ISS:ARUK-UCL.
DR   GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IGI:ARUK-UCL.
DR   GO; GO:1903347; P:negative regulation of bicellular tight junction assembly; IDA:UniProtKB.
DR   GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:BHF-UCL.
DR   GO; GO:0061048; P:negative regulation of branching involved in lung morphogenesis; IDA:UniProtKB.
DR   GO; GO:0031327; P:negative regulation of cellular biosynthetic process; IDA:ARUK-UCL.
DR   GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IGI:ARUK-UCL.
DR   GO; GO:0002740; P:negative regulation of cytokine secretion involved in immune response; IDA:BHF-UCL.
DR   GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IEA:Ensembl.
DR   GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IDA:BHF-UCL.
DR   GO; GO:0045599; P:negative regulation of fat cell differentiation; NAS:BHF-UCL.
DR   GO; GO:0010629; P:negative regulation of gene expression; IDA:UniProtKB.
DR   GO; GO:0046325; P:negative regulation of glucose import; IEA:Ensembl.
DR   GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:BHF-UCL.
DR   GO; GO:0050995; P:negative regulation of lipid catabolic process; IDA:BHF-UCL.
DR   GO; GO:0010888; P:negative regulation of lipid storage; NAS:BHF-UCL.
DR   GO; GO:0045930; P:negative regulation of mitotic cell cycle; IEA:Ensembl.
DR   GO; GO:0045662; P:negative regulation of myoblast differentiation; IEA:Ensembl.
DR   GO; GO:0035509; P:negative regulation of myosin-light-chain-phosphatase activity; IDA:UniProtKB.
DR   GO; GO:0050768; P:negative regulation of neurogenesis; TAS:ARUK-UCL.
DR   GO; GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Ensembl.
DR   GO; GO:1903799; P:negative regulation of production of miRNAs involved in gene silencing by miRNA; IDA:ARUK-UCL.
DR   GO; GO:0043242; P:negative regulation of protein-containing complex disassembly; IDA:UniProtKB.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR   GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR   GO; GO:0061044; P:negative regulation of vascular wound healing; IDA:BHF-UCL.
DR   GO; GO:0045071; P:negative regulation of viral genome replication; IDA:BHF-UCL.
DR   GO; GO:0030316; P:osteoclast differentiation; IEA:Ensembl.
DR   GO; GO:1902004; P:positive regulation of amyloid-beta formation; ISS:ARUK-UCL.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR   GO; GO:2000334; P:positive regulation of blood microparticle formation; IDA:BHF-UCL.
DR   GO; GO:0060559; P:positive regulation of calcidiol 1-monooxygenase activity; IDA:BHF-UCL.
DR   GO; GO:0070886; P:positive regulation of calcineurin-NFAT signaling cascade; IDA:MGI.
DR   GO; GO:0045785; P:positive regulation of cell adhesion; IMP:UniProtKB.
DR   GO; GO:2000304; P:positive regulation of ceramide biosynthetic process; TAS:Reactome.
DR   GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IDA:BHF-UCL.
DR   GO; GO:0045080; P:positive regulation of chemokine biosynthetic process; IDA:BHF-UCL.
DR   GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL.
DR   GO; GO:0090197; P:positive regulation of chemokine secretion; ISS:ARUK-UCL.
DR   GO; GO:0002876; P:positive regulation of chronic inflammatory response to antigenic stimulus; IEA:Ensembl.
DR   GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR   GO; GO:0001819; P:positive regulation of cytokine production; IDA:BHF-UCL.
DR   GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IDA:ARUK-UCL.
DR   GO; GO:0050715; P:positive regulation of cytokine secretion; IDA:BHF-UCL.
DR   GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IDA:BHF-UCL.
DR   GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; NAS:BHF-UCL.
DR   GO; GO:0031622; P:positive regulation of fever generation; ISS:BHF-UCL.
DR   GO; GO:0050754; P:positive regulation of fractalkine biosynthetic process; ISS:ARUK-UCL.
DR   GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB.
DR   GO; GO:0060252; P:positive regulation of glial cell proliferation; IDA:ARUK-UCL.
