TNF12_HUMAN
ID TNF12_HUMAN Reviewed; 249 AA.
AC O43508; Q8IZK7; Q8WUZ7;
DT 06-JUN-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 187.
DE RecName: Full=Tumor necrosis factor ligand superfamily member 12;
DE AltName: Full=APO3 ligand;
DE AltName: Full=TNF-related weak inducer of apoptosis;
DE Short=TWEAK;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 12, membrane form;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 12, secreted form;
GN Name=TNFSF12; Synonyms=APO3L, DR3LG; ORFNames=UNQ181/PRO207;
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 [MRNA] (ISOFORM 1), AND N-TERMINUS OF SOLUBLE FORM.
RC TISSUE=Fetal liver, and Tonsil;
RX PubMed=9405449; DOI=10.1074/jbc.272.51.32401;
RA Chicheportiche Y., Bourdon P.R., Xu H., Hsu Y.-M., Scott H., Hession C.,
RA Garcia I., Browning J.L.;
RT "TWEAK, a new secreted ligand in the tumor necrosis factor family that
RT weakly induces apoptosis.";
RL J. Biol. Chem. 272:32401-32410(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Fetal kidney;
RX PubMed=9560343; DOI=10.1016/s0960-9822(98)70204-0;
RA Marsters S.A., Sheridan J.P., Pitti R.M., Brush J., Goddard A.,
RA Ashkenazi A.;
RT "Identification of a ligand for the death-domain-containing receptor
RT Apo3.";
RL Curr. Biol. 8:525-528(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TWE-PRIL), AND SUBCELLULAR LOCATION.
RX PubMed=12411489; DOI=10.1093/emboj/cdf565;
RA Pradet-Balade B., Medema J.P., Lopez-Fraga M., Lozano J.C.,
RA Kolfschoten G.M., Picard A., Martinez-A C., Garcia-Sanz J.A., Hahne M.;
RT "An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface
RT TWEAK-APRIL fusion protein.";
RL EMBO J. 21:5711-5720(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Tonsil;
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 [7]
RP FUNCTION.
RX PubMed=10085077; DOI=10.1074/jbc.274.13.8455;
RA Lynch C.N., Wang Y.C., Lund J.K., Chen Y.-W., Leal J.A., Wiley S.R.;
RT "TWEAK induces angiogenesis and proliferation of endothelial cells.";
RL J. Biol. Chem. 274:8455-8459(1999).
RN [8]
RP INTERACTION WITH AGGF1/VG5Q.
RX PubMed=14961121; DOI=10.1038/nature02320.;
RA Tian X.-L., Kadaba R., You S.-A., Liu M., Timur A.A., Yang L., Chen Q.,
RA Szafranski P., Rao S., Wu L., Housman D.E., DiCorleto P.E., Driscoll D.J.,
RA Borrow J., Wang Q.;
RT "Identification of an angiogenic factor that when mutated causes
RT susceptibility to Klippel-Trenaunay syndrome.";
RL Nature 427:640-645(2004).
RN [9]
RP REVIEW.
RX PubMed=12787562; DOI=10.1016/s1359-6101(03)00019-4;
RA Wiley S.R., Winkles J.A.;
RT "TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that
RT binds the TweakR/Fn14 receptor.";
RL Cytokine Growth Factor Rev. 14:241-249(2003).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 97-249 IN COMPLEX WITH THE FAB
RP FRAGMENT OF A NEUTRALIZING ANTIBODY, FUNCTION, SUBUNIT, AND DISULFIDE BOND.
RX PubMed=23667509; DOI=10.1371/journal.pone.0062697;
RA Lammens A., Baehner M., Kohnert U., Niewoehner J., von Proff L.,
RA Schraeml M., Lammens K., Hopfner K.P.;
RT "Crystal structure of human TWEAK in complex with the Fab fragment of a
RT neutralizing antibody reveals insights into receptor binding.";
RL PLoS ONE 8:E62697-E62697(2013).
CC -!- FUNCTION: Binds to FN14 and possibly also to TNRFSF12/APO3. Weak
CC inducer of apoptosis in some cell types. Mediates NF-kappa-B
CC activation. Promotes angiogenesis and the proliferation of endothelial
CC cells. Also involved in induction of inflammatory cytokines. Promotes
CC IL8 secretion. {ECO:0000269|PubMed:10085077,
CC ECO:0000269|PubMed:23667509}.
CC -!- SUBUNIT: Homotrimer (Probable). Interacts with the angiogenic factor
CC AGGF1/VG5Q. {ECO:0000269|PubMed:14961121, ECO:0000269|PubMed:23667509,
CC ECO:0000305}.
