TNFA_HUMAN
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 03-AUG-2022, entry version 264.
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 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 [25]
RP FUNCTION.
RX PubMed=12794819; DOI=10.1002/art.11143;
RA Nakahara H., Song J., Sugimoto M., Hagihara K., Kishimoto T., Yoshizaki K.,
RA Nishimoto N.;
RT "Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial
RT growth factor production in rheumatoid arthritis.";
RL Arthritis Rheum. 48:1521-1529(2003).
RN [26]
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).
RN [27]
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 [28]
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 [29]
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 [30]
RP MYRISTOYLATION AT LYS-19 AND LYS-20, DEMYRISTOYLATION AT LYS-19 AND LYS-20,
RP SUBCELLULAR LOCATION (TUMOR NECROSIS FACTOR, SOLUBLE FORM), AND MUTAGENESIS
RP OF 19-LYS-LYS-20.
RX PubMed=23552949; DOI=10.1038/nature12038;
RA Jiang H., Khan S., Wang Y., Charron G., He B., Sebastian C., Du J., Kim R.,
RA Ge E., Mostoslavsky R., Hang H.C., Hao Q., Lin H.;
RT "SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty
RT acyl lysine.";
RL Nature 496:110-113(2013).
RN [31]
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 [32]
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 [33]
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 [34]
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 [35]
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 [36]
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).
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. Up-regulates 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). Plays a role in
CC angiogenesis by inducing VEGF production synergistically with IL1B and
CC IL6 (PubMed:12794819). {ECO:0000250|UniProtKB:P06804,
CC ECO:0000269|PubMed:12794819, 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; P05067: APP; NbExp=3; IntAct=EBI-359977, EBI-77613;
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; 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; Q8N6L0: KASH5; NbExp=3; IntAct=EBI-359977, EBI-749265;
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 {ECO:0000269|PubMed:23552949}.
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 -!- PTM: [Tumor necrosis factor, soluble form]: The soluble form is
CC demyristoylated at Lys-19 and Lys-20 by SIRT6, promoting its secretion.
CC {ECO:0000269|PubMed:23552949}.
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 variants affecting the gene represented in this 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 ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
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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 PDB; 6X81; X-ray; 2.81 A; A/B/C/D/E/F=77-233.
DR PDB; 6X82; X-ray; 2.75 A; A/B/C/D/E/F=77-233.
DR PDB; 6X83; X-ray; 2.83 A; A/B/C/D/E/F=77-233.
DR PDB; 6X85; X-ray; 2.85 A; A/B/C/D/E/F=77-233.
DR PDB; 6X86; X-ray; 2.93 A; A/B/C/D/E/F=77-233.
DR PDB; 7ASY; NMR; -; A=28-60.
DR PDB; 7AT7; NMR; -; A=28-60.
DR PDB; 7ATB; NMR; -; A=28-60.
DR PDB; 7JRA; X-ray; 2.10 A; A/B/C=77-233.
DR PDB; 7KP9; X-ray; 2.15 A; A/B/C=77-233.
DR PDB; 7KPA; X-ray; 2.30 A; A/B/C=77-233.
DR PDB; 7KPB; X-ray; 3.00 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 PDBsum; 6X81; -.
DR PDBsum; 6X82; -.
DR PDBsum; 6X83; -.
DR PDBsum; 6X85; -.
DR PDBsum; 6X86; -.
DR PDBsum; 7ASY; -.
DR PDBsum; 7AT7; -.
DR PDBsum; 7ATB; -.
DR PDBsum; 7JRA; -.
DR PDBsum; 7KP9; -.
DR PDBsum; 7KPA; -.
DR PDBsum; 7KPB; -.
DR AlphaFoldDB; P01375; -.
DR SMR; P01375; -.
DR BioGRID; 112979; 332.
DR CORUM; P01375; -.
DR DIP; DIP-2895N; -.
DR IntAct; P01375; 113.
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; DB11752; Bryostatin 1.
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; DB13751; Glycyrrhizic acid.
DR DrugBank; DB06674; Golimumab.
DR DrugBank; DB00065; Infliximab.
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; 3 O-Linked glycans (1 site).
