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   24-JAN-2024, entry version 195.
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   GlyCosmos; O43508; 2 sites, 1 glycan.
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   PaxDb; 9606-ENSP00000293825; -.
DR   PeptideAtlas; O43508; -.
DR   ProteomicsDB; 49000; -. [O43508-1]
DR   ProteomicsDB; 71365; -.
DR   ABCD; O43508; 1 sequenced antibody.
DR   Antibodypedia; 34916; 649 antibodies from 42 providers.
DR   DNASU; 407977; -.
DR   DNASU; 8742; -.
DR   Ensembl; ENST00000293825.11; ENSP00000293825.6; ENSG00000239697.12. [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   AGR; HGNC:11927; -.
DR   AGR; HGNC:33537; -.
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; ENSGT00940000163167; -.
DR   HOGENOM; CLU_090519_0_0_1; -.
DR   InParanoid; O43508; -.
DR   OMA; DMLALRC; -.
DR   OrthoDB; 5358224at2759; -.
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   SIGNOR; O43508; -.
DR   BioGRID-ORCS; 407977; 12 hits in 665 CRISPR screens.
DR   BioGRID-ORCS; 8742; 11 hits in 758 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 97 other cell types or tissues.
DR   ExpressionAtlas; O43508; baseline and differential.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0005615; C:extracellular space; IBA:GO_Central.
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; IEA:UniProtKB-KW.
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: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   PANTHER; PTHR15151; PROTEIN EIGER; 1.
DR   PANTHER; PTHR15151:SF20; TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY MEMBER 12; 1.
DR   Pfam; PF00229; TNF; 1.
DR   SMART; SM00207; TNF; 1.
DR   SUPFAM; SSF49842; TNF-like; 1.
DR   PROSITE; PS50049; TNF_2; 1.
DR   Genevisible; O43508; HS.
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
//