APELA

Summary

APELA (apelin receptor early endogenous ligand, HGNC:48925) is a protein-coding gene on chromosome 4q32.3, encoding Apelin receptor early endogenous ligand (P0DMC3). Peptide hormone that functions as endogenous ligand for the G-protein-coupled apelin receptor (APLNR/APJ), that plays a role in the regulation of normal cardiovascular function and fluid homeostasis.

This gene encodes a peptide hormone that binds to the Apelin receptor. The encoded protein is required for heart development in zebrafish and has been shown to maintain self-renewal of human embryonic stem cells through activation of the PI3K/AKT pathway. Experiments in human and mouse cell lines point to additional roles for the encoded protein in angiogenesis and regulation of vascular tone.

Source: NCBI Gene 100506013 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 3 total
• MANE Select transcript: NM_001297550

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:48925
Approved symbol	APELA
Name	apelin receptor early endogenous ligand
Location	4q32.3
Locus type	gene with protein product
Status	Approved
Aliases	Ende, ELA, tdl
Ensembl gene	ENSG00000248329
Ensembl biotype	protein_coding
OMIM	615594
Entrez	100506013

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000505269, ENST00000507152, ENST00000510062, ENST00000515275, ENST00000515405, ENST00000914507, ENST00000914508, ENST00000914509, ENST00000914510

RefSeq mRNA: 1 — MANE Select: NM_001297550 NM_001297550

CCDS: CCDS77980

Canonical transcript exons

ENST00000507152 — 3 exons

Exon	Start	End
ENSE00002045192	164877178	164877407
ENSE00002073571	164878920	164879009
ENSE00002082665	164895416	164897527

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 78.53.

FANTOM5 (CAGE): breadth broad, TPM avg 6.0364 / max 519.9449, expressed in 242 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50422	2.9105	207
50418	1.3521	146
50420	0.6104	101
50421	0.5576	96
50423	0.2018	81
50424	0.2005	74
50419	0.1322	51
50425	0.0712	41

Top tissues by expression

231 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	78.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.21	silver quality
buccal mucosa cell	CL:0002336	73.13	silver quality
mucosa of paranasal sinus	UBERON:0005030	71.42	gold quality
palpebral conjunctiva	UBERON:0001812	69.96	gold quality
lower esophagus mucosa	UBERON:0035834	61.81	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	61.04	gold quality
prostate gland	UBERON:0002367	60.59	gold quality
adrenal tissue	UBERON:0018303	57.89	gold quality
metanephros cortex	UBERON:0010533	56.92	gold quality
nasal cavity mucosa	UBERON:0001826	56.03	gold quality
skin of abdomen	UBERON:0001416	55.37	gold quality
placenta	UBERON:0001987	55.27	gold quality
metanephros	UBERON:0000081	55.06	gold quality
skin of hip	UBERON:0001554	55.01	silver quality
lower lobe of lung	UBERON:0008949	54.25	silver quality
cerebellar vermis	UBERON:0004720	53.28	gold quality
calcaneal tendon	UBERON:0003701	52.90	gold quality
zone of skin	UBERON:0000014	52.13	gold quality
kidney	UBERON:0002113	50.69	gold quality
skin of leg	UBERON:0001511	50.15	gold quality
sural nerve	UBERON:0015488	49.83	silver quality
tendon	UBERON:0000043	49.53	gold quality
adult mammalian kidney	UBERON:0000082	49.35	gold quality
cortex of kidney	UBERON:0001225	49.16	gold quality
bronchial epithelial cell	CL:0002328	49.09	silver quality
smooth muscle tissue	UBERON:0001135	48.94	gold quality
tonsil	UBERON:0002372	48.71	gold quality
bronchus	UBERON:0002185	48.66	silver quality
rectum	UBERON:0001052	48.42	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-109979	yes	57.44
E-MTAB-3929	yes	32.96
E-MTAB-9388	yes	12.16
E-MTAB-8271	yes	8.55
E-ANND-3	yes	3.92
E-MTAB-6524	no	264.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

136 targeting APELA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 28)