DR GlyGen; P01375; 1 site, 5 O-linked glycans (1 site).
DR iPTMnet; P01375; -.
DR PhosphoSitePlus; P01375; -.
DR SwissPalm; P01375; -.
DR BioMuta; TNF; -.
DR DMDM; 135934; -.
DR MassIVE; P01375; -.
DR PaxDb; P01375; -.
DR PeptideAtlas; P01375; -.
DR PRIDE; P01375; -.
DR ProteomicsDB; 51379; -.
DR ABCD; P01375; 41 sequenced antibodies.
DR Antibodypedia; 27196; 4706 antibodies from 56 providers.
DR DNASU; 7124; -.
DR Ensembl; ENST00000376122.3; ENSP00000365290.3; ENSG00000204490.3.
DR Ensembl; ENST00000383496.4; ENSP00000372988.4; ENSG00000206439.5.
DR Ensembl; ENST00000412275.2; ENSP00000392858.2; ENSG00000228321.3.
DR Ensembl; ENST00000420425.2; ENSP00000410668.2; ENSG00000228849.3.
DR Ensembl; ENST00000443707.2; ENSP00000389492.2; ENSG00000230108.3.
DR Ensembl; ENST00000448781.2; ENSP00000389490.2; ENSG00000223952.3.
DR Ensembl; ENST00000449264.3; ENSP00000398698.2; ENSG00000232810.4.
DR GeneID; 7124; -.
DR KEGG; hsa:7124; -.
DR MANE-Select; ENST00000449264.3; ENSP00000398698.2; NM_000594.4; NP_000585.2.
DR CTD; 7124; -.
DR DisGeNET; 7124; -.
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 VEuPathDB; HostDB:ENSG00000232810; -.
DR eggNOG; ENOG502S4K8; Eukaryota.
DR GeneTree; ENSGT01050000244878; -.
DR HOGENOM; CLU_070352_3_1_1; -.
DR InParanoid; P01375; -.
DR OMA; GATMLFC; -.
DR OrthoDB; 1124938at2759; -.
DR PhylomeDB; P01375; -.
DR TreeFam; TF332169; -.
DR PathwayCommons; P01375; -.
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 SignaLink; P01375; -.
DR SIGNOR; P01375; -.
DR BioGRID-ORCS; 7124; 8 hits in 1074 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 granulocyte and 89 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:0043025; C:neuronal cell body; IEA:Ensembl.
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:0000976; F:transcription cis-regulatory region 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:0002526; P:acute inflammatory response; IEA:Ensembl.
DR GO; GO:0048143; P:astrocyte activation; NAS:ARUK-UCL.
DR GO; GO:0019722; P:calcium-mediated signaling; IEA:Ensembl.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:1904646; P:cellular response to amyloid-beta; IEA:Ensembl.
DR GO; GO:0071346; P:cellular response to interferon-gamma; 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:0071300; P:cellular response to retinoic acid; IEA:Ensembl.
DR GO; GO:0097237; P:cellular response to toxic substance; IEA:Ensembl.
DR GO; GO:0002439; P:chronic inflammatory response to antigenic stimulus; IMP:BHF-UCL.
DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl.
DR GO; GO:0050890; P:cognition; TAS:ARUK-UCL.
DR GO; GO:0030866; P:cortical actin cytoskeleton organization; IDA:UniProtKB.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; 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; IEA:Ensembl.
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:0002523; P:leukocyte migration involved in inflammatory response; 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:0097421; P:liver regeneration; IEA:Ensembl.
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:0120190; P:negative regulation of bile acid secretion; IEA:Ensembl.
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:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IGI:ARUK-UCL.
DR GO; GO:0002719; P:negative regulation of cytokine production 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:0010459; P:negative regulation of heart rate; IEA:Ensembl.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:BHF-UCL.
DR GO; GO:0002037; P:negative regulation of L-glutamate import across plasma membrane; IEA:Ensembl.
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:1903799; P:negative regulation of miRNA maturation; IDA:ARUK-UCL.
DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0031642; P:negative regulation of myelination; 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:0090324; P:negative regulation of oxidative phosphorylation; IEA:Ensembl.
