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P01375 (TNFA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 192. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Tumor necrosis factor
Alternative name(s):
Cachectin
TNF-alpha
Tumor necrosis factor ligand superfamily member 2
Short name=TNF-a

Cleaved into the following 6 chains:

  1. Tumor necrosis factor, membrane form
    Alternative name(s):
    N-terminal fragment
    Short name=NTF
  2. Intracellular domain 1
    Short name=ICD1
  3. Intracellular domain 2
    Short name=ICD2
  4. C-domain 1
  5. C-domain 2
  6. Tumor necrosis factor, soluble form
Gene names
Name:TNF
Synonyms:TNFA, TNFSF2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length233 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. Ref.24

The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. Ref.24

Subunit structure

Homotrimer. Interacts with SPPL2B. Ref.25

Subcellular location

Cell membrane; Single-pass type II membrane protein Ref.24.

Tumor necrosis factor, membrane form: Membrane; Single-pass type II membrane protein Ref.24.

Tumor necrosis factor, soluble form: Secreted Ref.24.

C-domain 1: Secreted Ref.24.

C-domain 2: Secreted Ref.24.

Post-translational modification

The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space.

The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1. Ref.18 Ref.19

O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid. Ref.15

Polymorphism

Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].

Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162].

Involvement in disease

Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis).
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.

Sequence similarities

Belongs to the tumor necrosis factor family.

Sequence caution

The sequence AAF71992.1 differs from that shown. Reason: Frameshift at positions 91 and 157.

The sequence CAA75070.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
   Cellular componentCell membrane
Membrane
Secreted
   Coding sequence diversityPolymorphism
   DomainSignal-anchor
Transmembrane
Transmembrane helix
   Molecular functionCytokine
   PTMDisulfide bond
Glycoprotein
Lipoprotein
Myristate
Phosphoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processJNK cascade

Inferred from electronic annotation. Source: Ensembl

MAPK cascade

Inferred from mutant phenotype PubMed 21147091. Source: UniProtKB

activation of MAPK activity

Inferred from direct assay PubMed 10748004. Source: BHF-UCL

activation of MAPKKK activity

Inferred from direct assay PubMed 15310755. Source: BHF-UCL

activation of cysteine-type endopeptidase activity involved in apoptotic process

Inferred from direct assay PubMed 16723520. Source: UniProtKB

apoptotic process

Traceable author statement. Source: Reactome

apoptotic signaling pathway

Traceable author statement. Source: Reactome

calcium-mediated signaling

Inferred from electronic annotation. Source: Ensembl

cell activation

Inferred from electronic annotation. Source: Ensembl

cellular amino acid biosynthetic process

Inferred from electronic annotation. Source: Ensembl

cellular response to amino acid stimulus

Inferred from electronic annotation. Source: Ensembl

cellular response to nicotine

Inferred from direct assay PubMed 18676776. Source: UniProtKB

cellular response to organic cyclic compound

Inferred from direct assay PubMed 21147091. Source: UniProtKB

chronic inflammatory response to antigenic stimulus

Inferred from mutant phenotype PubMed 14512626. Source: BHF-UCL

defense response to Gram-positive bacterium

Inferred from electronic annotation. Source: Ensembl

embryonic digestive tract development

Inferred from expression pattern PubMed 20875417. Source: DFLAT

epithelial cell proliferation involved in salivary gland morphogenesis

Inferred from electronic annotation. Source: Ensembl

extracellular matrix organization

Inferred from electronic annotation. Source: Ensembl

extrinsic apoptotic signaling pathway

Inferred from direct assay PubMed 11577081PubMed 16611992. Source: UniProtKB

extrinsic apoptotic signaling pathway via death domain receptors

Inferred from direct assay PubMed 18676776. Source: UniProtKB

glucose metabolic process

Inferred from electronic annotation. Source: Ensembl

humoral immune response

Inferred from electronic annotation. Source: Ensembl

inflammatory response

Inferred from direct assay PubMed 21147091. Source: UniProtKB

intrinsic apoptotic signaling pathway in response to DNA damage

Inferred from electronic annotation. Source: Ensembl

leukocyte tethering or rolling

Inferred from direct assay PubMed 10820279. Source: BHF-UCL

lipopolysaccharide-mediated signaling pathway

Inferred from direct assay PubMed 21147091. Source: UniProtKB

necroptotic signaling pathway

Inferred from direct assay PubMed 22265413PubMed 22265414PubMed 22817896. Source: UniProtKB

