O43508 (TNF12_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tumor necrosis factor ligand superfamily member 12

Alternative name(s):
APO3 ligand
TNF-related weak inducer of apoptosis
Short name=TWEAK

Cleaved into the following 2 chains:

1. Tumor necrosis factor ligand superfamily member 12, membrane form
2. Tumor necrosis factor ligand superfamily member 12, secreted form

Gene names

Name:	TNFSF12
Synonyms:	APO3L, DR3LG
ORF Names:	UNQ181/PRO207

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	249 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Binds to FN14 and possibly also to TNRFSF12/APO3. Weak inducer of apoptosis in some cell types. Mediates NF-kappa-B activation. Promotes angiogenesis and the proliferation of endothelial cells. Also involved in induction of inflammatory cytokines. Ref.7
Subunit structure	Homotrimer Potential. Interacts with the angiogenic factor AGGF1/VG5Q. Ref.8
Subcellular location	Cell membrane; Single-pass type II membrane protein Ref.3. Tumor necrosis factor ligand superfamily member 12, secreted form: Secreted Ref.3. Isoform TWE-PRIL: Cell membrane; Single-pass membrane protein Ref.3.
Tissue specificity	Highly expressed in adult heart, pancreas, skeletal muscle, brain, colon, small intestine, lung, ovary, prostate, spleen, lymph node, appendix and peripheral blood lymphocytes. Low expression in kidney, testis, liver, placenta, thymus and bone marrow. Also detected in fetal kidney, liver, lung and brain.
Post-translational modification	The soluble form derives from the membrane form by proteolytic processing.
Sequence similarities	Belongs to the tumor necrosis factor family.
Sequence caution	The sequence AAH19047.1 differs from that shown. Reason: Frameshift at position 125.

Ontologies

Keywords
Biological process	Angiogenesis Apoptosis Differentiation
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Cytokine Developmental protein
PTM	Cleavage on pair of basic residues Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW apoptotic signaling pathway Traceable author statement PubMed 21525013. Source: UniProtKB cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW endothelial cell migration Traceable author statement Ref.8. Source: UniProtKB immune response Inferred from electronic annotation. Source: InterPro induction of apoptosis Traceable author statement Ref.2. Source: ProtInc positive regulation of angiogenesis Traceable author statement Ref.8. Source: UniProtKB positive regulation of endothelial cell proliferation Traceable author statement Ref.8. Source: UniProtKB positive regulation of extrinsic apoptotic signaling pathway Inferred from direct assay PubMed 21525013. Source: UniProtKB signal transduction Traceable author statement Ref.2. Source: ProtInc
Cellular_component	extracellular space Inferred from electronic annotation. Source: UniProtKB-KW integral to plasma membrane Traceable author statement Ref.2. Source: ProtInc perinuclear region of cytoplasm Inferred from direct assay Ref.8. Source: UniProtKB
Molecular_function	cytokine activity Traceable author statement PubMed 21525013. Source: UniProtKB receptor binding Traceable author statement Ref.2. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O43508-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform TWE-PRIL (identifier: O43508-2)

Also known as: TNFSF12-TNFSF13;

The sequence of this isoform differs from the canonical sequence as follows:
     167-249: VHFDEGKAVY...LTYFGLFQVH → SSDALEAWEN...HGTFLGFVKL

Note: Endogenous hybrid transcript between TWEAK and APRIL. Expressed at protein level in primary T-lymphocytes and monocytic cell lines.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 249	249	Tumor necrosis factor ligand superfamily member 12, membrane form		PRO_0000034520
	Chain	94 – 249	156	Tumor necrosis factor ligand superfamily member 12, secreted form		PRO_0000034521
Regions
	Topological domain	1 – 21	21	Cytoplasmic Potential
	Transmembrane	22 – 42	21	Helical; Signal-anchor for type II membrane protein; Potential
	Topological domain	43 – 249	207	Extracellular Potential
Sites
	Site	93 – 94	2	Cleavage
Amino acid modifications
	Glycosylation	139	1	N-linked (GlcNAc...)
Natural variations
	Alternative sequence	167 – 249	83	VHFDE…LFQVH → SSDALEAWENGERSRKRRAV LTQKQKKQHSVLHLVPINAT SKDDSDVTEVMWQPALRRGR GLQAQGYGVRIQDAGVYLLY SQVLFQDVTFTMGQVVSREG QGRQETLFRCIRSMPSHPDR AYNSCYSAGVFHLHQGDILS VIIPRARAKLNLSPHGTFLG FVKL in isoform TWE-PRIL.		VSP_045245