DR   GO; GO:0051798; P:positive regulation of hair follicle development; IEA:Ensembl.
DR   GO; GO:0034116; P:positive regulation of heterotypic cell-cell adhesion; IDA:BHF-UCL.
DR   GO; GO:0002925; P:positive regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl.
DR   GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IDA:BHF-UCL.
DR   GO; GO:1903721; P:positive regulation of I-kappaB phosphorylation; IDA:ARUK-UCL.
DR   GO; GO:0050729; P:positive regulation of inflammatory response; TAS:ARUK-UCL.
DR   GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl.
DR   GO; GO:0050725; P:positive regulation of interleukin-1 beta biosynthetic process; IDA:ARUK-UCL.
DR   GO; GO:0150125; P:positive regulation of interleukin-33 biosynthetic process; IDA:ARUK-UCL.
DR   GO; GO:0045410; P:positive regulation of interleukin-6 biosynthetic process; ISS:ARUK-UCL.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:ARUK-UCL.
DR   GO; GO:2000778; P:positive regulation of interleukin-6 secretion; ISS:ARUK-UCL.
DR   GO; GO:0045416; P:positive regulation of interleukin-8 biosynthetic process; IDA:BHF-UCL.
DR   GO; GO:0032757; P:positive regulation of interleukin-8 production; IMP:UniProtKB.
DR   GO; GO:2000484; P:positive regulation of interleukin-8 secretion; IGI:ARUK-UCL.
DR   GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:UniProtKB.
DR   GO; GO:1904999; P:positive regulation of leukocyte adhesion to arterial endothelial cell; IDA:BHF-UCL.
DR   GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IDA:BHF-UCL.
DR   GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:UniProtKB.
DR   GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL.
DR   GO; GO:0071677; P:positive regulation of mononuclear cell migration; NAS:BHF-UCL.
DR   GO; GO:0150078; P:positive regulation of neuroinflammatory response; TAS:ARUK-UCL.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:ARUK-UCL.
DR   GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR   GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IDA:UniProtKB.
DR   GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:BHF-UCL.
DR   GO; GO:0051000; P:positive regulation of nitric-oxide synthase activity; IC:ARUK-UCL.
DR   GO; GO:0051173; P:positive regulation of nitrogen compound metabolic process; ISS:ARUK-UCL.
DR   GO; GO:0045672; P:positive regulation of osteoclast differentiation; IDA:BHF-UCL.
DR   GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR   GO; GO:0050766; P:positive regulation of phagocytosis; IMP:AgBase.
DR   GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISS:ARUK-UCL.
DR   GO; GO:0071803; P:positive regulation of podosome assembly; IDA:BHF-UCL.
DR   GO; GO:1902895; P:positive regulation of pri-miRNA transcription by RNA polymerase II; IDA:BHF-UCL.
DR   GO; GO:0043068; P:positive regulation of programmed cell death; IDA:UniProtKB.
DR   GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:AgBase.
DR   GO; GO:0045860; P:positive regulation of protein kinase activity; IDA:AgBase.
DR   GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISS:ARUK-UCL.
DR   GO; GO:2000010; P:positive regulation of protein localization to cell surface; IDA:BHF-UCL.
DR   GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:ARUK-UCL.
DR   GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:UniProtKB.
DR   GO; GO:0051222; P:positive regulation of protein transport; IDA:BHF-UCL.
DR   GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL.
DR   GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; IDA:UniProtKB.
DR   GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; ISS:ARUK-UCL.
DR   GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:BHF-UCL.
DR   GO; GO:1901671; P:positive regulation of superoxide dismutase activity; IDA:BHF-UCL.
DR   GO; GO:0050806; P:positive regulation of synaptic transmission; ISS:ARUK-UCL.
DR   GO; GO:1901647; P:positive regulation of synoviocyte proliferation; IDA:ARUK-UCL.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR   GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR   GO; GO:0045994; P:positive regulation of translational initiation by iron; IEA:Ensembl.
DR   GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISS:ARUK-UCL.
DR   GO; GO:1904707; P:positive regulation of vascular smooth muscle cell proliferation; IEA:Ensembl.