DR GO; GO:0043242; P:negative regulation of protein-containing complex disassembly; IDA:UniProtKB.
DR GO; GO:2000272; P:negative regulation of signaling receptor activity; IDA:BHF-UCL.
DR GO; GO:0003085; P:negative regulation of systemic arterial blood pressure; IEA:Ensembl.
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:0045760; P:positive regulation of action potential; 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:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IDA:BHF-UCL.
DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-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:2001272; P:positive regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis; IEA:Ensembl.
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:2000573; P:positive regulation of DNA biosynthetic process; IEA:Ensembl.
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:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IBA:GO_Central.
DR GO; GO:0031622; P:positive regulation of fever generation; ISS:BHF-UCL.
DR GO; GO:0032724; P:positive regulation of fractalkine production; 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:2000347; P:positive regulation of hepatocyte proliferation; 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:0032731; P:positive regulation of interleukin-1 beta production; IDA:ARUK-UCL.
DR GO; GO:0032741; P:positive regulation of interleukin-18 production; IEA:Ensembl.
DR GO; GO:0150129; P:positive regulation of interleukin-33 production; IDA:ARUK-UCL.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:ARUK-UCL.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
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:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL.
DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL.
DR GO; GO:1902895; P:positive regulation of miRNA transcription; IDA:BHF-UCL.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IEA:Ensembl.
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:1902565; P:positive regulation of neutrophil activation; IEA:Ensembl.
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:1903223; P:positive regulation of oxidative stress-induced neuron death; IEA:Ensembl.
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: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 associated 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: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:0002637; P:regulation of immunoglobulin production; IEA:Ensembl.
DR GO; GO:0050796; P:regulation of insulin secretion; IDA:BHF-UCL.
DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IEA:Ensembl.
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:1905242; P:response to 3,3',5-triiodo-L-thyronine; IEA:Ensembl.
DR GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid; IDA:BHF-UCL.
DR GO; GO:1990268; P:response to gold nanoparticle; IEA:Ensembl.
DR GO; GO:0140460; P:response to Gram-negative bacterium; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:1901554; P:response to paracetamol; IEA:Ensembl.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
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:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0030730; P:sequestering of triglyceride; IDA:BHF-UCL.
DR GO; GO:0003009; P:skeletal muscle contraction; IEA:Ensembl.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; IEA:Ensembl.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IDA:ARUK-UCL.
DR GO; GO:0010573; P:vascular endothelial growth factor production; IDA:UniProtKB.
DR GO; GO:0042311; P:vasodilation; IEA:Ensembl.
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; Reference proteome; Secreted; Signal-anchor; Transmembrane;
KW 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 ECO:0000269|PubMed:23552949"
FT LIPID 20
FT /note="N6-myristoyl lysine"
FT /evidence="ECO:0000269|PubMed:1402651,
FT ECO:0000269|PubMed:23552949"
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 19..20
FT /note="KK->RR: Abolished myristoylation."
FT /evidence="ECO:0000269|PubMed:23552949"
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 HELIX 32..35
FT /evidence="ECO:0007829|PDB:7ASY"
FT HELIX 37..53
FT /evidence="ECO:0007829|PDB:7ASY"
FT STRAND 89..94
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 96..98
FT /evidence="ECO:0007829|PDB:5M2I"
FT STRAND 99..101
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 104..106
FT /evidence="ECO:0007829|PDB:2ZJC"
FT STRAND 108..110
FT /evidence="ECO:0007829|PDB:5M2J"
FT STRAND 112..114
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 118..120
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 123..125
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 128..143
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 146..148
FT /evidence="ECO:0007829|PDB:2ZPX"
FT STRAND 152..159
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 161..163
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 166..174
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 177..179
FT /evidence="ECO:0007829|PDB:1A8M"
FT STRAND 182..185
FT /evidence="ECO:0007829|PDB:4TSV"
FT STRAND 189..202
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 207..213
FT /evidence="ECO:0007829|PDB:5UUI"
FT HELIX 215..217
FT /evidence="ECO:0007829|PDB:5UUI"
FT STRAND 221..223
FT /evidence="ECO:0007829|PDB:3IT8"
FT STRAND 225..232
FT /evidence="ECO:0007829|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