negative regulation of L-glutamate transport

Inferred from electronic annotation. Source: Ensembl

negative regulation of alkaline phosphatase activity

Inferred from electronic annotation. Source: Ensembl

negative regulation of branching involved in lung morphogenesis

Inferred from direct assay PubMed 17350185. Source: UniProtKB

negative regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

negative regulation of cytokine secretion involved in immune response

Inferred from direct assay PubMed 10443688. Source: BHF-UCL

negative regulation of extrinsic apoptotic signaling pathway in absence of ligand

Inferred from direct assay PubMed 10666185PubMed 10748004. Source: BHF-UCL

negative regulation of fat cell differentiation

Non-traceable author statement PubMed 16464856. Source: BHF-UCL

negative regulation of gene expression

Inferred from direct assay PubMed 15345745. Source: UniProtKB

negative regulation of glucose import

Inferred from electronic annotation. Source: Ensembl

negative regulation of growth of symbiont in host

Inferred from electronic annotation. Source: Ensembl

negative regulation of interleukin-6 production

Inferred from direct assay PubMed 10443688. Source: BHF-UCL

negative regulation of lipid catabolic process

Inferred from direct assay PubMed 19032770. Source: BHF-UCL

negative regulation of lipid storage

Non-traceable author statement PubMed 16464856. Source: BHF-UCL

negative regulation of osteoblast differentiation

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein complex disassembly

Inferred from direct assay PubMed 17389591. Source: UniProtKB

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 15345745. Source: UniProtKB

negative regulation of transcription, DNA-templated

Inferred from direct assay PubMed 16895791PubMed 17350185. Source: UniProtKB

negative regulation of viral genome replication

Inferred from direct assay PubMed 10490959. Source: BHF-UCL

organ morphogenesis

Inferred from electronic annotation. Source: Ensembl

osteoclast differentiation

Inferred from electronic annotation. Source: Ensembl

positive regulation of ERK1 and ERK2 cascade

Non-traceable author statement PubMed 18606301. Source: BHF-UCL

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from direct assay PubMed 15310755PubMed 17922812. Source: BHF-UCL

positive regulation of JNK cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of JUN kinase activity

Inferred from direct assay PubMed 17389591. Source: UniProtKB

positive regulation of MAP kinase activity

Inferred from direct assay PubMed 17389591. Source: UniProtKB

positive regulation of NF-kappaB import into nucleus

Inferred from direct assay PubMed 17922812. Source: BHF-UCL

positive regulation of NF-kappaB transcription factor activity

Inferred from direct assay PubMed 16280327PubMed 16611992. Source: UniProtKB

positive regulation of NFAT protein import into nucleus

Inferred from direct assay PubMed 16803872. Source: MGI

positive regulation of apoptotic process

Inferred from direct assay PubMed 16723520PubMed 17389591PubMed 22173242. Source: UniProtKB

positive regulation of calcidiol 1-monooxygenase activity

Inferred from direct assay PubMed 1690216. Source: BHF-UCL

positive regulation of chemokine (C-X-C motif) ligand 2 production

Inferred from direct assay PubMed 20551324. Source: BHF-UCL

positive regulation of chemokine biosynthetic process

Inferred from direct assay PubMed 10490959. Source: BHF-UCL

positive regulation of chemokine production

Inferred from direct assay PubMed 10490959. Source: BHF-UCL

positive regulation of chronic inflammatory response to antigenic stimulus

Inferred from electronic annotation. Source: Ensembl

positive regulation of cysteine-type endopeptidase activity involved in apoptotic process

