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Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]

 TNFA_PANTR              Reviewed;         232 AA.
Q8HZD9; Q1XHZ6;
23-MAY-2003, integrated into UniProtKB/Swiss-Prot.
23-MAY-2003, sequence version 2.
16-JAN-2019, entry version 125.
RecName: Full=Tumor necrosis factor;
AltName: Full=Cachectin;
AltName: Full=TNF-alpha;
AltName: Full=Tumor necrosis factor ligand superfamily member 2;
Short=TNF-a;
Contains:
RecName: Full=Tumor necrosis factor, membrane form;
AltName: Full=N-terminal fragment;
Short=NTF;
Contains:
RecName: Full=Intracellular domain 1;
Short=ICD1;
Contains:
RecName: Full=Intracellular domain 2;
Short=ICD2;
Contains:
RecName: Full=C-domain 1;
Contains:
RecName: Full=C-domain 2;
Contains:
RecName: Full=Tumor necrosis factor, soluble form;
Flags: Precursor;
Name=TNF; Synonyms=TNFA, TNFSF2;
Pan troglodytes (Chimpanzee).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Pan.
NCBI_TaxID=9598;
[1]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
PubMed=12493009; DOI=10.1034/j.1600-065X.2002.19008.x;
Kulski J.K., Shiina T., Anzai T., Kohara S., Inoko H.;
"Comparative genomic analysis of the MHC: the evolution of class I
duplication blocks, diversity and complexity from shark to man.";
Immunol. Rev. 190:95-122(2002).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=12799463; DOI=10.1073/pnas.1230533100;
Anzai T., Shiina T., Kimura N., Yanagiya K., Kohara S., Shigenari A.,
Yamagata T., Kulski J.K., Naruse T.K., Fujimori Y., Fukuzumi Y.,
Yamazaki M., Tashiro H., Iwamoto C., Umehara Y., Imanishi T.,
Meyer A., Ikeo K., Gojobori T., Bahram S., Inoko H.;
"Comparative sequencing of human and chimpanzee MHC class I regions
unveils insertions/deletions as the major path to genomic
divergence.";
Proc. Natl. Acad. Sci. U.S.A. 100:7708-7713(2003).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=16702430; DOI=10.1534/genetics.106.057034;
Shiina T., Ota M., Shimizu S., Katsuyama Y., Hashimoto N., Takasu M.,
Anzai T., Kulski J.K., Kikkawa E., Naruse T., Kimura N., Yanagiya K.,
Watanabe A., Hosomichi K., Kohara S., Iwamoto C., Umehara Y.,
Meyer A., Wanner V., Sano K., Macquin C., Ikeo K., Tokunaga K.,
Gojobori T., Inoko H., Bahram S.;
"Rapid evolution of major histocompatibility complex class I genes in
primates generates new disease alleles in humans via hitchhiking
diversity.";
Genetics 173:1555-1570(2006).
[4]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 33-186.
O'Huigin C., Tichy H., Klein J.;
"Molecular evolution in higher primates; gene specific and organism
specific characteristics.";
Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
-!- 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 (By similarity).
Induces insulin resistance in adipocytes via inhibition of
insulin-induced IRS1 tyrosine phosphorylation and insulin-induced
glucose uptake. Induces GKAP42 protein degradation in adipocytes
which is partially responsible for TNF-induced insulin resistance
(By similarity). {ECO:0000250|UniProtKB:P01375,
ECO:0000250|UniProtKB:P06804}.
-!- FUNCTION: The TNF intracellular domain (ICD) form induces IL12
production in dendritic cells. {ECO:0000250|UniProtKB:P01375}.
-!- SUBUNIT: Homotrimer. Interacts with SPPL2B (By similarity).
{ECO:0000250}.
-!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass
type II membrane protein {ECO:0000250}.
-!- SUBCELLULAR LOCATION: Tumor necrosis factor, membrane form:
Membrane {ECO:0000250}; Single-pass type II membrane protein
{ECO:0000250}.
-!- SUBCELLULAR LOCATION: Tumor necrosis factor, soluble form:
Secreted {ECO:0000250}.