• These results show ELA exhibits a cardiovascular profile comparable to apelin, is down-regulated in human disease and rodent Pulmonary Arterial Hypertension (PAH) models and that exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use for PAH in man. (PMID:28137936)
• The ELA-APJ axis protects from pressure overload-induced heart failure possibly via suppression of ACE expression and pathogenic angiotensin II signaling. (PMID:28371822)
• Studies indicate that the Elabela-APJ (apelin receptor) axis may protect against pressure overload-induced heart failure. (PMID:29036564)
• Disruption of APELA expression in OCCC cell lines suppressed cell growth and migration, and altered cell-cycle progression. (PMID:29079036)
• ELA has an angiogenetic role in the progression of glial tumors (PMID:29694663)
• The results showed that the serum ELA levels decreased gradually with the deterioration of diabetic kidney disease from the stages of normal albuminuria, microalbuminuria, macroalbuminuria, to macroalbuminuria and elevated serum creatinine. (PMID:30048993)
• Given the role of apelin/APJ and Elabela/APJ in cardiovascular and other diseases, we believe that the combination of these agonists and antagonists with apelin and Elabela will play a corresponding role in various pathophysiological effects with further development of research. (PMID:30070701)
• The properties and biological functions of ELABELA are discussed in comparison with those of Apelin. (REVIEW) (PMID:30267732)
• No significant difference was found in plasma ELABELA levels in pregnant women who developed preeclampsia versus those who did not. (PMID:30576665)
• Variants in the 5’-UTR of APELA gene may account for variability of APELA expression among individuals with preeclampsia (PE) and may play a negative regulatory role in the pathogenesis of PE. (PMID:30719741)
• This study identified ELA as significantly decreased in late-onset preeclampsia. An in vitro study showed that the addition of ELA significantly increased the invasion ability and proliferation of trophoblast cells. (PMID:30860880)
• Apela Promotes Cardiomyocyte Differentiation from Transgenic Human Embryonic Stem Cell Lines. (PMID:31025171)
• decreased in maternal and cord blood in pre-eclampsia, relative to controls (PMID:31064239)
• Reduced ELABELA expression attenuates trophoblast invasion through the PI3K/AKT/mTOR pathway in early onset preeclampsia. (PMID:31546152)
• Peptide hormone ELABELA enhances extravillous trophoblast differentiation, but placenta is not the major source of circulating ELABELA in pregnancy. (PMID:31836787)
• Circulating levels of Elabela and Apelin in the second and third trimesters of pregnancies with gestational diabetes mellitus. (PMID:32208782)
• Elabela/Toddler and apelin bind differently to the apelin receptor. (PMID:32301550)
• ELA/APELA precursor cleaved by furin displays tumor suppressor function in renal cell carcinoma through mTORC1 activation. (PMID:32516140)
• Serum Elabela Levels Are Elevated in Patients with Hyperthyroidism. (PMID:32713880)
• Association between ELABELA Serum Concentrations in First Trimester and Pregnancy-Induced Hypertension. (PMID:33062670)
• Elabela levels in patients with type 2 diabetes: can it be a marker for diabetic nephropathy? (PMID:33163050)
• Elabela/toddler: New peptide with a promising future in cancer diagnostic and therapy. (PMID:34090960)
• Plasma Level of Elabela in Patients with Coronary Heart Disease and Its Correlation with the Disease Classification. (PMID:34276017)
• A Case-Control Study of the APELA Gene and Hypertensive Disorders of Pregnancy. (PMID:35630008)
• Reduced Apela/APJ system expression in patients with pulmonary artery hypertension secondary to chronic obstructive pulmonary disease. (PMID:36669444)
• Betatrophin, elabela, asprosin, glucagon and subfatin peptides in breast tissue, blood and milk in gestational diabetes. (PMID:36825397)
• Apelin/ELABELA-APJ system in cardiac hypertrophy: Regulatory mechanisms and therapeutic potential. (PMID:37062502)
• Therapeutic potential of apelin and Elabela in cardiovascular disease. (PMID:37562237)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Apelin receptor early endogenous ligand — P0DMC3 (reviewed: P0DMC3)