DR   GO; GO:0060557; P:positive regulation of vitamin D biosynthetic process; IDA:BHF-UCL.
DR   GO; GO:0043491; P:protein kinase B signaling; IMP:UniProtKB.
DR   GO; GO:0072659; P:protein localization to plasma membrane; IDA:UniProtKB.
DR   GO; GO:0032800; P:receptor biosynthetic process; IDA:BHF-UCL.
DR   GO; GO:0060693; P:regulation of branching involved in salivary gland morphogenesis; IEA:Ensembl.
DR   GO; GO:2000351; P:regulation of endothelial cell apoptotic process; IMP:ARUK-UCL.
DR   GO; GO:1903140; P:regulation of establishment of endothelial barrier; IDA:UniProtKB.
DR   GO; GO:0045598; P:regulation of fat cell differentiation; ISS:ARUK-UCL.
DR   GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; IDA:BHF-UCL.
DR   GO; GO:0051023; P:regulation of immunoglobulin secretion; IEA:Ensembl.
DR   GO; GO:0050796; P:regulation of insulin secretion; IDA:BHF-UCL.
DR   GO; GO:0050807; P:regulation of synapse organization; ISS:ARUK-UCL.
DR   GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; TAS:ARUK-UCL.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISS:ARUK-UCL.
DR   GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; TAS:Reactome.
DR   GO; GO:0051384; P:response to glucocorticoid; IDA:BHF-UCL.
DR   GO; GO:0009651; P:response to salt stress; TAS:BHF-UCL.
DR   GO; GO:0009615; P:response to virus; IDA:BHF-UCL.
DR   GO; GO:0030730; P:sequestering of triglyceride; IDA:BHF-UCL.
DR   GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IDA:ARUK-UCL.
DR   CDD; cd00184; TNF; 1.
DR   Gene3D; 2.60.120.40; -; 1.
DR   InterPro; IPR006053; TNF.
DR   InterPro; IPR002959; TNF_alpha.
DR   InterPro; IPR021184; TNF_CS.
DR   InterPro; IPR006052; TNF_dom.
DR   InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR   PANTHER; PTHR11471:SF23; PTHR11471:SF23; 1.
DR   Pfam; PF00229; TNF; 1.
DR   PRINTS; PR01234; TNECROSISFCT.
DR   PRINTS; PR01235; TNFALPHA.
DR   SMART; SM00207; TNF; 1.
DR   SUPFAM; SSF49842; SSF49842; 1.
DR   PROSITE; PS00251; TNF_1; 1.
DR   PROSITE; PS50049; TNF_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Cell membrane; Cytokine; Direct protein sequencing;
KW   Disulfide bond; Glycoprotein; Lipoprotein; Membrane; Myristate;
KW   Phosphoprotein; Polymorphism; Reference proteome; Secreted; Signal-anchor;
KW   Transmembrane; Transmembrane helix.
FT   CHAIN           1..233
FT                   /note="Tumor necrosis factor, membrane form"
FT                   /id="PRO_0000034423"
FT   CHAIN           1..39
FT                   /note="Intracellular domain 1"
FT                   /id="PRO_0000417231"
FT   CHAIN           1..35
FT                   /note="Intracellular domain 2"
FT                   /id="PRO_0000417232"
FT   CHAIN           50..?
FT                   /note="C-domain 1"
FT                   /id="PRO_0000417233"
FT   CHAIN           52..?
