ID A9LMQ0_CANLF Unreviewed; 233 AA. AC A9LMQ0; DT 05-FEB-2008, integrated into UniProtKB/TrEMBL. DT 05-FEB-2008, sequence version 1. DT 27-MAR-2024, entry version 112. DE RecName: Full=Tumor necrosis factor {ECO:0000256|RuleBase:RU368112}; DE Short=TNF-a {ECO:0000256|RuleBase:RU368112}; DE AltName: Full=Cachectin {ECO:0000256|RuleBase:RU368112}; DE AltName: Full=TNF-alpha {ECO:0000256|RuleBase:RU368112}; DE AltName: Full=Tumor necrosis factor ligand superfamily member 2 {ECO:0000256|RuleBase:RU368112}; DE Contains: DE RecName: Full=Intracellular domain 1 {ECO:0000256|RuleBase:RU368112}; DE Short=ICD1 {ECO:0000256|RuleBase:RU368112}; DE Contains: DE RecName: Full=Intracellular domain 2 {ECO:0000256|RuleBase:RU368112}; DE Short=ICD2 {ECO:0000256|RuleBase:RU368112}; DE Contains: DE RecName: Full=C-domain 1 {ECO:0000256|RuleBase:RU368112}; DE Contains: DE RecName: Full=C-domain 2 {ECO:0000256|RuleBase:RU368112}; DE Contains: DE RecName: Full=Tumor necrosis factor, soluble form {ECO:0000256|RuleBase:RU368112}; GN Name=TNF {ECO:0000313|EMBL:ABX26051.1}; GN Synonyms=TNLG1F {ECO:0000313|EMBL:CTQ86237.1}; OS Canis lupus familiaris (Dog) (Canis familiaris). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis. OX NCBI_TaxID=9615 {ECO:0000313|EMBL:ABX26051.1}; RN [1] {ECO:0000313|EMBL:ABX26051.1} RP NUCLEOTIDE SEQUENCE. RA Rachakonda P.S., Rai M.F., Schmidt M.F.G.; RT "Application of an intelligent cytokine responsive promoter for in vitro RT arthritis model."; RL Submitted (OCT-2007) to the EMBL/GenBank/DDBJ databases. RN [2] {ECO:0000313|EMBL:ABX26051.1} RP NUCLEOTIDE SEQUENCE. RX PubMed=18343681; DOI=10.1016/j.cyto.2008.02.004; RA Rai M.F., Sivaramakrishna Rachakonda P., Manning K., Vorwerk B., RA Brunnberg L., Kohn B., Schmidt M.F.; RT "Quantification of cytokines and inflammatory mediators in a three- RT dimensional model of inflammatory arthritis."; RL Cytokine 42:8-17(2008). RN [3] {ECO:0000313|EMBL:CTQ86237.1} RP NUCLEOTIDE SEQUENCE. RX PubMed=26646413; DOI=10.1007/s00251-015-0887-5; RA Premzl M.; RT "Comparative genomic analysis of eutherian tumor necrosis factor ligand RT genes."; RL Immunogenetics 68:125-132(2016). RN [4] {ECO:0000313|EMBL:CTQ86237.1} RP NUCLEOTIDE SEQUENCE. RX DOI=10.1016/j.genrep.2019.100414; RA Premzl M.; RT "Eutherian third-party data gene collections."; RL Gene Rep 16:100414-100414(2019). 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. 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. Plays a role in angiogenesis by CC inducing VEGF production synergistically with IL1B and IL6. CC {ECO:0000256|RuleBase:RU368112}. CC -!- FUNCTION: The TNF intracellular domain (ICD) form induces IL12 CC production in dendritic cells. {ECO:0000256|ARBA:ARBA00003559, CC ECO:0000256|RuleBase:RU368112}. CC -!- SUBUNIT: Homotrimer. Interacts with SPPL2B. CC {ECO:0000256|ARBA:ARBA00025967, ECO:0000256|RuleBase:RU368112}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000256|ARBA:ARBA00004401, CC ECO:0000256|RuleBase:RU368112}; Single-pass type II membrane protein CC {ECO:0000256|ARBA:ARBA00004401, ECO:0000256|RuleBase:RU368112}. CC -!- SUBCELLULAR LOCATION: [C-domain 2]: Secreted CC {ECO:0000256|RuleBase:RU368112}. CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, soluble form]: Secreted CC {ECO:0000256|RuleBase:RU368112}. CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, membrane form]: Membrane CC {ECO:0000256|RuleBase:RU368112}; Single-pass type II membrane protein CC {ECO:0000256|RuleBase:RU368112}. CC -!- SUBCELLULAR LOCATION: [C-domain 1]: Secreted CC {ECO:0000256|RuleBase:RU368112}. CC -!- PTM: O-glycosylated; glycans contain galactose, N-acetylgalactosamine CC and N-acetylneuraminic acid. {ECO:0000256|RuleBase:RU368112}. 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:0000256|RuleBase:RU368112}. 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:0000256|RuleBase:RU368112}. CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. CC {ECO:0000256|ARBA:ARBA00008670, ECO:0000256|RuleBase:RU368112}. 