Alternative names: Protein Elabela, Protein Toddler

All UniProt accessions (2): P0DMC3, X5D2P3

UniProt curated annotations — full annotation on UniProt →

Function. Peptide hormone that functions as endogenous ligand for the G-protein-coupled apelin receptor (APLNR/APJ), that plays a role in the regulation of normal cardiovascular function and fluid homeostasis. Functions as a balanced agonist activating both G(i) protein pathway and beta-arrestin pathway of APLNR. Downstream G proteins activation, apelin can inhibit cAMP production and activate key intracellular effectors such as ERKs. On the other hand, APLNR activation induces beta-arrestin recruitment to the membrane leading to desensitization and internalization of the receptor. Required for mesendodermal differentiation, blood vessels formation and heart morphogenesis during early development and for adult cardiovascular homeostasis. Acts as a motogen by promoting mesendodermal cell migration during gastrulation by binding and activating APLNR. Acts as an early embryonic regulator of cellular movement with a role in migration and development of cardiac progenitor cells. May act as a chemoattractant for the activation of angioblast migration toward the embryonic midline, i.e. the position of the future vessel formation, during vasculogenesis. Positively regulates sinus venosus (SV)-derived endothelial cells migration into the developing heart to promote coronary blood vessel sprouting. Plays a role in placental vascular development; promotes placental trophoblast invasion and spiral artery remodeling in the uterus. Involved in the regulation of maternal cardiovascular homeostasis to prevent gestational hypertension and for potent cardioprotective functions during heart failure. Mediates myocardial contractility in an ERK1/2-dependent manner.

Subunit / interactions. Interacts with APLNR.

Subcellular location. Secreted. Extracellular space.

Tissue specificity. Expressed in the intima of blood vessels. Expressed in endothelial cells in blood vessels in the heart and lung. Expressed in cytotrophoblasts and syncytiotrophoblasts of first-trimester placental tissue and term placentas (at protein level). Not detected in smooth muscle cells or cardiomyocytes (at protein level). Expressed in kidney. Expressed in blood vessels. Expressed in embryonic (ESCs) and induced (iPSCs) pluripotent stem cells. Most highly expressed in undifferentiated embryonic stem cell and is rapidly down-regulated during differentiation.

Similarity. Belongs to the Elabela/Toddler family.

RefSeq proteins (1): NP_001284479* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR047853	ELA	Family

Pfam: PF22050

UniProt features (4 total): signal peptide 1, chain 1, glycosylation site 1, helix 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7W0P	ELECTRON MICROSCOPY	3.16
7W0O	ELECTRON MICROSCOPY	3.78
7W0N	ELECTRON MICROSCOPY	4.21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DMC3-F1	72.73	0.20

Antibody-complex structures (SAbDab): 3 — 7W0N, 7W0O, 7W0P

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1): 27

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 142 (showing top): GOBP_G_PROTEIN_COUPLED_RECEPTOR_INTERNALIZATION, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, chr4q32, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_PLACENTA_BLOOD_VESSEL_DEVELOPMENT

GO Biological Process (23): angiogenesis (GO:0001525), vasculogenesis (GO:0001570), G protein-coupled receptor signaling pathway (GO:0007186), endoderm development (GO:0007492), heart development (GO:0007507), mesoderm migration involved in gastrulation (GO:0007509), adult heart development (GO:0007512), embryonic heart tube development (GO:0035050), positive regulation of angiogenesis (GO:0045766), positive regulation of heart contraction (GO:0045823), apelin receptor signaling pathway (GO:0060183), placenta blood vessel development (GO:0060674), coronary vasculature development (GO:0060976), positive regulation of ERK1 and ERK2 cascade (GO:0070374), mesendoderm migration (GO:0090133), cell migration involved in mesendoderm migration (GO:0090134), positive regulation of trophoblast cell migration (GO:1901165), positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:1903589), positive regulation of G protein-coupled receptor internalization (GO:1904022), G protein-coupled receptor internalization (GO:0002031), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), gastrulation (GO:0007369), cell differentiation (GO:0030154)

GO Molecular Function (2): hormone activity (GO:0005179), apelin receptor binding (GO:0031704)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heart development	3
blood vessel morphogenesis	2
cell migration involved in gastrulation	2
blood vessel development	2
cellular anatomical structure	2
anatomical structure formation involved in morphogenesis	1
cell differentiation	1
G protein-coupled receptor activity	1
signal transduction	1
tissue development	1
animal organ development	1
circulatory system development	1
mesoderm formation	1
mesodermal cell migration	1
tissue migration	1
tube development	1
embryonic organ development	1
epithelium development	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
regulation of heart contraction	1
heart contraction	1
positive regulation of blood circulation	1
G protein-coupled receptor signaling pathway	1
placenta development	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
gastrulation	1
mesendoderm development	1
epithelium migration	1
mesendoderm migration	1
positive regulation of cell migration	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
trophoblast cell migration	1
regulation of trophoblast cell migration	1
positive regulation of reproductive process	1
positive regulation of endothelial cell proliferation	1