CC -!- INTERACTION:
CC O43508; P05067: APP; NbExp=3; IntAct=EBI-6932080, EBI-77613;
CC O43508; P06493: CDK1; NbExp=3; IntAct=EBI-6932080, EBI-444308;
CC O43508; P35638: DDIT3; NbExp=3; IntAct=EBI-6932080, EBI-742651;
CC O43508; Q9UPY3: DICER1; NbExp=3; IntAct=EBI-6932080, EBI-395506;
CC O43508; O43765: SGTA; NbExp=3; IntAct=EBI-6932080, EBI-347996;
CC O43508; Q9NP84: TNFRSF12A; NbExp=2; IntAct=EBI-6932080, EBI-2851995;
CC O43508; Q6SIX7: tnfrsf12a.L; Xeno; NbExp=2; IntAct=EBI-6932080, EBI-8445678;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:12411489};
CC Single-pass type II membrane protein {ECO:0000269|PubMed:12411489}.
CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor ligand superfamily member
CC 12, secreted form]: Secreted.
CC -!- SUBCELLULAR LOCATION: [Isoform TWE-PRIL]: Cell membrane; Single-pass
CC membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O43508-1; Sequence=Displayed;
CC Name=TWE-PRIL; Synonyms=TNFSF12-TNFSF13;
CC IsoId=O43508-2; Sequence=VSP_045245;
CC -!- TISSUE SPECIFICITY: Highly expressed in adult heart, pancreas, skeletal
CC muscle, brain, colon, small intestine, lung, ovary, prostate, spleen,
CC lymph node, appendix and peripheral blood lymphocytes. Low expression
CC in kidney, testis, liver, placenta, thymus and bone marrow. Also
CC detected in fetal kidney, liver, lung and brain.
CC -!- PTM: The soluble form derives from the membrane form by proteolytic
CC processing.
CC -!- MISCELLANEOUS: [Isoform TWE-PRIL]: Based on a readthrough transcript
CC which may produce a TWE-PRIL (TNFSF12-TNFSF13) fusion protein.
CC Expressed at protein level in primary T-lymphocytes and monocytic cell
CC lines. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH19047.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF030099; AAC51923.1; -; mRNA.
DR EMBL; AF055872; AAC39724.1; -; mRNA.
DR EMBL; AY081051; AAL90443.1; -; mRNA.
DR EMBL; AY358870; AAQ89229.1; -; mRNA.
DR EMBL; AC016876; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC019047; AAH19047.1; ALT_FRAME; mRNA.
DR CCDS; CCDS11109.1; -. [O43508-1]
DR RefSeq; NP_003800.1; NM_003809.2. [O43508-1]
DR RefSeq; NP_742086.1; NM_172089.3. [O43508-2]
DR PDB; 4HT1; X-ray; 2.50 A; T=97-249.
DR PDBsum; 4HT1; -.
DR AlphaFoldDB; O43508; -.
DR SMR; O43508; -.
DR BioGRID; 114279; 22.
DR BioGRID; 135910; 47.
DR IntAct; O43508; 10.
DR MINT; O43508; -.
DR STRING; 9606.ENSP00000293825; -.
DR ChEMBL; CHEMBL3713023; -.
DR GlyGen; O43508; 2 sites, 1 O-linked glycan (1 site).
DR iPTMnet; O43508; -.
DR PhosphoSitePlus; O43508; -.
DR BioMuta; TNFSF12; -.
DR jPOST; O43508; -.
DR MassIVE; O43508; -.
DR PeptideAtlas; O43508; -.
DR PRIDE; O43508; -.
DR ProteomicsDB; 49000; -. [O43508-1]
DR ProteomicsDB; 71365; -.
DR ABCD; O43508; 1 sequenced antibody.
DR Antibodypedia; 34916; 550 antibodies from 41 providers.
DR DNASU; 407977; -.
DR DNASU; 8742; -.
DR Ensembl; ENST00000293825.11; ENSP00000293825.6; ENSG00000239697.11. [O43508-1]
DR GeneID; 407977; -.
DR GeneID; 8742; -.
DR KEGG; hsa:407977; -.
DR KEGG; hsa:8742; -.
DR MANE-Select; ENST00000293825.11; ENSP00000293825.6; NM_003809.3; NP_003800.1.
DR CTD; 407977; -.
DR CTD; 8742; -.
DR DisGeNET; 407977; -.
DR DisGeNET; 8742; -.
DR GeneCards; TNFSF12; -.
DR HGNC; HGNC:11927; TNFSF12.
DR HPA; ENSG00000239697; Low tissue specificity.
DR MalaCards; TNFSF12; -.
DR MIM; 602695; gene.
DR neXtProt; NX_O43508; -.
DR OpenTargets; ENSG00000239697; -.
DR OpenTargets; ENSG00000248871; -.
DR Orphanet; 1572; Common variable immunodeficiency.
DR PharmGKB; PA162406662; -.
DR PharmGKB; PA36620; -.
DR VEuPathDB; HostDB:ENSG00000239697; -.
DR eggNOG; ENOG502S27R; Eukaryota.
DR GeneTree; ENSGT00940000161488; -.
DR GeneTree; ENSGT00940000163167; -.
DR HOGENOM; CLU_090519_0_0_1; -.
DR InParanoid; O43508; -.
DR OMA; PRCELNP; -.
DR OrthoDB; 702827at2759; -.
