LFTY2_HUMAN
ID LFTY2_HUMAN Reviewed; 366 AA.
AC O00292; B3KNH4; B4E332; E9PDM4; O75611; Q5TE89; Q8NBQ9;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 21-FEB-2001, sequence version 2.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Left-right determination factor 2;
DE AltName: Full=Endometrial bleeding-associated factor;
DE AltName: Full=Left-right determination factor A;
DE AltName: Full=Protein lefty-2;
DE AltName: Full=Protein lefty-A;
DE AltName: Full=Transforming growth factor beta-4;
DE Short=TGF-beta-4;
DE Flags: Precursor;
GN Name=LEFTY2; Synonyms=EBAF, LEFTA, LEFTYA, TGFB4; ORFNames=PSEC0024;
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).
RC TISSUE=Placenta;
RX PubMed=9153275; DOI=10.1172/jci119415;
RA Kothapalli R., Buyuksal I., Wu S.-Q., Chegini N., Tabibzadeh S.;
RT "Detection of ebaf, a novel human gene of the transforming growth factor
RT beta superfamily association of gene expression with endometrial
RT bleeding.";
RL J. Clin. Invest. 99:2342-2350(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LRAM ASN-342.
RC TISSUE=Placenta;
RX PubMed=10053005; DOI=10.1086/302289;
RA Kosaki K., Bassi M.T., Kosaki R., Lewin M., Belmont J., Schauer G.,
RA Casey B.;
RT "Characterization and mutation analysis of human LEFTY A and LEFTY B,
RT homologues of murine genes implicated in left-right axis development.";
RL Am. J. Hum. Genet. 64:712-721(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Uterus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Teratocarcinoma;
RX PubMed=16303743; DOI=10.1093/dnares/12.2.117;
RA Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J.,
RA Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S.,
RA Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y.,
RA Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S.,
RA Isogai T.;
RT "Signal sequence and keyword trap in silico for selection of full-length
RT human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA
RT libraries.";
RL DNA Res. 12:117-126(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Ovary;
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).
CC -!- FUNCTION: Required for left-right (L-R) asymmetry determination of
CC organ systems in mammals. May play a role in endometrial bleeding.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O00292-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O00292-2; Sequence=VSP_045264;
CC -!- TISSUE SPECIFICITY: Mesenchymal cells of the endometrial stroma.
CC -!- DEVELOPMENTAL STAGE: Transiently expressed before and during menstrual
CC bleeding.
CC -!- PTM: The processing of the protein may also occur at the second R-X-X-R
CC site located at AA 132-135. Processing appears to be regulated in a
CC cell-type specific manner.
CC -!- DISEASE: Left-right axis malformations (LRAM) [MIM:601877]: The defect
CC includes left pulmonary isomerism, with cardiac anomalies characterized
CC by complete atrioventricular canal defect and hypoplastic left
CC ventricle, and interrupted inferior vena cava.
CC {ECO:0000269|PubMed:10053005}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB53269.1; Type=Miscellaneous discrepancy; Note=Authors have revised their sequence, but have not submitted the revised DNA sequence.; Evidence={ECO:0000305};
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DR EMBL; U81523; AAB53269.1; ALT_SEQ; mRNA.
DR EMBL; AF081511; AAC32600.1; -; Genomic_DNA.
DR EMBL; AF081508; AAC32600.1; JOINED; Genomic_DNA.
DR EMBL; AF081509; AAC32600.1; JOINED; Genomic_DNA.
DR EMBL; AF081510; AAC32600.1; JOINED; Genomic_DNA.
DR EMBL; AF081513; AAD48145.1; -; mRNA.
DR EMBL; AK027520; BAG51336.1; -; mRNA.
DR EMBL; AK075344; BAC11556.1; -; mRNA.
DR EMBL; AK304549; BAG65344.1; -; mRNA.
DR EMBL; AL117348; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC035718; AAH35718.1; -; mRNA.
DR CCDS; CCDS1549.1; -. [O00292-1]
DR CCDS; CCDS53479.1; -. [O00292-2]
DR RefSeq; NP_001165896.1; NM_001172425.2. [O00292-2]
DR RefSeq; NP_003231.2; NM_003240.4. [O00292-1]
DR AlphaFoldDB; O00292; -.
DR BioGRID; 112902; 17.
DR IntAct; O00292; 3.
DR STRING; 9606.ENSP00000355785; -.
DR GlyGen; O00292; 1 site.
DR iPTMnet; O00292; -.
DR PhosphoSitePlus; O00292; -.
DR BioMuta; LEFTY2; -.
DR EPD; O00292; -.
DR jPOST; O00292; -.
DR MassIVE; O00292; -.
DR PaxDb; O00292; -.
DR PeptideAtlas; O00292; -.
DR PRIDE; O00292; -.
DR ProteomicsDB; 19703; -.
DR ProteomicsDB; 47824; -. [O00292-1]
DR Antibodypedia; 20763; 294 antibodies from 35 providers.
DR DNASU; 7044; -.
DR Ensembl; ENST00000366820.10; ENSP00000355785.5; ENSG00000143768.13. [O00292-1]
DR Ensembl; ENST00000420304.6; ENSP00000388009.2; ENSG00000143768.13. [O00292-2]
DR GeneID; 7044; -.
DR KEGG; hsa:7044; -.
