ELA_DANRE
ID ELA_DANRE Reviewed; 58 AA.
AC P0DMC2;
DT 19-FEB-2014, integrated into UniProtKB/Swiss-Prot.
DT 19-FEB-2014, sequence version 1.
DT 03-AUG-2022, entry version 46.
DE RecName: Full=Apelin receptor early endogenous ligand {ECO:0000250|UniProtKB:P0DMC3};
DE AltName: Full=Protein Elabela {ECO:0000303|PubMed:24316148};
DE Short=ELA {ECO:0000303|PubMed:24316148};
DE AltName: Full=Protein Toddler {ECO:0000303|PubMed:24407481};
DE Flags: Precursor;
GN Name=apela {ECO:0000250|UniProtKB:P0DMC3}; Synonyms=ela, tdl;
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [2]
RP FUNCTION, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE, AND INTERACTION WITH
RP APLNRA AND APLNRB.
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 [3]
RP FUNCTION, SIGNAL SEQUENCE CLEAVAGE SITE, TISSUE SPECIFICITY, IDENTIFICATION
RP BY MASS SPECTROMETRY, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND
RP MUTAGENESIS OF ALA-22.
RX PubMed=24407481; DOI=10.1126/science.1248636;
RA Pauli A., Norris M.L., Valen E., Chew G.L., Gagnon J.A., Zimmerman S.,
RA Mitchell A., Ma J., Dubrulle J., Reyon D., Tsai S.Q., Joung J.K.,
RA Saghatelian A., Schier A.F.;
RT "Toddler: an embryonic signal that promotes cell movement via apelin
RT receptors.";
RL Science 343:1248636-1248636(2014).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26017639; DOI=10.7554/elife.06726;
RA Helker C.S., Schuermann A., Pollmann C., Chng S.C., Kiefer F.,
RA Reversade B., Herzog W.;
RT "The hormonal peptide Elabela guides angioblasts to the midline during
RT vasculogenesis.";
RL Elife 4:0-0(2015).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29117894; DOI=10.7554/elife.22626;
RA Norris M.L., Pauli A., Gagnon J.A., Lord N.D., Rogers K.W., Mosimann C.,
RA Zon L.I., Schier A.F.;
RT "Toddler signaling regulates mesodermal cell migration downstream of Nodal
RT signaling.";
RL Elife 6:0-0(2017).
CC -!- FUNCTION: Endogenous ligand for the apelin receptor (aplnra and/or
CC aplnrb) (PubMed:24316148, PubMed:24407481). Hormone required for
CC mesendodermal differentiation, blood vessels formation and heart
CC morphogenesis during early development and for adult cardiovascular
CC homeostasis (PubMed:24316148, PubMed:24407481, PubMed:26017639,
CC PubMed:29117894). Acts as a motogen by promoting mesendodermal cell
CC migration during gastrulation by binding and activating the apelin
CC receptor (PubMed:24316148, PubMed:24407481, PubMed:29117894). Acts as
CC an early embryonic regulator of cellular movement with a role in
CC migration and development of cardiac progenitor cells (PubMed:24316148,
CC PubMed:24407481). May act as a chemoattractant for the activation of
CC angioblast migration toward the embryonic midline, i.e. the position of
CC the future vessel formation, during vasculogenesis (PubMed:26017639).
CC Positively regulates sinus venosus (SV)-derived endothelial cells
CC migration into the developing heart to promote coronary blood vessel
CC sprouting. Involved in cardioprotective functions during heart failure.
CC Mediates myocardial contractility in an ERK1/2-dependent manner (By
CC similarity). {ECO:0000250|UniProtKB:P0DMC3,
CC ECO:0000250|UniProtKB:P0DMC4, ECO:0000250|UniProtKB:P0DP76,
CC ECO:0000269|PubMed:24316148, ECO:0000269|PubMed:24407481,
CC ECO:0000269|PubMed:26017639, ECO:0000269|PubMed:29117894}.
CC -!- SUBUNIT: Interacts with aplnra and aplnrb (PubMed:24316148).
CC {ECO:0000269|PubMed:24316148}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:24407481}. Secreted,
CC extracellular space {ECO:0000269|PubMed:24407481}.
CC -!- TISSUE SPECIFICITY: Expressed ubiquitously during late blastula and
CC gastrula stages and becomes restricted to the lateral mesoderm,
CC endoderm, and anterior and posterior notochord after gastrulation
CC (PubMed:24407481). {ECO:0000269|PubMed:24407481}.
CC -!- DEVELOPMENTAL STAGE: Expressed from the mid-blastula transition (MBT)
CC to 3 days post-fertilization (dpf) (PubMed:24316148). Ubiquitously
CC expressed in dividing cells of the blastoderm before becoming
CC restricted after gastrulation to axial structures, with most prominent
CC expression in the neural tube (PubMed:24316148).
CC {ECO:0000269|PubMed:24316148}.
CC -!- DISRUPTION PHENOTYPE: Zinc-finger-nuclease (ZFN)- or TALEN-mediated
CC apela gene inactivation induces embryonic lethality due to heart
CC dysgenesis around 6 days post-fertilization (dpf) (PubMed:24316148,
CC PubMed:24407481). Mutant embryos show cardiac dysplasia ranging from a
CC rudimentary heart to no heart (PubMed:24316148, PubMed:24407481).