Inferred from direct assay PubMed 11577081. Source: UniProtKB

positive regulation of cytokine production

Inferred from direct assay PubMed 17922812. Source: BHF-UCL

positive regulation of cytokine secretion

Inferred from direct assay PubMed 10443688. Source: BHF-UCL

positive regulation of extrinsic apoptotic signaling pathway via death domain receptors

Inferred from electronic annotation. Source: Ensembl

positive regulation of fever generation

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of hair follicle development

Inferred from electronic annotation. Source: Ensembl

positive regulation of heterotypic cell-cell adhesion

Inferred from direct assay PubMed 10604883PubMed 20551324. Source: BHF-UCL

positive regulation of humoral immune response mediated by circulating immunoglobulin

Inferred from electronic annotation. Source: Ensembl

positive regulation of interferon-gamma production

Inferred from electronic annotation. Source: Ensembl

positive regulation of interleukin-18 production

Inferred from electronic annotation. Source: Ensembl

positive regulation of interleukin-6 production

Inferred from electronic annotation. Source: Ensembl

positive regulation of interleukin-8 biosynthetic process

Inferred from direct assay PubMed 20551324. Source: BHF-UCL

positive regulation of membrane protein ectodomain proteolysis

Inferred from direct assay PubMed 18373975. Source: BHF-UCL

positive regulation of mitosis

Inferred from electronic annotation. Source: Ensembl

positive regulation of mononuclear cell migration

Non-traceable author statement PubMed 21319131. Source: BHF-UCL

positive regulation of neuron apoptotic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of nitric oxide biosynthetic process

Inferred from direct assay PubMed 8383325. Source: BHF-UCL

positive regulation of osteoclast differentiation

Inferred from direct assay PubMed 17888176. Source: BHF-UCL

positive regulation of peptidyl-serine phosphorylation

Inferred from direct assay PubMed 17389591PubMed 18440775. Source: BHF-UCL

positive regulation of podosome assembly

Inferred from direct assay PubMed 15220135. Source: BHF-UCL

positive regulation of programmed cell death

Inferred from direct assay PubMed 16611992. Source: UniProtKB

positive regulation of protein complex assembly

Inferred from direct assay PubMed 12813029. Source: BHF-UCL

positive regulation of protein complex disassembly

Inferred from direct assay PubMed 17389591. Source: UniProtKB

positive regulation of protein kinase B signaling

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein localization to cell surface

Inferred from direct assay PubMed 19366699. Source: BHF-UCL

positive regulation of protein phosphorylation

Inferred from direct assay PubMed 16723520PubMed 17389591. Source: UniProtKB

positive regulation of protein transport

Inferred from direct assay PubMed 15310755. Source: BHF-UCL

positive regulation of sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 10748004. Source: BHF-UCL

positive regulation of smooth muscle cell proliferation

Inferred from direct assay PubMed 16518841. Source: BHF-UCL

positive regulation of synaptic transmission

Inferred from electronic annotation. Source: Ensembl

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 15345745. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from direct assay PubMed 17350185. Source: UniProtKB

positive regulation of translational initiation by iron

Inferred from electronic annotation. Source: Ensembl

positive regulation of vitamin D biosynthetic process

Inferred from direct assay PubMed 1690216. Source: BHF-UCL

protein import into nucleus, translocation

Inferred from direct assay PubMed 16280327. Source: UniProtKB

protein kinase B signaling

Inferred from mutant phenotype PubMed 21147091. Source: UniProtKB

receptor biosynthetic process

Inferred from direct assay PubMed 10443688. Source: BHF-UCL

regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from direct assay PubMed 10748004. Source: BHF-UCL