-!- SUBCELLULAR LOCATION: C-domain 1: Secreted {ECO:0000250}.
-!- SUBCELLULAR LOCATION: C-domain 2: Secreted {ECO:0000250}.
-!- PTM: 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 (By similarity).
{ECO:0000250}.
-!- PTM: 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 (By
similarity). {ECO:0000250}.
-!- PTM: O-glycosylated; glycans contain galactose, N-
acetylgalactosamine and N-acetylneuraminic acid. {ECO:0000250}.
-!- SIMILARITY: Belongs to the tumor necrosis factor family.
{ECO:0000305}.
-----------------------------------------------------------------------
Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
Distributed under the Creative Commons Attribution (CC BY 4.0) License
-----------------------------------------------------------------------
EMBL; AB054536; BAB83882.1; -; Genomic_DNA.
EMBL; BA000041; BAC78157.1; -; Genomic_DNA.
EMBL; AB210165; BAE92772.1; -; Genomic_DNA.
EMBL; AB210166; BAE92774.1; -; Genomic_DNA.
EMBL; AY091964; AAM76582.1; -; Genomic_DNA.
RefSeq; NP_001038976.1; NM_001045511.1.
RefSeq; XP_016810226.1; XM_016954737.1.
UniGene; Ptr.6340; -.
ProteinModelPortal; Q8HZD9; -.
SMR; Q8HZD9; -.
STRING; 9598.ENSPTRP00000054518; -.
PaxDb; Q8HZD9; -.
GeneID; 494186; -.
KEGG; ptr:494186; -.
CTD; 7124; -.
eggNOG; ENOG410ISAN; Eukaryota.
eggNOG; ENOG410YQC4; LUCA.
HOGENOM; HOG000048729; -.
HOVERGEN; HBG012516; -.
InParanoid; Q8HZD9; -.
KO; K03156; -.
OrthoDB; 1124938at2759; -.
TreeFam; TF332169; -.
Proteomes; UP000002277; Unplaced.
Bgee; ENSPTRG00000017965; Expressed in 4 organ(s), highest expression level in liver.
GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:InterPro.
GO; GO:0006955; P:immune response; IEA:InterPro.
GO; GO:0097527; P:necroptotic signaling pathway; ISS:UniProtKB.
GO; GO:0043242; P:negative regulation of protein complex disassembly; ISS:UniProtKB.
GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
GO; GO:0043507; P:positive regulation of JUN kinase activity; ISS:UniProtKB.
GO; GO:0043406; P:positive regulation of MAP kinase activity; ISS:UniProtKB.
GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
GO; GO:0043243; P:positive regulation of protein complex disassembly; ISS:UniProtKB.
GO; GO:0001934; P:positive regulation of protein phosphorylation; ISS:UniProtKB.
CDD; cd00184; TNF; 1.
Gene3D; 2.60.120.40; -; 1.
InterPro; IPR006053; TNF.
InterPro; IPR002959; TNF_alpha.
InterPro; IPR021184; TNF_CS.
InterPro; IPR006052; TNF_dom.
InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
PANTHER; PTHR11471:SF23; PTHR11471:SF23; 1.
Pfam; PF00229; TNF; 1.
PRINTS; PR01234; TNECROSISFCT.
PRINTS; PR01235; TNFALPHA.
SMART; SM00207; TNF; 1.
SUPFAM; SSF49842; SSF49842; 1.
PROSITE; PS00251; TNF_1; 1.
PROSITE; PS50049; TNF_2; 1.
3: Inferred from homology;
Cell membrane; Complete proteome; Cytokine; Disulfide bond;
Glycoprotein; Lipoprotein; Membrane; Myristate; Phosphoprotein;
Reference proteome; Secreted; Signal-anchor; Transmembrane;
Transmembrane helix.
CHAIN 1 232 Tumor necrosis factor, membrane form.
/FTId=PRO_0000034437.
CHAIN 1 39 Intracellular domain 1. {ECO:0000250}.
/FTId=PRO_0000417259.
