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   13-FEB-2019, entry version 183.
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;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; 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
RT   factor beta superfamily association of gene expression with
RT   endometrial 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
RT   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.,
RA   Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA   Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA   Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA   Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA   Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA   Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA   Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA   Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA   Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA   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.,
RA   Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA   Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA   Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA   Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA   Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA   Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA   Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA   Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA   Nakai K., Yada T., Nakamura Y., Ohara O., 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-
RT   length human cDNAs encoding secretion or membrane proteins from oligo-
RT   capped cDNA 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.,
RA   Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA   Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA   McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA   Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA   Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA   Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA   Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA   Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA   Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA   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.,
RA   Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA   Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA   Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA   Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA   Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA   Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA   Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA   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.,
RA   Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA   Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA   Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA   Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA   Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA   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
RT   project: 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         Note=No experimental confirmation available.;
CC   -!- TISSUE SPECIFICITY: Mesenchymal cells of the endometrial stroma.
CC   -!- DEVELOPMENTAL STAGE: Transiently expressed before and during
CC       menstrual bleeding.
CC   -!- PTM: The processing of the protein may also occur at the second R-
CC       X-X-R site located at AA 132-135. Processing appears to be
CC       regulated in a cell-type specific manner.
CC   -!- DISEASE: Left-right axis malformations (LRAM) [MIM:601877]: The
CC       defect includes left pulmonary isomerism, with cardiac anomalies
CC       characterized by complete atrioventricular canal defect and
CC       hypoplastic left ventricle, and interrupted inferior vena cava.
CC       {ECO:0000269|PubMed:10053005}. Note=The disease is caused by
CC       mutations 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   UniGene; Hs.520187; -.
DR   ProteinModelPortal; O00292; -.
DR   SMR; O00292; -.
DR   BioGrid; 112902; 3.
DR   IntAct; O00292; 2.
DR   STRING; 9606.ENSP00000355785; -.
DR   iPTMnet; O00292; -.
DR   PhosphoSitePlus; O00292; -.
DR   BioMuta; LEFTY2; -.
DR   EPD; O00292; -.
DR   jPOST; O00292; -.
DR   PaxDb; O00292; -.
DR   PeptideAtlas; O00292; -.
DR   PRIDE; O00292; -.
DR   ProteomicsDB; 47824; -.
DR   Ensembl; ENST00000366820; ENSP00000355785; ENSG00000143768. [O00292-1]
DR   Ensembl; ENST00000420304; ENSP00000388009; ENSG00000143768. [O00292-2]
DR   GeneID; 7044; -.
DR   KEGG; hsa:7044; -.
DR   UCSC; uc001hpt.3; human. [O00292-1]
DR   CTD; 7044; -.
DR   DisGeNET; 7044; -.
DR   EuPathDB; HostDB:ENSG00000143768.11; -.
DR   GeneCards; LEFTY2; -.
DR   HGNC; HGNC:3122; LEFTY2.
DR   HPA; CAB025801; -.
DR   HPA; HPA047883; -.
DR   HPA; HPA056210; -.
DR   MalaCards; LEFTY2; -.
DR   MIM; 601877; gene+phenotype.
DR   neXtProt; NX_O00292; -.
DR   OpenTargets; ENSG00000143768; -.
DR   Orphanet; 157769; Situs ambiguus.
DR   PharmGKB; PA27580; -.
DR   eggNOG; KOG3900; Eukaryota.
DR   eggNOG; ENOG410XT8Z; LUCA.
DR   GeneTree; ENSGT00390000010056; -.
DR   HOGENOM; HOG000113317; -.
DR   HOVERGEN; HBG074429; -.
DR   InParanoid; O00292; -.
DR   KO; K04668; -.
DR   OMA; ETGWKSF; -.
DR   OrthoDB; 751948at2759; -.
DR   PhylomeDB; O00292; -.
DR   TreeFam; TF106462; -.
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   SIGNOR; O00292; -.
DR   ChiTaRS; LEFTY2; human.
DR   GenomeRNAi; 7044; -.
DR   PRO; PR:O00292; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   Bgee; ENSG00000143768; Expressed in 113 organ(s), highest expression level in decidua.
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; IBA:GO_Central.
DR   GO; GO:0048468; P:cell development; IBA:GO_Central.
DR   GO; GO:0007275; P:multicellular organism development; TAS:ProtInc.
DR   GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR   GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IBA:GO_Central.
DR   GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central.
DR   GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central.
DR   GO; GO:0060395; P:SMAD protein signal transduction; IBA:GO_Central.
DR   GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:ProtInc.
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; Complete proteome; Cytokine;
KW   Developmental protein; Disease mutation; Disulfide bond; Glycoprotein;
KW   Growth factor; Heterotaxy; Polymorphism; Reference proteome; Secreted;
KW   Signal.
FT   SIGNAL        1     21       {ECO:0000255}.
FT   PROPEP       22     76       Or 135. {ECO:0000255}.
FT                                /FTId=PRO_0000033806.
FT   CHAIN        77    366       Left-right determination factor 2.
FT                                /FTId=PRO_0000033807.
FT   CARBOHYD    158    158       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   DISULFID    251    264       {ECO:0000250}.
FT   DISULFID    263    316       {ECO:0000250}.
FT   DISULFID    293    351       {ECO:0000250}.
FT   DISULFID    297    353       {ECO:0000250}.
FT   VAR_SEQ      94    127       Missing (in isoform 2).
FT                                {ECO:0000303|PubMed:14702039}.
FT                                /FTId=VSP_045264.
FT   VARIANT      92     92       S -> L (in dbSNP:rs366439).
FT                                /FTId=VAR_021980.
FT   VARIANT     286    286       P -> L (in dbSNP:rs2295418).
FT                                /FTId=VAR_021981.
FT   VARIANT     342    342       S -> N (in LRAM; dbSNP:rs121909126).
FT                                {ECO:0000269|PubMed:10053005}.
FT                                /FTId=VAR_010385.
FT   CONFLICT    132    132       R -> G (in Ref. 3; BAG65344).
FT                                {ECO:0000305}.
FT   CONFLICT    183    183       A -> P (in Ref. 4; BAC11556).
FT                                {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
//