CC Embryos have minimal blood circulation, with an excess of erythrocytes
CC accumulating at the intermediate cell mass (ICM) (PubMed:24316148,
CC PubMed:24407481). Larvae display variable posterior truncations and, at
CC times, tailbud duplications (PubMed:24316148). Posterior tissue defects
CC range from loss of the ventral fin to complete tail and trunk
CC truncations (PubMed:24316148). Embryos also display malformed
CC pharyngeal endoderm, abnormal left-right positioning and formation of
CC the liver (PubMed:24407481). By mid-gastrulation, embryos show reduced
CC endodermal cell numbers and endodermal and mesodermal progenitor cell
CC migration toward the animal pole (PubMed:24316148, PubMed:24407481).
CC CRISPR-induced apela null mutations show also reduced endodermal cell
CC numbers, increased rates of endodermal cells death and reduced
CC endodermal and mesodermal cell migration at mid-gastrulation
CC (PubMed:29117894). Show a strong decrease in the angioblast migration
CC to the embryonic midline during late gastrulation (PubMed:26017639).
CC {ECO:0000269|PubMed:24316148, ECO:0000269|PubMed:24407481,
CC ECO:0000269|PubMed:26017639, ECO:0000269|PubMed:29117894}.
CC -!- MISCELLANEOUS: Was named Toddler based on the phenotype.
CC {ECO:0000305|PubMed:24407481}.
CC -!- SIMILARITY: Belongs to the Elabela/Toddler family. {ECO:0000305}.
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DR EMBL; BX323590; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_001284476.1; NM_001297547.1.
DR AlphaFoldDB; P0DMC2; -.
DR Ensembl; ENSDART00000148219; ENSDARP00000138546; ENSDARG00000094729.
DR Ensembl; ENSDART00000192420; ENSDARP00000157341; ENSDARG00000113515.
DR GeneID; 100536023; -.
DR KEGG; dre:100536023; -.
DR CTD; 100506013; -.
DR ZFIN; ZDB-GENE-090313-116; apela.
DR GeneTree; ENSGT01040000240855; -.
DR HOGENOM; CLU_3049692_0_0_1; -.
DR OMA; GCSHRRC; -.
DR OrthoDB; 1635238at2759; -.
DR PRO; PR:P0DMC2; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 1.
DR Bgee; ENSDARG00000094729; Expressed in gastrula and 7 other tissues.
DR ExpressionAtlas; P0DMC2; baseline.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:ZFIN.
DR GO; GO:0031704; F:apelin receptor binding; IDA:UniProtKB.
DR GO; GO:0005179; F:hormone activity; IMP:UniProtKB.
DR GO; GO:0048018; F:receptor ligand activity; TAS:ZFIN.
DR GO; GO:0007512; P:adult heart development; ISS:UniProtKB.
DR GO; GO:0035479; P:angioblast cell migration from lateral mesoderm to midline; IMP:ZFIN.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0060183; P:apelin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0042074; P:cell migration involved in gastrulation; IMP:ZFIN.
DR GO; GO:0090134; P:cell migration involved in mesendoderm migration; IDA:ZFIN.
DR GO; GO:0043009; P:chordate embryonic development; IMP:ZFIN.
DR GO; GO:0060976; P:coronary vasculature development; ISS:UniProtKB.
DR GO; GO:0061371; P:determination of heart left/right asymmetry; IMP:ZFIN.
DR GO; GO:0007368; P:determination of left/right symmetry; IMP:ZFIN.
DR GO; GO:0071910; P:determination of liver left/right asymmetry; IMP:ZFIN.
DR GO; GO:0035050; P:embryonic heart tube development; ISS:UniProtKB.
DR GO; GO:0007492; P:endoderm development; IMP:UniProtKB.
DR GO; GO:0035987; P:endodermal cell differentiation; IMP:ZFIN.
DR GO; GO:0007507; P:heart development; IMP:UniProtKB.
DR GO; GO:0070121; P:Kupffer's vesicle development; IMP:ZFIN.
DR GO; GO:0090133; P:mesendoderm migration; IMP:UniProtKB.
DR GO; GO:0007509; P:mesoderm migration involved in gastrulation; IMP:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISS: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:0045823; P:positive regulation of heart contraction; ISS:UniProtKB.
DR GO; GO:1901165; P:positive regulation of trophoblast cell migration; ISS:UniProtKB.
DR GO; GO:0001570; P:vasculogenesis; ISS:UniProtKB.
PE 1: Evidence at protein level;
KW Angiogenesis; Developmental protein; Differentiation; Gastrulation;
KW Hormone; Reference proteome; Secreted; Signal.
FT SIGNAL 1..22
FT /evidence="ECO:0000305|PubMed:24407481"
FT CHAIN 23..58
FT /note="Apelin receptor early endogenous ligand"
FT /id="PRO_0000425559"
FT MUTAGEN 22
FT /note="A->W: Abolishes extracellular localization."
FT /evidence="ECO:0000269|PubMed:24407481"
SQ SEQUENCE 58 AA; 7021 MW; BC4E7D945707AA2F CRC64;
MRFFHPLYLL LLLLTVLVLI SADKHGTKHD FLNLRRKYRR HNCPKKRCLP LHSRVPFP
