ELA_HUMAN
ID ELA_HUMAN Reviewed; 54 AA.
AC P0DMC3;
DT 19-FEB-2014, integrated into UniProtKB/Swiss-Prot.
DT 19-FEB-2014, sequence version 1.
DT 03-AUG-2022, entry version 50.
DE RecName: Full=Apelin receptor early endogenous ligand {ECO:0000312|HGNC:HGNC:48925};
DE AltName: Full=Protein Elabela {ECO:0000250|UniProtKB:P0DMC2};
DE Short=ELA {ECO:0000250|UniProtKB:P0DMC2};
DE AltName: Full=Protein Toddler {ECO:0000250|UniProtKB:P0DMC2};
DE Flags: Precursor;
GN Name=APELA {ECO:0000312|HGNC:HGNC:48925}; Synonyms=ELA, TDL;
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 [LARGE SCALE MRNA].
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [3]
RP INTERACTION WITH APLNR, SUBCELLULAR LOCATION, SIGNAL SEQUENCE CLEAVAGE
RP SITE, AND TISSUE SPECIFICITY.
RX PubMed=24316148; DOI=10.1016/j.devcel.2013.11.002;
RA Chng S.C., Ho L., Tian J., Reversade B.;
RT "ELABELA: a hormone essential for heart development signals via the apelin
RT receptor.";
RL Dev. Cell 27:672-680(2013).
RN [4]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=25639753; DOI=10.1038/srep08170;
RA Wang Z., Yu D., Wang M., Wang Q., Kouznetsova J., Yang R., Qian K., Wu W.,
RA Shuldiner A., Sztalryd C., Zou M., Zheng W., Gong D.W.;
RT "Elabela-apelin receptor signaling pathway is functional in mammalian
RT systems.";
RL Sci. Rep. 5:8170-8170(2015).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=28137936; DOI=10.1161/circulationaha.116.023218;
RA Yang P., Read C., Kuc R.E., Buonincontri G., Southwood M., Torella R.,
RA Upton P.D., Crosby A., Sawiak S.J., Carpenter T.A., Glen R.C.,
RA Morrell N.W., Maguire J.J., Davenport A.P.;
RT "Elabela/Toddler is an endogenous agonist of the apelin APJ receptor in the
RT adult cardiovascular system, and exogenous administration of the peptide
RT compensates for the downregulation of its expression in pulmonary arterial
RT hypertension.";
RL Circulation 135:1160-1173(2017).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=28663440; DOI=10.1126/science.aam6607;
RA Ho L., van Dijk M., Chye S.T.J., Messerschmidt D.M., Chng S.C., Ong S.,
RA Yi L.K., Boussata S., Goh G.H., Afink G.B., Lim C.Y., Dunn N.R., Solter D.,
RA Knowles B.B., Reversade B.;
RT "ELABELA deficiency promotes preeclampsia and cardiovascular malformations
RT in mice.";
RL Science 357:707-713(2017).
CC -!- FUNCTION: Endogenous ligand for the apelin receptor (APLNR)
CC (PubMed:25639753, PubMed:28137936). Hormone required for mesendodermal
CC differentiation, blood vessels formation and heart morphogenesis during
CC early development and for adult cardiovascular homeostasis
CC (PubMed:25639753, PubMed:28137936). Drives internalization of APLNR.
CC Acts as a motogen by promoting mesendodermal cell migration during
CC gastrulation by binding and activating APLNR. Acts as an early
CC embryonic regulator of cellular movement with a role in migration and
CC development of cardiac progenitor cells. May act as a chemoattractant
CC for the activation of angioblast migration toward the embryonic
CC midline, i.e. the position of the future vessel formation, during
CC vasculogenesis. Positively regulates sinus venosus (SV)-derived
CC endothelial cells migration into the developing heart to promote
CC coronary blood vessel sprouting. Plays a role in placental vascular
CC development; promotes placental trophoblast invasion and spiral artery
CC remodeling in the uterus. Involved in the regulation of maternal
CC cardiovascular homeostasis to prevent gestational hypertension and for
CC potent cardioprotective functions during heart failure. Mediates
CC myocardial contractility in an ERK1/2-dependent manner (By similarity).
CC {ECO:0000250|UniProtKB:P0DMC2, ECO:0000250|UniProtKB:P0DMC4,
CC ECO:0000250|UniProtKB:P0DP76, ECO:0000269|PubMed:25639753,
CC ECO:0000269|PubMed:28137936}.
CC -!- SUBUNIT: Interacts with APLNR (PubMed:24316148).
CC {ECO:0000269|PubMed:24316148}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:24316148,
CC ECO:0000269|PubMed:28137936}. Secreted, extracellular space
CC {ECO:0000269|PubMed:28137936}. Note=Found in blood plasma
CC (PubMed:28137936). Found in serum of pregnant mice, peaking at
CC midgestation; indicating a maternal and zygotic origin of circulating
CC APELA during pregnancy (By similarity). {ECO:0000250|UniProtKB:P0DMC4}.
CC -!- TISSUE SPECIFICITY: Expressed in the intima of blood vessels
CC (PubMed:28137936). Expressed in endothelial cells in blood vessels in
CC the heart and lung (PubMed:28137936). Expressed in cytotrophoblasts and
CC syncytiotrophoblasts of first-trimester placental tissue and term
CC placentas (at protein level) (PubMed:28663440). Not detected in smooth
CC muscle cells or cardiomyocytes (at protein level) (PubMed:28137936).