Protein interactions and networks

STRING

174 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APELA	APLNR	P35414	994
APELA	APLN	Q9ULZ1	859
APELA	SLN	O00631	438
APELA	ARRB2	P32121	422
APELA	ARRB1	P49407	391
APELA	AGT	P01019	370
APELA	STRIT1	P0DN84	349
APELA	F13A1	P00488	348
APELA	AP2B1	P21851	338
APELA	RBPJ	Q06330	335
APELA	ACE2	Q9BYF1	313
APELA	REN	P00797	309
APELA	AGTR1	P30556	297
APELA	OR14J1	Q9UGF5	290
APELA	GPR25	O00155	274
APELA	XPR1	Q9UBH6	274

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A0A2K253, A0A125S9D8, A0A125S9E9, A3EXD4, A9JLI3, B1P1C7, C7DQC2, C7DQY0, D2DGD9, D2Y2C5, D2Y2C6, D2Y2C7, D2Y2C8, E9Q7F5, F6JWU9, F6JWV2, O08546, O09133, O36403, O46227, O55758, O94339, P01500, P0C8U8, P0C8U9, P0C9G6, P0C9K1, P0DMC3, P0DP76, P0DPW1, P0DPW2, P0DTX2, P0DTX4, P18557, P18559, P26702, P36705, P89035, Q1A3Q7, Q2V311

Diamond homologs: P0DMC2, P0DMC3, P0DMC4, P0DP76

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

3 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

365 predictions. Top by Δscore:

Variant	Effect	Δscore
4:164878919:GTTA:G	acceptor_gain	1.0000
4:164878918:A:AG	acceptor_gain	0.9900
4:164878919:G:GG	acceptor_gain	0.9900
4:164878919:GTT:G	acceptor_gain	0.9800
4:164878994:G:GG	donor_gain	0.9800
4:164892750:A:T	acceptor_gain	0.9800
4:164895414:A:AG	acceptor_gain	0.9700
4:164895415:G:GG	acceptor_gain	0.9700
4:164878919:GTTAA:G	acceptor_gain	0.9600
4:164878971:GAT:G	donor_gain	0.9600
4:164895409:A:G	acceptor_gain	0.9600
4:164895411:TATA:T	acceptor_loss	0.9600
4:164895414:AGAT:A	acceptor_loss	0.9600
4:164895413:T:G	acceptor_gain	0.9500
4:164878914:CTTCA:C	acceptor_loss	0.9400
4:164878915:TTCA:T	acceptor_loss	0.9400
4:164878917:CA:C	acceptor_loss	0.9400
4:164891745:A:G	donor_gain	0.9300
4:164895415:GAT:G	acceptor_gain	0.9300
4:164895415:GATCT:G	acceptor_gain	0.9300
4:164879007:G:GT	donor_gain	0.9200
4:164895408:A:AG	acceptor_gain	0.9200
4:164878919:GT:G	acceptor_gain	0.9100
4:164879005:CTGAG:C	donor_loss	0.9100
4:164879006:TGAGG:T	donor_loss	0.9100
4:164879007:GAGG:G	donor_loss	0.9100
4:164879008:AG:A	donor_loss	0.9100
4:164879009:G:GC	donor_loss	0.9100
4:164879010:GT:G	donor_loss	0.9100
4:164879011:T:G	donor_loss	0.9100

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001358 (4:164884617 T>C), RS1000036066 (4:164879659 G>A,T), RS1000087907 (4:164896378 C>A,T), RS1000102997 (4:164881438 T>C), RS1000230742 (4:164898408 A>G), RS1000283353 (4:164898725 G>A), RS10005705 (4:164891216 A>C,G), RS1000735524 (4:164879670 C>T), RS1000794018 (4:164892131 CA>C), RS1000927868 (4:164897554 G>C), RS1001153367 (4:164891244 G>T), RS1001513547 (4:164886947 T>A), RS1001565713 (4:164887061 C>T), RS1001684254 (4:164898985 C>T), RS1002183257 (4:164876539 G>A,T)

Disease associations

OMIM: gene MIM:615594 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010219_7	Attention deficit hyperactivity disorder (inattention symptoms)	1.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
trichostatin A	increases expression	2
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
tebuconazole	decreases expression	1
entinostat	increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
belinostat	increases expression	1
Vorinostat	increases expression	1
Panobinostat	increases expression	1
Ethanol	decreases expression	1
Estradiol	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin M1	decreases expression	1
Okadaic Acid	decreases expression	1
p-Chloromercuribenzoic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.