DR PhylomeDB; O43508; -.
DR TreeFam; TF332331; -.
DR PathwayCommons; O43508; -.
DR Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway.
DR Reactome; R-HSA-5676594; TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway.
DR SignaLink; O43508; -.
DR BioGRID-ORCS; 407977; 10 hits in 608 CRISPR screens.
DR BioGRID-ORCS; 8742; 11 hits in 686 CRISPR screens.
DR GeneWiki; TNFSF12; -.
DR GeneWiki; TNFSF12-TNFSF13; -.
DR Pharos; O43508; Tbio.
DR PRO; PR:O43508; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; O43508; protein.
DR Bgee; ENSG00000239697; Expressed in right coronary artery and 96 other tissues.
DR ExpressionAtlas; O43508; baseline and differential.
DR Genevisible; O43508; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005125; F:cytokine activity; TAS:UniProtKB.
DR GO; GO:0048018; F:receptor ligand activity; IBA:GO_Central.
DR GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:InterPro.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0043542; P:endothelial cell migration; TAS:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IBA:GO_Central.
DR GO; GO:0006955; P:immune response; IEA:InterPro.
DR GO; GO:0045766; P:positive regulation of angiogenesis; TAS:UniProtKB.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; TAS:UniProtKB.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:MGI.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR CDD; cd00184; TNF; 1.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR006052; TNF_dom.
DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR Pfam; PF00229; TNF; 1.
DR SMART; SM00207; TNF; 1.
DR SUPFAM; SSF49842; SSF49842; 1.
DR PROSITE; PS50049; TNF_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Angiogenesis; Apoptosis; Cell membrane;
KW Cleavage on pair of basic residues; Cytokine; Developmental protein;
KW Differentiation; Disulfide bond; Glycoprotein; Membrane;
KW Reference proteome; Secreted; Signal-anchor; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..249
FT /note="Tumor necrosis factor ligand superfamily member 12,
FT membrane form"
FT /id="PRO_0000034520"
FT CHAIN 94..249
FT /note="Tumor necrosis factor ligand superfamily member 12,
FT secreted form"
FT /id="PRO_0000034521"
FT TOPO_DOM 1..21
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 22..42
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 43..249
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT REGION 55..85
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 93..94
FT /note="Cleavage"
FT CARBOHYD 139
FT /note="N-linked (GlcNAc...) asparagine"
FT DISULFID 191..210
FT /evidence="ECO:0000269|PubMed:23667509"
FT VAR_SEQ 167..249
FT /note="VHFDEGKAVYLKLDLLVDGVLALRCLEEFSATAASSLGPQLRLCQVSGLLAL
FT RPGSSLRIRTLPWAHLKAAPFLTYFGLFQVH -> SSDALEAWENGERSRKRRAVLTQK
FT QKKQHSVLHLVPINATSKDDSDVTEVMWQPALRRGRGLQAQGYGVRIQDAGVYLLYSQV
FT LFQDVTFTMGQVVSREGQGRQETLFRCIRSMPSHPDRAYNSCYSAGVFHLHQGDILSVI
FT IPRARAKLNLSPHGTFLGFVKL (in isoform TWE-PRIL)"
FT /evidence="ECO:0000303|PubMed:12411489"
FT /id="VSP_045245"
FT STRAND 108..113
FT /evidence="ECO:0007829|PDB:4HT1"
FT STRAND 133..135
FT /evidence="ECO:0007829|PDB:4HT1"
FT STRAND 143..146
FT /evidence="ECO:0007829|PDB:4HT1"
FT TURN 148..150
FT /evidence="ECO:0007829|PDB:4HT1"
FT STRAND 153..155
FT /evidence="ECO:0007829|PDB:4HT1"
FT STRAND 159..173
FT /evidence="ECO:0007829|PDB:4HT1"
FT STRAND 175..183
FT /evidence="ECO:0007829|PDB:4HT1"
FT STRAND 186..193
FT /evidence="ECO:0007829|PDB:4HT1"
FT STRAND 205..218
FT /evidence="ECO:0007829|PDB:4HT1"
FT STRAND 223..227
FT /evidence="ECO:0007829|PDB:4HT1"
FT TURN 238..240
FT /evidence="ECO:0007829|PDB:4HT1"
FT STRAND 241..247
FT /evidence="ECO:0007829|PDB:4HT1"
SQ SEQUENCE 249 AA; 27216 MW; E660843361C28EBA CRC64;
MAARRSQRRR GRRGEPGTAL LVPLALGLGL ALACLGLLLA VVSLGSRASL SAQEPAQEEL
VAEEDQDPSE LNPQTEESQD PAPFLNRLVR PRRSAPKGRK TRARRAIAAH YEVHPRPGQD
GAQAGVDGTV SGWEEARINS SSPLRYNRQI GEFIVTRAGL YYLYCQVHFD EGKAVYLKLD
LLVDGVLALR CLEEFSATAA SSLGPQLRLC QVSGLLALRP GSSLRIRTLP WAHLKAAPFL
TYFGLFQVH