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; EU249361; ABX26051.1; -; mRNA. DR EMBL; LN874472; CTQ86237.1; -; mRNA. DR RefSeq; NP_001003244.4; NM_001003244.4. DR AlphaFoldDB; A9LMQ0; -. DR SMR; A9LMQ0; -. DR GeneID; 403922; -. DR KEGG; cfa:403922; -. DR CTD; 7124; -. DR VEuPathDB; HostDB:ENSCAFG00845010558; -. DR HOGENOM; CLU_070352_3_1_1; -. DR OMA; GATMLFC; -. DR OrthoDB; 2909163at2759; -. DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl. DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-UniRule. DR GO; GO:0045121; C:membrane raft; IEA:Ensembl. DR GO; GO:0001891; C:phagocytic cup; IEA:Ensembl. DR GO; GO:0055037; C:recycling endosome; IEA:Ensembl. DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-UniRule. DR GO; GO:0038177; F:death receptor agonist activity; IEA:Ensembl. DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl. DR GO; GO:0002020; F:protease binding; IEA:Ensembl. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IEA:Ensembl. DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:UniProtKB-UniRule. DR GO; GO:0140374; P:antiviral innate immune response; IEA:Ensembl. DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl. DR GO; GO:0071316; P:cellular response to nicotine; 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; IEA:Ensembl. DR GO; GO:0030866; P:cortical actin cytoskeleton organization; IEA:Ensembl. DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl. DR GO; GO:0048566; P:embryonic digestive tract development; IEA:Ensembl. 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:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl. DR GO; GO:0006006; P:glucose metabolic process; IEA:Ensembl. DR GO; GO:0006959; P:humoral immune response; IEA:Ensembl. DR GO; GO:0090594; P:inflammatory response to wounding; IEA:Ensembl. DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IEA:Ensembl. DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl. DR GO; GO:0050901; P:leukocyte tethering or rolling; IEA:Ensembl. DR GO; GO:0002281; P:macrophage activation involved in immune response; IEA:Ensembl. DR GO; GO:0001774; P:microglial cell activation; IEA:Ensembl. DR GO; GO:0097527; P:necroptotic signaling pathway; IEA:UniProtKB-UniRule. DR GO; GO:1900222; P:negative regulation of amyloid-beta clearance; IEA:Ensembl. DR GO; GO:1903347; P:negative regulation of bicellular tight junction assembly; IEA:Ensembl. DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IEA:Ensembl. DR GO; GO:0061048; P:negative regulation of branching involved in lung morphogenesis; IEA:Ensembl. DR GO; GO:0002719; P:negative regulation of cytokine production involved in immune response; IEA:Ensembl. 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; IEA:Ensembl. DR GO; GO:0046325; P:negative regulation of glucose import; IEA:Ensembl. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl. DR GO; GO:0050995; P:negative regulation of lipid catabolic process; IEA:Ensembl. DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IEA:Ensembl. DR GO; GO:0045662; P:negative regulation of myoblast differentiation; IEA:Ensembl. DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Ensembl. DR GO; GO:0043242; P:negative regulation of protein-containing complex disassembly; IEA:Ensembl. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0061044; P:negative regulation of vascular wound healing; IEA:Ensembl. DR GO; GO:0045071; P:negative regulation of viral genome replication; IEA:Ensembl. 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:1902004; P:positive regulation of amyloid-beta formation; IEA:Ensembl. DR GO; GO:2000334; P:positive regulation of blood microparticle formation; IEA:Ensembl. DR GO; GO:0070886; P:positive regulation of calcineurin-NFAT signaling cascade; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IEA:Ensembl. DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IEA:Ensembl. DR GO; GO:0002876; P:positive regulation of chronic inflammatory response to antigenic stimulus; IEA:Ensembl. DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IEA:Ensembl. DR GO; GO:0031622; P:positive regulation of fever generation; IEA:Ensembl. DR GO; GO:0060252; P:positive regulation of glial cell proliferation; IEA:Ensembl. DR GO; GO:0051798; P:positive regulation of hair follicle development; IEA:Ensembl. DR GO; GO:0034116; P:positive regulation of heterotypic cell-cell adhesion; IEA:Ensembl. 