CC Expressed in kidney (PubMed:25639753). Expressed in blood vessels
CC (PubMed:28137936). Expressed in embryonic (ESCs) and induced (iPSCs)
CC pluripotent stem cells (PubMed:25639753). Most highly expressed in
CC undifferentiated embryonic stem cell and is rapidly down-regulated
CC during differentiation (PubMed:24316148). {ECO:0000269|PubMed:24316148,
CC ECO:0000269|PubMed:25639753, ECO:0000269|PubMed:28137936,
CC ECO:0000269|PubMed:28663440}.
CC -!- SIMILARITY: Belongs to the Elabela/Toddler family. {ECO:0000305}.
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DR EMBL; AK092578; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC104620; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS77980.1; -.
DR RefSeq; NP_001284479.1; NM_001297550.1.
DR RefSeq; XP_016863112.1; XM_017007623.1.
DR AlphaFoldDB; P0DMC3; -.
DR SMR; P0DMC3; -.
DR STRING; 9606.ENSP00000484618; -.
DR GlyGen; P0DMC3; 1 site.
DR BioMuta; APELA; -.
DR PRIDE; P0DMC3; -.
DR DNASU; 100506013; -.
DR Ensembl; ENST00000507152.6; ENSP00000484618.1; ENSG00000248329.6.
DR Ensembl; ENST00000510062.5; ENSP00000478306.1; ENSG00000248329.6.
DR Ensembl; ENST00000515275.1; ENSP00000480045.1; ENSG00000248329.6.
DR GeneID; 100506013; -.
DR KEGG; hsa:100506013; -.
DR MANE-Select; ENST00000507152.6; ENSP00000484618.1; NM_001297550.2; NP_001284479.1.
DR CTD; 100506013; -.
DR DisGeNET; 100506013; -.
DR GeneCards; APELA; -.
DR HGNC; HGNC:48925; APELA.
DR HPA; ENSG00000248329; Tissue enhanced (kidney, prostate).
DR MIM; 615594; gene.
DR neXtProt; NX_P0DMC3; -.
DR OpenTargets; ENSG00000248329; -.
DR VEuPathDB; HostDB:ENSG00000248329; -.
DR eggNOG; ENOG502TDEQ; Eukaryota.
DR GeneTree; ENSGT00950000183347; -.
DR HOGENOM; CLU_3049692_0_0_1; -.
DR OMA; GCSHRRC; -.
DR OrthoDB; 1635238at2759; -.
DR PathwayCommons; P0DMC3; -.
DR BioGRID-ORCS; 100506013; 2 hits in 64 CRISPR screens.
DR GenomeRNAi; 100506013; -.
DR Pharos; P0DMC3; Tbio.
DR PRO; PR:P0DMC3; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P0DMC3; protein.
DR Bgee; ENSG00000248329; Expressed in tibia and 97 other tissues.
DR ExpressionAtlas; P0DMC3; baseline and differential.
DR Genevisible; P0DMC3; HS.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; ISS:UniProtKB.
DR GO; GO:0031704; F:apelin receptor binding; IDA:UniProtKB.
DR GO; GO:0005179; F:hormone activity; IMP:UniProtKB.
DR GO; GO:0007512; P:adult heart development; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0060183; P:apelin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0090134; P:cell migration involved in mesendoderm migration; ISS:UniProtKB.
DR GO; GO:0060976; P:coronary vasculature development; ISS:UniProtKB.
DR GO; GO:0035050; P:embryonic heart tube development; ISS:UniProtKB.
DR GO; GO:0007492; P:endoderm development; ISS:UniProtKB.
DR GO; GO:0007507; P:heart development; ISS:UniProtKB.
DR GO; GO:0090133; P:mesendoderm migration; ISS:UniProtKB.
DR GO; GO:0007509; P:mesoderm migration involved in gastrulation; ISS:UniProtKB.
DR GO; GO:0060674; P:placenta blood vessel development; ISS:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:UniProtKB.
DR GO; GO:1903589; P:positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis; ISS:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:1904022; P:positive regulation of G protein-coupled receptor internalization; IMP:UniProtKB.
DR GO; GO:0045823; P:positive regulation of heart contraction; ISS:UniProtKB.
DR GO; GO:1901165; P:positive regulation of trophoblast cell migration; IMP:UniProtKB.
DR GO; GO:0001570; P:vasculogenesis; ISS:UniProtKB.
PE 1: Evidence at protein level;
KW Angiogenesis; Developmental protein; Differentiation; Gastrulation;
KW Glycoprotein; Hormone; Reference proteome; Secreted; Signal.
FT SIGNAL 1..22
FT /evidence="ECO:0000305|PubMed:24316148"
FT CHAIN 23..54
FT /note="Apelin receptor early endogenous ligand"
FT /id="PRO_0000425557"
FT CARBOHYD 27
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
SQ SEQUENCE 54 AA; 6622 MW; 6BDEB3DAFCF8BAB2 CRC64;
MRFQQFLFAF FIFIMSLLLI SGQRPVNLTM RRKLRKHNCL QRRCMPLHSR VPFP
