O95859 (TSN12_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Tetraspanin-12
Short name=Tspan-12

Alternative name(s):
Tetraspan NET-2
Transmembrane 4 superfamily member 12

Gene names

Name:	TSPAN12
Synonyms:	NET2, TM4SF12
ORF Names:	UNQ774/PRO1568

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	305 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Regulator of cell surface receptor signal transduction. Plays a central role in retinal vascularization by regulating norrin (NDP) signal transduction. Acts in concert with norrin (NDP) to promote FZD4 multimerization and subsequent activation of FZD4, leading to promote accumulation of beta-catenin (CTNNB1) and stimulate LEF/TCF-mediated transcriptional programs. Suprisingly, it only activate the norrin (NDP)-dependent activation of FZD4, while it does not activate the Wnt-dependent activation of FZD4, suggesting the existence of a Wnt-independent signaling that also promote accumulation the beta-catenin (CTNNB1) By similarity. Acts as a regulator of membrane proteinases such as ADAM10 and MMP14/MT1-MMP. Activates ADAM10-dependent cleavage activity of amyloid precursor protein (APP). Activates MMP14/MT1-MMP-dependent cleavage activity. Ref.7 Ref.8
Subunit structure	Component of a complex, at least composed of TSPAN12, FZD4 and norrin (NDP) By similarity. Interacts (when palmitoylated) with ADAM10. Interacts with MMP14/MT1-MMP. Ref.7
Subcellular location	Cell membrane; Multi-pass membrane protein By similarity.
Post-translational modification	Palmitoylated; required for interaction with ADAM10. The precise position of palmitoylated residues is unclear and occurs either on Cys-9, Cys-12 and/or Cys-83. Ref.7
Involvement in disease	Vitreoretinopathy, exudative 5 (EVR5) [MIM:613310]: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. Note: The disease is caused by mutations affecting the gene represented in this entry. TSPAN12 dominant and recessive mutations have been identified in patients with exudative vitreoretinopathy. Patients with mutations in both alleles of TSPAN12 have severe exudative vitreoretinopathy or retinal dysplasia. These mutations appear to result in a milder phenotype in heterozygous mutation carriers (Ref.11). Ref.9 Ref.10 Ref.11
Sequence similarities	Belongs to the tetraspanin (TM4SF) family.

Ontologies

Keywords
Biological process	Angiogenesis
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Transmembrane Transmembrane helix
PTM	Lipoprotein Palmitate
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW cell surface receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB regulation of angiogenesis Inferred from sequence or structural similarity. Source: UniProtKB retina layer formation Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	integral to plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Alternative products

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

Isoform 1 (identifier: O95859-1)

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 2 (identifier: O95859-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-120: MAREDSVKCL...GVWTYEQELM → MAHKLLL