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; IEA:Ensembl. DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Ensembl. DR GO; GO:0150129; P:positive regulation of interleukin-33 production; IEA:Ensembl. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IEA:Ensembl. DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl. DR GO; GO:1904999; P:positive regulation of leukocyte adhesion to arterial endothelial cell; IEA:Ensembl. DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IEA:Ensembl. DR GO; GO:1902895; P:positive regulation of miRNA transcription; IEA:Ensembl. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IEA:Ensembl. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IEA:Ensembl. DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IEA:Ensembl. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IEA:Ensembl. DR GO; GO:0071803; P:positive regulation of podosome assembly; IEA:Ensembl. DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IEA:Ensembl. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IEA:Ensembl. DR GO; GO:0051222; P:positive regulation of protein transport; IEA:Ensembl. DR GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; IEA:Ensembl. DR GO; GO:0050806; P:positive regulation of synaptic transmission; IEA:Ensembl. DR GO; GO:1901647; P:positive regulation of synoviocyte proliferation; IEA:Ensembl. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl. 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: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; IEA:Ensembl. DR GO; GO:0072659; P:protein localization to plasma membrane; IEA:Ensembl. DR GO; GO:0060693; P:regulation of branching involved in salivary gland morphogenesis; IEA:Ensembl. DR GO; GO:2000351; P:regulation of endothelial cell apoptotic process; IEA:Ensembl. DR GO; GO:1903140; P:regulation of establishment of endothelial barrier; IEA:Ensembl. DR GO; GO:0002637; P:regulation of immunoglobulin production; IEA:Ensembl. DR GO; GO:0050796; P:regulation of insulin secretion; IEA:Ensembl. 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; IEA:Ensembl. DR GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl. DR GO; GO:0030730; P:sequestering of triglyceride; IEA:Ensembl. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IEA:Ensembl. DR GO; GO:0010573; P:vascular endothelial growth factor production; IEA:UniProtKB-UniRule. 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. PE 2: Evidence at transcript level; KW Cell membrane {ECO:0000256|ARBA:ARBA00022475, KW ECO:0000256|RuleBase:RU368112}; KW Cytokine {ECO:0000256|ARBA:ARBA00022514, ECO:0000256|RuleBase:RU368112}; KW Disulfide bond {ECO:0000256|ARBA:ARBA00023157, KW ECO:0000256|RuleBase:RU368112}; KW Lipoprotein {ECO:0000256|ARBA:ARBA00023288, ECO:0000256|RuleBase:RU368112}; KW Membrane {ECO:0000256|ARBA:ARBA00023136, ECO:0000256|RuleBase:RU368112}; KW Myristate {ECO:0000256|ARBA:ARBA00022707, ECO:0000256|RuleBase:RU368112}; KW Phosphoprotein {ECO:0000256|RuleBase:RU368112}; KW Secreted {ECO:0000256|ARBA:ARBA00022525, ECO:0000256|RuleBase:RU368112}; KW Signal-anchor {ECO:0000256|ARBA:ARBA00022968, KW ECO:0000256|RuleBase:RU368112}; KW Transmembrane {ECO:0000256|ARBA:ARBA00022692, KW ECO:0000256|RuleBase:RU368112}; KW Transmembrane helix {ECO:0000256|ARBA:ARBA00022989, KW ECO:0000256|RuleBase:RU368112}. FT TRANSMEM 30..55 FT /note="Helical" FT /evidence="ECO:0000256|RuleBase:RU368112" FT DOMAIN 89..233 FT /note="TNF family profile" FT /evidence="ECO:0000259|PROSITE:PS50049" FT REGION 1..25 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" SQ SEQUENCE 233 AA; 25447 MW; 7B2588FBC8B25340 CRC64; MSTESMIRDV ELAEEPLPKK AGGPPGSRRC FCLSLFSFLL VAGATTLFCL LHFGVIGPQR EELPNGLQLI SPLAQTVKSS SRTPSDKPVA HVVANPEAEG QLQWLSRRAN ALLANGVELT DNQLIVPSDG LYLIYSQVLF KGQGCPSTHV LLTHTISRFA VSYQTKVNLL SAIKSPCQRE TPEGTEAKPW YEPIYLGGVF QLEKGDRLSA EINLPNYLDF AESGQVYFGI IAL //