DR MANE-Select; ENST00000366820.10; ENSP00000355785.5; NM_003240.5; NP_003231.2.
DR UCSC; uc001hpt.3; human. [O00292-1]
DR CTD; 7044; -.
DR DisGeNET; 7044; -.
DR GeneCards; LEFTY2; -.
DR HGNC; HGNC:3122; LEFTY2.
DR HPA; ENSG00000143768; Tissue enhanced (cervix, endometrium).
DR MalaCards; LEFTY2; -.
DR MIM; 601877; gene+phenotype.
DR neXtProt; NX_O00292; -.
DR OpenTargets; ENSG00000143768; -.
DR Orphanet; 157769; Situs ambiguus.
DR PharmGKB; PA27580; -.
DR VEuPathDB; HostDB:ENSG00000143768; -.
DR eggNOG; KOG3900; Eukaryota.
DR GeneTree; ENSGT00390000010056; -.
DR HOGENOM; CLU_064098_0_0_1; -.
DR InParanoid; O00292; -.
DR OMA; VSVYWVQ; -.
DR PhylomeDB; O00292; -.
DR TreeFam; TF106462; -.
DR PathwayCommons; O00292; -.
DR Reactome; R-HSA-114608; Platelet degranulation.
DR Reactome; R-HSA-1181150; Signaling by NODAL.
DR Reactome; R-HSA-1433617; Regulation of signaling by NODAL.
DR SignaLink; O00292; -.
DR SIGNOR; O00292; -.
DR BioGRID-ORCS; 7044; 11 hits in 1054 CRISPR screens.
DR ChiTaRS; LEFTY2; human.
DR GenomeRNAi; 7044; -.
DR Pharos; O00292; Tbio.
DR PRO; PR:O00292; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; O00292; protein.
DR Bgee; ENSG00000143768; Expressed in decidua and 126 other tissues.
DR ExpressionAtlas; O00292; baseline and differential.
DR Genevisible; O00292; HS.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW.
DR GO; GO:0005160; F:transforming growth factor beta receptor binding; IEA:InterPro.
DR GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central.
DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IBA:GO_Central.
DR GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
DR Gene3D; 2.10.90.10; -; 1.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR003942; LRDF.
DR InterPro; IPR001839; TGF-b_C.
DR InterPro; IPR001111; TGF-b_propeptide.
DR InterPro; IPR015615; TGF-beta-rel.
DR InterPro; IPR017948; TGFb_CS.
DR PANTHER; PTHR11848; PTHR11848; 1.
DR Pfam; PF00019; TGF_beta; 1.
DR Pfam; PF00688; TGFb_propeptide; 1.
DR PIRSF; PIRSF037402; TGFb4; 1.
DR PRINTS; PR01427; TGFBETA4.
DR SMART; SM00204; TGFB; 1.
DR SUPFAM; SSF57501; SSF57501; 1.
DR PROSITE; PS00250; TGF_BETA_1; 1.
DR PROSITE; PS51362; TGF_BETA_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytokine; Developmental protein; Disease variant;
KW Disulfide bond; Glycoprotein; Growth factor; Heterotaxy;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..76
FT /note="Or 135"
FT /evidence="ECO:0000255"
FT /id="PRO_0000033806"
FT CHAIN 77..366
FT /note="Left-right determination factor 2"
FT /id="PRO_0000033807"
FT CARBOHYD 158
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 251..264
FT /evidence="ECO:0000250"
FT DISULFID 263..316
FT /evidence="ECO:0000250"
FT DISULFID 293..351
FT /evidence="ECO:0000250"
FT DISULFID 297..353
FT /evidence="ECO:0000250"
FT VAR_SEQ 94..127
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045264"
FT VARIANT 92
FT /note="S -> L (in dbSNP:rs366439)"
FT /id="VAR_021980"
FT VARIANT 286
FT /note="P -> L (in dbSNP:rs2295418)"
FT /id="VAR_021981"
FT VARIANT 342
FT /note="S -> N (in LRAM; dbSNP:rs121909126)"
FT /evidence="ECO:0000269|PubMed:10053005"
FT /id="VAR_010385"
FT CONFLICT 132
FT /note="R -> G (in Ref. 3; BAG65344)"
FT /evidence="ECO:0000305"
FT CONFLICT 183
FT /note="A -> P (in Ref. 4; BAC11556)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 366 AA; 40920 MW; 63A416CAE30F7A39 CRC64;
MWPLWLCWAL WVLPLAGPGA ALTEEQLLGS LLRQLQLSEV PVLDRADMEK LVIPAHVRAQ
YVVLLRRSHG DRSRGKRFSQ SFREVAGRFL ASEASTHLLV FGMEQRLPPN SELVQAVLRL
FQEPVPKAAL HRHGRLSPRS AQARVTVEWL RVRDDGSNRT SLIDSRLVSV HESGWKAFDV
TEAVNFWQQL SRPRQPLLLQ VSVQREHLGP LASGAHKLVR FASQGAPAGL GEPQLELHTL
DLRDYGAQGD CDPEAPMTEG TRCCRQEMYI DLQGMKWAKN WVLEPPGFLA YECVGTCQQP
PEALAFNWPF LGPRQCIASE TASLPMIVSI KEGGRTRPQV VSLPNMRVQK CSCASDGALV
PRRLQP