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 305	305	Tetraspanin-12		PRO_0000219257
Regions
	Topological domain	1 – 12	12	Cytoplasmic Potential
	Transmembrane	13 – 33	21	Helical; Potential
	Topological domain	34 – 59	26	Extracellular Potential
	Transmembrane	60 – 80	21	Helical; Potential
	Topological domain	81 – 89	9	Cytoplasmic Potential
	Transmembrane	90 – 110	21	Helical; Potential
	Topological domain	111 – 224	114	Extracellular Potential
	Transmembrane	225 – 245	21	Helical; Potential
	Topological domain	246 – 305	60	Cytoplasmic Potential
Amino acid modifications
	Lipidation	9	1	S-palmitoyl cysteine By similarity
	Lipidation	12	1	S-palmitoyl cysteine By similarity
	Lipidation	83	1	S-palmitoyl cysteine By similarity
Natural variations
	Alternative sequence	1 – 120	120	MARED…EQELM → MAHKLLL in isoform 2.		VSP_038525
	Natural variant	49	1	T → M in EVR5. Ref.11		VAR_068899
	Natural variant	57	1	L → S. Ref.6 Corresponds to variant rs17852934 [ dbSNP | Ensembl ].		VAR_062253
	Natural variant	101	1	L → H in EVR5. Ref.10		VAR_063576
	Natural variant	138	1	Y → C in EVR5. Ref.11		VAR_068900
	Natural variant	188	1	G → R in EVR5. Ref.9		VAR_063577
	Natural variant	210	1	M → R in EVR5. Ref.10		VAR_063578
	Natural variant	223	1	L → P in EVR5. Ref.11		VAR_068901
	Natural variant	237	1	A → P in EVR5. Ref.9		VAR_063579
Experimental info
	Mutagenesis	9	1	C → S: Impairs interaction with ADAM10; when associated with S-12 and S-83. Ref.7
	Mutagenesis	12	1	C → S: Impairs interaction with ADAM10; when associated with S-9 and S-83. Ref.7
	Mutagenesis	83	1	C → S: Impairs interaction with ADAM10; when associated with S-9 and S-12. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: EBF4D5E1371E92DC	FASTA	305	35,383
	10 20 30 40 50 60 MAREDSVKCL RCLLYALNLL FWLMSISVLA VSAWMRDYLN NVLTLTAETR VEEAVILTYF 70 80 90 100 110 120 PVVHPVMIAV CCFLIIVGML GYCGTVKRNL LLLAWYFGSL LVIFCVELAC GVWTYEQELM 130 140 150 160 170 180 VPVQWSDMVT LKARMTNYGL PRYRWLTHAW NFFQREFKCC GVVYFTDWLE MTEMDWPPDS 190 200 210 220 230 240 CCVREFPGCS KQAHQEDLSD LYQEGCGKKM YSFLRGTKQL QVLRFLGISI GVTQILAMIL 250 260 270 280 290 300 TITLLWALYY DRREPGTDQM MSLKNDNSQH LSCPSVELLK PSLSRIFEHT SMANSFNTHF EMEEL
	Isoform 2 [UniParc]. Checksum: E789CE4F377F3F17	FASTA	192	22,511
	10 20 30 40 50 60 MAHKLLLVPV QWSDMVTLKA RMTNYGLPRY RWLTHAWNFF QREFKCCGVV YFTDWLEMTE 70 80 90 100 110 120 MDWPPDSCCV REFPGCSKQA HQEDLSDLYQ EGCGKKMYSF LRGTKQLQVL RFLGISIGVT 130 140 150 160 170 180 QILAMILTIT LLWALYYDRR EPGTDQMMSL KNDNSQHLSC PSVELLKPSL SRIFEHTSMA 190 NSFNTHFEME EL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequence and expression of seven new tetraspans." Serru V., Dessen P., Boucheix C., Rubinstein E. Biochim. Biophys. Acta 1478:159-163(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"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).
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Adrenal gland and Teratocarcinoma.
[4]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Human chromosome 7: DNA sequence and biology." Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., Kanematsu E., Gentles S. , Christopoulos C.C., Choufani S., Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., Adams M.D., Tsui L.-C. Science 300:767-772(2003) [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), VARIANT SER-57. Tissue: Brain.
[7]	"Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein." Xu D., Sharma C., Hemler M.E. FASEB J. 23:3674-3681(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH ADAM10, PALMITOYLATION, MUTAGENESIS OF CYS-9; CYS-12 AND CYS-83.