regulation of branching involved in salivary gland morphogenesis

Inferred from electronic annotation. Source: Ensembl

regulation of immunoglobulin secretion

Inferred from electronic annotation. Source: Ensembl

regulation of insulin secretion

Inferred from direct assay PubMed 8383325. Source: BHF-UCL

response to activity

Inferred from electronic annotation. Source: Ensembl

response to drug

Inferred from electronic annotation. Source: Ensembl

response to glucocorticoid

Inferred from direct assay PubMed 10443688. Source: BHF-UCL

response to hypoxia

Inferred from electronic annotation. Source: Ensembl

response to mechanical stimulus

Inferred from electronic annotation. Source: Ensembl

response to salt stress

Traceable author statement PubMed 18355445. Source: BHF-UCL

response to virus

Inferred from direct assay PubMed 10490959. Source: BHF-UCL

sequestering of triglyceride

Inferred from direct assay PubMed 19032770. Source: BHF-UCL

skeletal muscle contraction

Inferred from electronic annotation. Source: Ensembl

transformed cell apoptotic process

Inferred from direct assay Ref.3. Source: BHF-UCL

tumor necrosis factor-mediated signaling pathway

Inferred from mutant phenotype PubMed 10748004. Source: BHF-UCL

   Cellular_componentcell surface

Inferred from direct assay PubMed 18355445. Source: BHF-UCL

external side of plasma membrane

Inferred from sequence or structural similarity. Source: BHF-UCL

extracellular region

Traceable author statement. Source: Reactome

extracellular space

Inferred from direct assay PubMed 10443688PubMed 18355445Ref.6. Source: BHF-UCL

integral component of plasma membrane

Inferred from direct assay PubMed 18355445. Source: BHF-UCL

membrane raft

Inferred from direct assay PubMed 17010968. Source: BHF-UCL

phagocytic cup

Inferred from sequence or structural similarity. Source: BHF-UCL

plasma membrane

Traceable author statement. Source: Reactome

recycling endosome

Inferred from sequence or structural similarity. Source: BHF-UCL

   Molecular_functioncytokine activity

Inferred from direct assay PubMed 10748004. Source: BHF-UCL

identical protein binding

Inferred from direct assay PubMed 14512626. Source: BHF-UCL

protease binding

Inferred from physical interaction PubMed 12777399. Source: BHF-UCL

transcription regulatory region DNA binding

Inferred from direct assay PubMed 17350185. Source: UniProtKB

tumor necrosis factor receptor binding

Inferred from direct assay PubMed 14512626. Source: BHF-UCL

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

crmEQ8UYL33EBI-359977,EBI-7539950From a different organism.
IKBKGQ9Y6K92EBI-359977,EBI-81279
TNFRSF1AP194388EBI-359977,EBI-299451
TNFRSF1BP203332EBI-359977,EBI-358983

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 233233Tumor necrosis factor, membrane form
PRO_0000034423
Chain1 – 3939Intracellular domain 1
PRO_0000417231
Chain1 – 3535Intracellular domain 2
PRO_0000417232
Chain50 – ?C-domain 1PRO_0000417233
Chain52 – ?C-domain 2PRO_0000417234
Chain77 – 233157Tumor necrosis factor, soluble form Ref.5
PRO_0000034424

Regions

Topological domain1 – 3535Cytoplasmic Potential
Transmembrane36 – 5621Helical; Signal-anchor for type II membrane protein; Potential
Topological domain57 – 233177Extracellular Potential

Sites

Site35 – 362Cleavage; by SPPL2A or SPPL2B
Site39 – 402Cleavage; by SPPL2A or SPPL2B
Site49 – 502Cleavage; by SPPL2A or SPPL2B
Site51 – 522Cleavage; by SPPL2A or SPPL2B
Site76 – 772Cleavage; by ADAM17

Amino acid modifications

Modified residue21Phosphoserine; by CK1 Probable
Lipidation191N6-myristoyl lysine Ref.21
Lipidation201N6-myristoyl lysine Ref.21
Glycosylation801O-linked (GalNAc...); in soluble form Ref.15
Disulfide bond145 ↔ 177