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 1, 1998. Version 1. Checksum: E660843361C28EBA	FASTA	249	27,216
	10 20 30 40 50 60 MAARRSQRRR GRRGEPGTAL LVPLALGLGL ALACLGLLLA VVSLGSRASL SAQEPAQEEL 70 80 90 100 110 120 VAEEDQDPSE LNPQTEESQD PAPFLNRLVR PRRSAPKGRK TRARRAIAAH YEVHPRPGQD 130 140 150 160 170 180 GAQAGVDGTV SGWEEARINS SSPLRYNRQI GEFIVTRAGL YYLYCQVHFD EGKAVYLKLD 190 200 210 220 230 240 LLVDGVLALR CLEEFSATAA SSLGPQLRLC QVSGLLALRP GSSLRIRTLP WAHLKAAPFL TYFGLFQVH
	Isoform TWE-PRIL (TNFSF12-TNFSF13) [UniParc]. Checksum: FC6F3BCA29C029AE	FASTA	330	36,589
	10 20 30 40 50 60 MAARRSQRRR GRRGEPGTAL LVPLALGLGL ALACLGLLLA VVSLGSRASL SAQEPAQEEL 70 80 90 100 110 120 VAEEDQDPSE LNPQTEESQD PAPFLNRLVR PRRSAPKGRK TRARRAIAAH YEVHPRPGQD 130 140 150 160 170 180 GAQAGVDGTV SGWEEARINS SSPLRYNRQI GEFIVTRAGL YYLYCQSSDA LEAWENGERS 190 200 210 220 230 240 RKRRAVLTQK QKKQHSVLHL VPINATSKDD SDVTEVMWQP ALRRGRGLQA QGYGVRIQDA 250 260 270 280 290 300 GVYLLYSQVL FQDVTFTMGQ VVSREGQGRQ ETLFRCIRSM PSHPDRAYNS CYSAGVFHLH 310 320 330 QGDILSVIIP RARAKLNLSP HGTFLGFVKL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis." Chicheportiche Y., Bourdon P.R., Xu H., Hsu Y.-M., Scott H., Hession C., Garcia I., Browning J.L. J. Biol. Chem. 272:32401-32410(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), N-TERMINUS OF SOLUBLE FORM. Tissue: Fetal liver and Tonsil.
[2]	"Identification of a ligand for the death-domain-containing receptor Apo3." Marsters S.A., Sheridan J.P., Pitti R.M., Brush J., Goddard A., Ashkenazi A. Curr. Biol. 8:525-528(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Fetal kidney.
[3]	"An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein." Pradet-Balade B., Medema J.P., Lopez-Fraga M., Lozano J.C., Kolfschoten G.M., Picard A., Martinez-A C., Garcia-Sanz J.A., Hahne M. EMBO J. 21:5711-5720(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TWE-PRIL), SUBCELLULAR LOCATION.
[4]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[5]	"DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage." Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., Chang J.L. , Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C. Nature 440:1045-1049(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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] (ISOFORM 1). Tissue: Tonsil.
[7]	"TWEAK induces angiogenesis and proliferation of endothelial cells." Lynch C.N., Wang Y.C., Lund J.K., Chen Y.-W., Leal J.A., Wiley S.R. J. Biol. Chem. 274:8455-8459(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[8]	"Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome." Tian X.-L., Kadaba R., You S.-A., Liu M., Timur A.A., Yang L., Chen Q., Szafranski P., Rao S., Wu L., Housman D.E., DiCorleto P.E., Driscoll D.J., Borrow J., Wang Q. Nature 427:640-645(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH AGGF1/VG5Q.
[9]	"TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor." Wiley S.R., Winkles J.A. Cytokine Growth Factor Rev. 14:241-249(2003) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF030099 mRNA. Translation: AAC51923.1. AF055872 mRNA. Translation: AAC39724.1. AY081051 mRNA. Translation: AAL90443.1. AY358870 mRNA. Translation: AAQ89229.1. AC016876 Genomic DNA. No translation available. BC019047 mRNA. Translation: AAH19047.1. Frameshift.
IPI	IPI00021900. IPI00218017.
RefSeq	NP_003800.1. NM_003809.2. NP_742086.1. NM_172089.3.
UniGene	Hs.54673.
3D structure databases
ProteinModelPortal	O43508.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-8415042.
STRING	9606.ENSP00000293826.
PTM databases
PhosphoSite	O43508.
Proteomic databases
PaxDb	O43508.
PRIDE	O43508.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000293825; ENSP00000293825; ENSG00000239697. ENST00000557233; ENSP00000451451; ENSG00000239697.
GeneID	407977. 8742.
KEGG	hsa:407977. hsa:8742.
UCSC	uc002ghg.3. human. uc002ghi.1. human.
Organism-specific databases
CTD	407977. 8742.
GeneCards	GC17P007452.
HGNC	HGNC:11927. TNFSF12.
MIM	602695. gene.
neXtProt	NX_O43508.
PharmGKB	PA36620.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG45253.
HOGENOM	HOG000134435.
HOVERGEN	HBG055510.
KO	K05474.
OMA	CQTELQS.
OrthoDB	EOG4CZBH5.
Gene expression databases
ArrayExpress	O43508.
Bgee	O43508.
Genevestigator	O43508.
GermOnline	ENSG00000161955. Homo sapiens.
Family and domain databases
Gene3D	2.60.120.40. 1 hit.
InterPro	IPR006052. TNF. IPR008983. Tumour_necrosis_fac-like_dom. [Graphical view]
Pfam	PF00229. TNF. 1 hit. [Graphical view]
SMART	SM00207. TNF. 1 hit. [Graphical view]
SUPFAM	SSF49842. TNF_like. 1 hit.
PROSITE	PS00251. TNF_1. False negative. PS50049. TNF_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	TNFSF12-TNFSF13. human.
GenomeRNAi	8742.
NextBio	108346.
SOURCE	Search...

Entry information

Entry name

TNF12_HUMAN

Accession

Primary (citable) accession number: O43508
Secondary accession number(s): Q8IZK7, Q8WUZ7

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 6, 2002
Last sequence update:	June 1, 1998
Last modified:	May 29, 2013
This is version 118 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.