[8]	"Tetraspanin proteins regulate membrane type-1 matrix metalloproteinase-dependent pericellular proteolysis." Lafleur M.A., Xu D., Hemler M.E. Mol. Biol. Cell 20:2030-2040(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[9]	"Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy." Nikopoulos K., Gilissen C., Hoischen A., van Nouhuys C.E., Boonstra F.N., Blokland E.A., Arts P., Wieskamp N., Strom T.M., Ayuso C., Tilanus M.A., Bouwhuis S., Mukhopadhyay A., Scheffer H., Hoefsloot L.H., Veltman J.A., Cremers F.P., Collin R.W. Am. J. Hum. Genet. 86:240-247(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS EVR5 ARG-188 AND PRO-237.
[10]	"Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy." Poulter J.A., Ali M., Gilmour D.F., Rice A., Kondo H., Hayashi K., Mackey D.A., Kearns L.S., Ruddle J.B., Craig J.E., Pierce E.A., Downey L.M., Mohamed M.D., Markham A.F., Inglehearn C.F., Toomes C. Am. J. Hum. Genet. 86:248-253(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS EVR5 HIS-101 AND ARG-210.
[11]	"Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR)." Poulter J.A., Davidson A.E., Ali M., Gilmour D.F., Parry D.A., Mintz-Hittner H.A., Carr I.M., Bottomley H.M., Long V.W., Downey L.M., Sergouniotis P.I., Wright G.A., MacLaren R.E., Moore A.T., Webster A.R., Inglehearn C.F., Toomes C. Invest. Ophthalmol. Vis. Sci. 53:2873-2879(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS EVR5 MET-49; CYS-138 AND PRO-223.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF124522 mRNA. Translation: AAD17317.1. AY358703 mRNA. Translation: AAQ89066.1. AK299247 mRNA. Translation: BAG61278.1. AK312239 mRNA. Translation: BAG35172.1. AC004456 Genomic DNA. Translation: AAQ96879.1. CH236947 Genomic DNA. Translation: EAL24349.1. BC031265 mRNA. Translation: AAH31265.1.
IPI	IPI00000737. IPI00954561.
RefSeq	NP_036470.1. NM_012338.3.
UniGene	Hs.16529.
3D structure databases
ProteinModelPortal	O95859.
ModBase	Search...
Protein-protein interaction databases
IntAct	O95859. 3 interactions.
STRING	9606.ENSP00000222747.
PTM databases
PhosphoSite	O95859.
Proteomic databases
PaxDb	O95859.
PRIDE	O95859.
Protocols and materials databases
DNASU	23554.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000222747; ENSP00000222747; ENSG00000106025. ENST00000415871; ENSP00000397699; ENSG00000106025.
GeneID	23554.
KEGG	hsa:23554.
UCSC	uc003vjk.3. human.
Organism-specific databases
CTD	23554.
GeneCards	GC07M120427.
HGNC	HGNC:21641. TSPAN12.
HPA	HPA051570.
MIM	613138. gene. 613310. phenotype.
neXtProt	NX_O95859.
Orphanet	891. Familial exudative vitreoretinopathy.
PharmGKB	PA134954047.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG257008.
HOGENOM	HOG000252919.
HOVERGEN	HBG054253.
InParanoid	O95859.
OMA	TYEQEIM.
OrthoDB	EOG4Q58PT.
PhylomeDB	O95859.
Gene expression databases
ArrayExpress	O95859.
Bgee	O95859.
CleanEx	HS_TSPAN12.
Genevestigator	O95859.
GermOnline	ENSG00000106025. Homo sapiens.
Family and domain databases
InterPro	IPR000301. Tetraspanin. IPR018499. Tetraspanin/Peripherin. IPR018503. Tetraspanin_CS. IPR008952. Tetraspanin_EC2. [Graphical view]
Pfam	PF00335. Tetraspannin. 1 hit. [Graphical view]
PIRSF	PIRSF002419. Tetraspanin. 1 hit.
PRINTS	PR00259. TMFOUR.
SUPFAM	SSF48652. Tetraspanin. 1 hit.
PROSITE	PS00421. TM4_1. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	23554.
NextBio	46116.
SOURCE	Search...

Entry information

Entry name

TSN12_HUMAN

Accession

Primary (citable) accession number: O95859
Secondary accession number(s): A4D0V8 , B4DRG6, Q549U9, Q8N5Y0

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	May 1, 1999
Last modified:	May 1, 2013
This is version 101 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.