Natural variations

Natural variant841P → L. Ref.13
Corresponds to variant rs4645843 [ dbSNP | Ensembl ].
VAR_019378
Natural variant941A → T.
Corresponds to variant rs1800620 [ dbSNP | Ensembl ].
VAR_011927

Experimental info

Mutagenesis1051L → S: Low activity.
Mutagenesis1081R → W: Biologically inactive.
Mutagenesis1121L → F: Biologically inactive.
Mutagenesis1601A → V: Biologically inactive.
Mutagenesis1621S → F: Biologically inactive.
Mutagenesis1671V → A or D: Biologically inactive.
Mutagenesis2221E → K: Biologically inactive.
Sequence conflict631F → S in AAA61198. Ref.5
Sequence conflict84 – 863PSD → VNR in AAF71992. Ref.17
Sequence conflict1831E → R in AAC03542. Ref.16

Secondary structure

...................................... 233
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P01375 [UniParc].

Last modified July 21, 1986. Version 1.
Checksum: 3DF90F96C9031FFE

FASTA23325,644
        10         20         30         40         50         60 
MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL LHFGVIGPQR 

        70         80         90        100        110        120 
EEFPRDLSLI SPLAQAVRSS SRTPSDKPVA HVVANPQAEG QLQWLNRRAN ALLANGVELR 

       130        140        150        160        170        180 
DNQLVVPSEG LYLIYSQVLF KGQGCPSTHV LLTHTISRIA VSYQTKVNLL SAIKSPCQRE 

