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 27-MAR-2024, entry version 273. 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; DOI=10.1002/j.1460-2075.1991.tb08015.x; 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). Promotes osteoclastogenesis and therefore CC mediates bone resorption (By similarity). CC {ECO:0000250|UniProtKB:P06804, ECO:0000269|PubMed:12794819, CC ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:22517918, CC 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; P31949: S100A11; NbExp=3; IntAct=EBI-359977, EBI-701862; CC P01375; P80511: S100A12; NbExp=3; IntAct=EBI-359977, EBI-2823305; CC P01375; Q99584: S100A13; NbExp=2; IntAct=EBI-359977, EBI-721909; 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=4; IntAct=EBI-359977, EBI-529119; CC P01375; Q60769: Tnfaip3; Xeno; NbExp=2; IntAct=EBI-359977, EBI-646595; CC P01375; P25118: Tnfrsf1a; Xeno; NbExp=4; 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="https://atlasgeneticsoncology.org/gene/319/TNFa"; 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 CC --------------------------------------------------------------------------- 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 PDB; 7QLF; NMR; -; A=178-191. DR PDB; 7TA3; X-ray; 2.50 A; B/D=77-233. DR PDB; 7TA6; X-ray; 2.67 A; A/B/C/D/E/F/G/H=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 PDBsum; 7QLF; -. DR PDBsum; 7TA3; -. DR PDBsum; 7TA6; -. DR AlphaFoldDB; P01375; -. DR SMR; P01375; -. DR BioGRID; 112979; 345. DR CORUM; P01375; -. DR DIP; DIP-2895N; -. DR IntAct; P01375; 116. 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; DB04297; Trichostatin A. DR DrugBank; DB05470; VX-702. DR DrugBank; DB05017; YSIL6. DR DrugCentral; P01375; -. DR GlyConnect; 609; 3 O-Linked glycans (1 site). DR GlyCosmos; P01375; 1 site, 5 glycans. 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; 9606-ENSP00000398698; -. DR PeptideAtlas; P01375; -. DR ProteomicsDB; 51379; -. DR ABCD; P01375; 142 sequenced antibodies. DR Antibodypedia; 27196; 5666 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; ENSG00000232810.5. DR GeneID; 7124; -. DR KEGG; hsa:7124; -. DR MANE-Select; ENST00000449264.3; ENSP00000398698.2; NM_000594.4; NP_000585.2. DR AGR; HGNC:11892; -. 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; ENSGT01060000248544; -. DR HOGENOM; CLU_070352_3_1_1; -. DR InParanoid; P01375; -. DR OMA; GATMLFC; -. DR OrthoDB; 2909163at2759; -. 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 NF-kappa-B 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; 11 hits in 1165 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 90 other cell types or tissues. DR ExpressionAtlas; P01375; baseline and differential. 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:Reactome. DR GO; GO:0005615; C:extracellular space; IDA:BHF-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; IDA:BHF-UCL. DR GO; GO:0055037; C:recycling endosome; ISS:BHF-UCL. DR GO; GO:0005125; F:cytokine activity; IDA:BHF-UCL. DR GO; GO:0038177; F:death receptor agonist activity; IDA:UniProt. 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:0140374; P:antiviral innate immune response; IDA:UniProt. 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:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:0071316; P:cellular response to nicotine; 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:0071346; P:cellular response to type II interferon; 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:0006954; P:inflammatory response; IDA:BHF-UCL. DR GO; GO:0090594; P:inflammatory response to wounding; IDA:UniProt. 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:0097421; P:liver regeneration; IEA:Ensembl. DR GO; GO:0002281; P:macrophage activation involved in immune response; IEA:Ensembl. DR GO; GO:0001774; P:microglial cell activation; ISS:ARUK-UCL. DR GO; GO:0097527; P:necroptotic signaling pathway; IDA:UniProtKB. 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:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. 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:1902894; P:negative regulation of miRNA transcription; NAS:BHF-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: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:0043491; P:phosphatidylinositol 3-kinase/protein kinase B signal transduction; 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:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:AgBase. 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: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:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. 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: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: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:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:BHF-UCL. DR GO; GO:0051173; P:positive regulation of nitrogen compound metabolic process; ISS:ARUK-UCL. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IDA:UniProtKB. 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:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; 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: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:0045994; P:positive regulation of translational initiation by iron; IEA:Ensembl. DR GO; GO:0032729; P:positive regulation of type II interferon production; 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: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:0043122; P:regulation of canonical NF-kappaB signal transduction; IDA:BHF-UCL. 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:0002637; P:regulation of immunoglobulin production; IEA:Ensembl. DR GO; GO:0050796; P:regulation of insulin secretion; IDA:BHF-UCL. DR GO; GO:1905038; P:regulation of membrane lipid metabolic process; IEA:Ensembl. 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: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:0009750; P:response to fructose; 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:0035900; P:response to isolation stress; IEA:Ensembl. DR GO; GO:1902065; P:response to L-glutamate; IEA:Ensembl. DR GO; GO:0036005; P:response to macrophage colony-stimulating factor; IEA:Ensembl. DR GO; GO:0031667; P:response to nutrient levels; 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; TUMOR NECROSIS FACTOR; 1. DR PANTHER; PTHR11471; TUMOR NECROSIS FACTOR FAMILY MEMBER; 1. DR Pfam; PF00229; TNF; 1. DR PRINTS; PR01234; TNECROSISFCT. DR PRINTS; PR01235; TNFALPHA. DR SMART; SM00207; TNF; 1. DR SUPFAM; SSF49842; TNF-like; 1. DR PROSITE; PS00251; TNF_1; 1. DR PROSITE; PS50049; TNF_2; 1. DR Genevisible; P01375; HS. 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 TURN 84..86 FT /evidence="ECO:0007829|PDB:7TA6" 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 TURN 221..224 FT /evidence="ECO:0007829|PDB:7TA6" 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 //