CHAIN 1 35 Intracellular domain 2. {ECO:0000250}.
/FTId=PRO_0000417260.
CHAIN 50 ? C-domain 1. {ECO:0000250}.
/FTId=PRO_0000417261.
CHAIN 52 ? C-domain 2. {ECO:0000250}.
/FTId=PRO_0000417262.
CHAIN 77 232 Tumor necrosis factor, soluble form.
{ECO:0000250}.
/FTId=PRO_0000034438.
TOPO_DOM 1 34 Cytoplasmic. {ECO:0000255}.
TRANSMEM 35 57 Helical; Signal-anchor for type II
membrane protein. {ECO:0000250}.
TOPO_DOM 58 232 Extracellular. {ECO:0000255}.
SITE 34 35 Cleavage; by SPPL2A or SPPL2B.
{ECO:0000250}.
SITE 39 40 Cleavage; by SPPL2A or SPPL2B.
{ECO:0000250}.
SITE 49 50 Cleavage; by SPPL2A or SPPL2B.
{ECO:0000250}.
SITE 51 52 Cleavage; by SPPL2A or SPPL2B.
{ECO:0000250}.
SITE 76 77 Cleavage; by ADAM17. {ECO:0000250}.
MOD_RES 2 2 Phosphoserine; by CK1. {ECO:0000250}.
LIPID 19 19 N6-myristoyl lysine. {ECO:0000250}.
LIPID 20 20 N6-myristoyl lysine. {ECO:0000250}.
CARBOHYD 79 79 O-linked (GalNAc...) serine; in soluble
form. {ECO:0000250}.
DISULFID 144 176 {ECO:0000250}.
CONFLICT 77 77 G -> VR (in Ref. 3 and 4). {ECO:0000305}.
SEQUENCE 232 AA; 25446 MW; E4D71B19C6AE0D03 CRC64;
MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL LHFGVIGPQR
EEFPRDLSLI SPLAQAGSSS RTPSDKPVAH VVANPQAEGQ LQWLNRRANA LLANGVELRD
NQLVVPSEGL YLIYSQVLFK GQGCPSTHVL LTHTISRIAV SYQTKVNLLS AIKSPCQRET
PEGAEAKPWY EPIYLGGVFQ LEKGDRLSAE INRPDYLDFA ESGQVYFGII AL


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Pathways :
WP1689: Porphyrin and chlorophyll metabolism
WP1046: Signaling of Hepatocyte Growth Factor Receptor
WP1162: Signaling of Hepatocyte Growth Factor Receptor
WP1206: Signaling of Hepatocyte Growth Factor Receptor
WP1235: Signaling of Hepatocyte Growth Factor Receptor
WP1789: Binding of RNA by Insulin-like Growth Factor-2 mRNA Binding Proteins (IGF2BPs/IMPs/VICKZs)
WP1899: Regulation of Insulin-like Growth Factor (IGF) Activity by Insulin-like Growth Factor Binding Proteins (IGFBPs)
WP193: Signaling of Hepatocyte Growth Factor Receptor
WP1983: Splicing factor NOVA regulated synpatic proteins
WP2148: Brain derived neurotrophic factor
WP2249: Metastatic brain tumor
WP272: Blood Clotting Cascade
WP313: Signaling of Hepatocyte Growth Factor Receptor
WP444: Signaling of Hepatocyte Growth Factor Receptor
WP810: Signaling of Hepatocyte Growth Factor Receptor
WP927: Signaling of Hepatocyte Growth Factor Receptor
WP94: Signaling of Hepatocyte Growth Factor Receptor
WP1566: Citrate cycle (TCA cycle)
WP32: Translation Factors
WP537: Translation Factors
WP107: Translation Factors
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[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form] (Fragment)
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]
[TNF TNFA TNFSF2] Tumor necrosis factor (Cachectin) (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) [Cleaved into: Tumor necrosis factor, membrane form (N-terminal fragment) (NTF); Intracellular domain 1 (ICD1); Intracellular domain 2 (ICD2); C-domain 1; C-domain 2; Tumor necrosis factor, soluble form]

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