       190        200        210        220        230 
TPEGAEAKPW YEPIYLGGVF QLEKGDRLSA EINRPDYLDF AESGQVYFGI IAL 

« Hide

References

« Hide 'large scale' references
[1]"Tandem arrangement of genes coding for tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) in the human genome."
Nedospasov S.A., Shakhov A.N., Turetskaya R.L., Mett V.A., Azizov M.M., Georgiev G.P., Korobko V.G., Dobrynin V.N., Filippov S.A., Bystrov N.S., Boldyreva E.F., Chuvpilo S.A., Chumakov A.M., Shingarova L.N., Ovchinnikov Y.A.
Cold Spring Harb. Symp. Quant. Biol. 51:611-624(1986) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]"Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin."
Pennica D., Nedwin G.E., Hayflick J.S., Seeburg P.H., Derynck R., Palladino M.A., Kohr W.J., Aggarwal B.B., Goeddel D.V.
Nature 312:724-729(1984) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[3]"Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor."
Shirai T., Yamaguchi H., Ito H., Todd C.W., Wallace R.B.
Nature 313:803-806(1985) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[4]"Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization."
Nedwin G.E., Naylor S.L., Sakaguchi A.Y., Smith D.H., Jarrett-Nedwin J., Pennica D., Goeddel D.V., Gray P.W.
Nucleic Acids Res. 13:6361-6373(1985) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[5]"Molecular cloning of the complementary DNA for human tumor necrosis factor."
Wang A.M., Creasey A.A., Ladner M.B., Lin L.S., Strickler J., van Arsdell J.N., Yamamoto R., Mark D.F.
Science 228:149-154(1985) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]"Molecular cloning and expression of human tumor necrosis factor and comparison with mouse tumor necrosis factor."
Marmenout A., Fransen L., Tavernier J., van der Heyden J., Tizard R., Kawashima E., Shaw A., Johnson M.J., Semon D., Mueller R., Ruysschaert M.-R., van Vliet A., Fiers W.
Eur. J. Biochem. 152:515-522(1985) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]"Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment."
Iris F.J.M., Bougueleret L., Prieur S., Caterina D., Primas G., Perrot V., Jurka J., Rodriguez-Tome P., Claverie J.-M., Dausset J., Cohen D.
Nat. Genet. 3:137-145(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[8]"A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC."
Neville M.J., Campbell R.D.
J. Immunol. 162:4745-4754(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[9]"Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse."
Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., Campbell R.D., Hood L.
Genome Res. 13:2621-2636(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]"Homo sapiens 2,229,817bp genomic DNA of 6p21.3 HLA class I region."
Shiina S., Tamiya G., Oka A., Inoko H.
Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[11]"Genome diversity in HLA: a new strategy for detection of genetic polymorphisms in expressed genes within the HLA class III and class I regions."
Shiina T., Ota M., Katsuyama Y., Hashimoto N., Inoko H.
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[12]SeattleSNPs variation discovery resource
Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[13]NIEHS SNPs program
Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LEU-84.
[14]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Blood.
[15]"O-glycosylated species of natural human tumor-necrosis factor-alpha."
Takakura-Yamamoto R., Yamamoto S., Fukuda S., Kurimoto M.
Eur. J. Biochem. 235:431-437(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 77-99, GLYCOSYLATION AT SER-80.
[16]Jang J.S., Kim B.E.
Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 77-233.
[17]Shao C., Yan W., Zhu F., Yue W., Chai Y., Zhao Z., Wang C.
Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 84-214.
Tissue: Prostatic carcinoma.
[18]"Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in transfected HeLa cells."
Pocsik E., Duda E., Wallach D.
J. Inflamm. 45:152-160(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION (MEMBRANE FORM).
[19]"A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in 'reverse signalling'."
Watts A.D., Hunt N.H., Wanigasekara Y., Bloomfield G., Wallach D., Roufogalis B.D., Chaudhri G.
EMBO J. 18:2119-2126(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY CK1, DEPHOSPHORYLATION.
[20]"Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis."
Ostade X.V., Tavernier J., Prange T., Fiers W.
EMBO J. 10:827-836(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS.
[21]"Myristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues."
Stevenson F.T., Bursten S.L., Locksley R.M., Lovett D.H.
J. Exp. Med. 176:1053-1062(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: MYRISTOYLATION AT LYS-19 AND LYS-20.
[22]"Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha."
Moss M.L., Jin S.-L.C., Milla M.E., Burkhart W., Carter H.L., Chen W.-J., Clay W.C., Didsbury J.R., Hassler D., Hoffman C.R., Kost T.A., Lambert M.H., Leesnitzer M.A., McCauley P., McGeehan G., Mitchell J., Moyer M., Pahel G. expand/collapse author list , Rocque W., Overton L.K., Schoenen F., Seaton T., Su J.-L., Warner J., Willard D., Becherer J.D.
Nature 385:733-736(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: CLEAVAGE BY ADAM17.
[23]"A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria."
Knight J.C., Udalova I., Hill A.V., Greenwood B.M., Peshu N., Marsh K., Kwiatkowski D.
Nat. Genet. 22:145-150(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: POLYMORPHISM, INVOLVEMENT IN SUSCEPTIBILITY TO MALARIA.
[24]"SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production."
Friedmann E., Hauben E., Maylandt K., Schleeger S., Vreugde S., Lichtenthaler S.F., Kuhn P.H., Stauffer D., Rovelli G., Martoglio B.
Nat. Cell Biol. 8:843-848(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION OF TNF INTRACELLULAR DOMAIN, CLEAVAGE BY SPPL2A AND SPPL2B, SUBCELLULAR LOCATION.
[25]"A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b."
Fluhrer R., Grammer G., Israel L., Condron M.M., Haffner C., Friedmann E., Bohland C., Imhof A., Martoglio B., Teplow D.B., Haass C.
Nat. Cell Biol. 8:894-896(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: CLEAVAGE BY SPPL2A AND SPPL2B, CLEAVAGE SITE, INTERACTION WITH SPPL2B, IDENTIFICATION BY MASS SPECTROMETRY.
[26]"Structure of tumour necrosis factor."
Jones E.Y., Stuart D.I., Walker N.P.
Nature 338:225-228(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
[27]"The structure of tumour necrosis factor -- implications for biological function."
Jones E.Y., Stuart D.I., Walker N.P.
J. Cell Sci. Suppl. 13:11-18(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
[28]"The structure of tumor necrosis factor-alpha at 2.6-A resolution. Implications for receptor binding."
Eck M.J., Sprang S.R.
J. Biol. Chem. 264:17595-17605(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
[29]"Crystal structure of TNF-alpha mutant R31D with greater affinity for receptor R1 compared with R2."
Reed C., Fu Z.Q., Wu J., Xue Y.N., Harrison R.W., Chen M.J., Weber I.T.
Protein Eng. 10:1101-1107(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF MUTANT ARG-107.
[30]"High resolution crystal structure of a human tumor necrosis factor-alpha mutant with low systemic toxicity."
Cha S.S., Kim J.S., Cho H.S., Shin N.K., Jeong W., Shin H.C., Kim Y.J., Hahn J.H., Oh B.H.
J. Biol. Chem. 273:2153-2160(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF MUTANT SER-3.
[31]"Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity."
Balding J., Kane D., Livingstone W., Mynett-Johnson L., Bresnihan B., Smith O., FitzGerald O.
Arthritis Rheum. 48:1408-1413(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN PSORIATIC ARTHRITIS SUSCEPTIBILITY.
[32]"Association of TNF-alpha promoter polymorphisms with the clearance of hepatitis B virus infection."
Kim Y.J., Lee H.-S., Yoon J.-H., Kim C.Y., Park M.H., Kim L.H., Park B.L., Shin H.D.
Hum. Mol. Genet. 12:2541-2546(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO HBV INFECTION.
+Additional computationally mapped references.