FT                   /note="C-domain 2"
FT                   /id="PRO_0000417234"
FT   CHAIN           77..233
FT                   /note="Tumor necrosis factor, soluble form"
FT                   /evidence="ECO:0000269|PubMed:3856324"
FT                   /id="PRO_0000034424"
FT   TOPO_DOM        1..35
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        36..56
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        57..233
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   SITE            35..36
FT                   /note="Cleavage; by SPPL2A or SPPL2B"
FT   SITE            39..40
FT                   /note="Cleavage; by SPPL2A or SPPL2B"
FT   SITE            49..50
FT                   /note="Cleavage; by SPPL2A or SPPL2B"
FT   SITE            51..52
FT                   /note="Cleavage; by SPPL2A or SPPL2B"
FT   SITE            76..77
FT                   /note="Cleavage; by ADAM17"
FT   MOD_RES         2
FT                   /note="Phosphoserine; by CK1"
FT                   /evidence="ECO:0000305"
FT   LIPID           19
FT                   /note="N6-myristoyl lysine"
FT                   /evidence="ECO:0000269|PubMed:1402651"
FT   LIPID           20
FT                   /note="N6-myristoyl lysine"
FT                   /evidence="ECO:0000269|PubMed:1402651"
FT   CARBOHYD        80
FT                   /note="O-linked (GalNAc...) serine; in soluble form"
FT                   /evidence="ECO:0000269|PubMed:8631363"
FT   DISULFID        145..177
FT   VARIANT         84
FT                   /note="P -> L (in dbSNP:rs4645843)"
FT                   /evidence="ECO:0000269|Ref.13"
FT                   /id="VAR_019378"
FT   VARIANT         94
FT                   /note="A -> T (in dbSNP:rs1800620)"
FT                   /id="VAR_011927"
FT   MUTAGEN         105
FT                   /note="L->S: Low activity."
FT                   /evidence="ECO:0000269|PubMed:2009860"
FT   MUTAGEN         108
FT                   /note="R->W: Biologically inactive."
FT                   /evidence="ECO:0000269|PubMed:2009860"
FT   MUTAGEN         112
FT                   /note="L->F: Biologically inactive."
FT                   /evidence="ECO:0000269|PubMed:2009860"
FT   MUTAGEN         160
FT                   /note="A->V: Biologically inactive."
FT                   /evidence="ECO:0000269|PubMed:2009860"
FT   MUTAGEN         162
FT                   /note="S->F: Biologically inactive."
FT                   /evidence="ECO:0000269|PubMed:2009860"
FT   MUTAGEN         167
FT                   /note="V->A,D: Biologically inactive."
FT                   /evidence="ECO:0000269|PubMed:2009860"
FT   MUTAGEN         222
FT                   /note="E->K: Biologically inactive."
FT                   /evidence="ECO:0000269|PubMed:2009860"
FT   CONFLICT        63
FT                   /note="F -> S (in Ref. 5; AAA61198)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        84..86
FT                   /note="PSD -> VNR (in Ref. 17; AAF71992)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        183
FT                   /note="E -> R (in Ref. 16; AAC03542)"
FT                   /evidence="ECO:0000305"
FT   STRAND          89..94
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          96..98
FT                   /evidence="ECO:0000244|PDB:5M2I"
FT   STRAND          99..101
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          104..106
FT                   /evidence="ECO:0000244|PDB:2ZJC"
FT   STRAND          108..110
FT                   /evidence="ECO:0000244|PDB:5M2J"
FT   STRAND          112..114
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          118..120
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          123..125
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          128..143
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          146..148
FT                   /evidence="ECO:0000244|PDB:2ZPX"
FT   STRAND          152..159
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          161..163
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          166..174
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          177..179
FT                   /evidence="ECO:0000244|PDB:1A8M"
FT   STRAND          182..185
FT                   /evidence="ECO:0000244|PDB:4TSV"
FT   STRAND          189..202
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          207..213
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   HELIX           215..217
FT                   /evidence="ECO:0000244|PDB:5UUI"
FT   STRAND          221..223
FT                   /evidence="ECO:0000244|PDB:3IT8"
FT   STRAND          225..232
FT                   /evidence="ECO:0000244|PDB:5UUI"
SQ   SEQUENCE   233 AA;  25644 MW;  3DF90F96C9031FFE CRC64;
     MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL LHFGVIGPQR
     EEFPRDLSLI SPLAQAVRSS SRTPSDKPVA HVVANPQAEG QLQWLNRRAN ALLANGVELR
     DNQLVVPSEG LYLIYSQVLF KGQGCPSTHV LLTHTISRIA VSYQTKVNLL SAIKSPCQRE
     TPEGAEAKPW YEPIYLGGVF QLEKGDRLSA EINRPDYLDF AESGQVYFGI IAL
//
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