Web resources

Wikipedia

Tumor necrosis factor alpha entry

Atlas of Genetics and Cytogenetics in Oncology and Haematology
NIEHS-SNPs
SeattleSNPs
SHMPD

The Singapore human mutation and polymorphism database

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M16441 Genomic DNA. Translation: AAA61200.1.
X02910 Genomic DNA. Translation: CAA26669.1.
X01394 mRNA. Translation: CAA25650.1.
M10988 mRNA. Translation: AAA61198.1.
M26331 Genomic DNA. Translation: AAA36758.1.
Z15026 Genomic DNA. Translation: CAA78745.1.
Y14768 Genomic DNA. Translation: CAA75070.1. Sequence problems.
AF129756 Genomic DNA. Translation: AAD18091.1.
BA000025 Genomic DNA. Translation: BAB63396.1.
AB088112 Genomic DNA. Translation: BAC54944.1.
AY066019 Genomic DNA. Translation: AAL47581.1.
AY214167 Genomic DNA. Translation: AAO21132.1.
BC028148 mRNA. Translation: AAH28148.1.
AF043342 mRNA. Translation: AAC03542.1.
AF098751 mRNA. Translation: AAF71992.1. Frameshift.
PIRQWHUN. A93585.
RefSeqNP_000585.2. NM_000594.3.
UniGeneHs.241570.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1A8MX-ray2.30A/B/C77-233[»]
1TNFX-ray2.60A/B/C77-233[»]
2AZ5X-ray2.10A/B/C/D86-233[»]
2E7AX-ray1.80A/B/C77-233[»]
2TUNX-ray3.10A/B/C/D/E/F77-233[»]
2ZJCX-ray2.50A/B/C77-233[»]
2ZPXX-ray2.83A/B/C77-233[»]
3ALQX-ray3.00A/B/C/D/E/F77-233[»]
3IT8X-ray2.80A/B/C/G/H/I82-233[»]
3L9JX-ray2.10T85-233[»]
3WD5X-ray3.10A77-233[»]
4G3YX-ray2.60C77-233[»]
4TSVX-ray1.80A84-233[»]
5TSWX-ray2.50A/B/C/D/E/F84-233[»]
ProteinModelPortalP01375.
SMRP01375. Positions 85-233.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112979. 44 interactions.
DIPDIP-2895N.
IntActP01375. 30 interactions.
MINTMINT-1131842.
STRING9606.ENSP00000392858.

Chemistry

BindingDBP01375.
ChEMBLCHEMBL1825.
DrugBankDB00051. Adalimumab.
DB00640. Adenosine.
DB01427. Amrinone.
DB01076. Atorvastatin.
DB00608. Chloroquine.
DB01407. Clenbuterol.
DB00005. Etanercept.
DB01296. Glucosamine.
DB00065. Infliximab.
DB00704. Naltrexone.
DB01411. Pranlukast.
DB01366. Procaterol.
DB01232. Saquinavir.
DB00641. Simvastatin.
DB01041. Thalidomide.
GuidetoPHARMACOLOGY2635.

PTM databases

PhosphoSiteP01375.
UniCarbKBP01375.

Polymorphism databases

DMDM135934.

Proteomic databases

PaxDbP01375.
PRIDEP01375.

Protocols and materials databases

DNASU7124.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000376122; ENSP00000365290; ENSG00000204490.
ENST00000383496; ENSP00000372988; ENSG00000206439.
ENST00000412275; ENSP00000392858; ENSG00000228321.
ENST00000420425; ENSP00000410668; ENSG00000228849.
ENST00000443707; ENSP00000389492; ENSG00000230108.
ENST00000448781; ENSP00000389490; ENSG00000223952.
ENST00000449264; ENSP00000398698; ENSG00000232810.
GeneID7124.
KEGGhsa:7124.
UCSCuc003nui.4. human.

Organism-specific databases

CTD7124.
GeneCardsGC06P031543.
GC06Pj31530.
GC06Pk31525.
GC06Pl31582.
GC06Pm31619.
GC06Pn31533.
GC06Po31533.
H-InvDBHIX0165948.
HGNCHGNC:11892. TNF.
MIM191160. gene.
607507. phenotype.
610424. phenotype.
611162. phenotype.
neXtProtNX_P01375.
Orphanet40050. Adult psoriatic arthritis.
PharmGKBPA435.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG40413.
HOGENOMHOG000048729.
HOVERGENHBG012516.
InParanoidP01375.
KOK03156.
OMAPWYEPIY.
OrthoDBEOG7V4B0Q.
PhylomeDBP01375.
TreeFamTF332169.

Enzyme and pathway databases

ReactomeREACT_578. Apoptosis.

Gene expression databases

ArrayExpressP01375.
BgeeP01375.
CleanExHS_TNF.
GenevestigatorP01375.

Family and domain databases

Gene3D2.60.120.40. 1 hit.
InterProIPR006053. TNF.
IPR002959. TNF_alpha.
IPR021184. TNF_CS.
IPR006052. TNF_dom.
IPR008064. TNFalpha/TNFSF15.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]
PANTHERPTHR11471:SF7. PTHR11471:SF7. 1 hit.
PfamPF00229. TNF. 1 hit.
[Graphical view]
PRINTSPR01234. TNECROSISFCT.
PR01235. TNFALPHA.
SMARTSM00207. TNF. 1 hit.
[Graphical view]
SUPFAMSSF49842. SSF49842. 1 hit.
PROSITEPS00251. TNF_1. 1 hit.
PS50049. TNF_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSTNF. human.
EvolutionaryTraceP01375.
GeneWikiTumor_necrosis_factor-alpha.
GenomeRNAi7124.
NextBio27879.
PMAP-CutDBP01375.
PROP01375.
SOURCESearch...

Entry information

Entry nameTNFA_HUMAN
AccessionPrimary (citable) accession number: P01375
Secondary accession number(s): O43647, Q9P1Q2, Q9UIV3
Entry history
Integrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: July 21, 1986
Last modified: April 16, 2014
This is version 192 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 6

Human chromosome 6: entries, gene names and cross-references to MIM