PRLR

Summary

PRLR (prolactin receptor, HGNC:9446) is a protein-coding gene on chromosome 5p13.2, encoding Prolactin receptor (P16471). This is a receptor for the anterior pituitary hormone prolactin (PRL).

This gene encodes a receptor for the anterior pituitary hormone, prolactin, and belongs to the type I cytokine receptor family. Prolactin-dependent signaling occurs as the result of ligand-induced dimerization of the prolactin receptor. Several alternatively spliced transcript variants encoding different membrane-bound and soluble isoforms have been described for this gene, which may function to modulate the endocrine and autocrine effects of prolactin in normal tissue and cancer.

Source: NCBI Gene 5618 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial hyperprolactinemia (Supportive, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 96 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes
• MANE Select transcript: NM_000949

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9446
Approved symbol	PRLR
Name	prolactin receptor
Location	5p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000113494
Ensembl biotype	protein_coding
OMIM	176761
Entrez	5618

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 21 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000231423, ENST00000310101, ENST00000348262, ENST00000397391, ENST00000503330, ENST00000504500, ENST00000508107, ENST00000509140, ENST00000509839, ENST00000509934, ENST00000511486, ENST00000513753, ENST00000514088, ENST00000514206, ENST00000515839, ENST00000542609, ENST00000618457, ENST00000618625, ENST00000619676, ENST00000620785, ENST00000852369, ENST00000852370, ENST00000852371, ENST00000852372, ENST00000852373

RefSeq mRNA: 6 — MANE Select: NM_000949 NM_000949, NM_001204314, NM_001204315, NM_001204316, NM_001204317, NM_001204318

CCDS: CCDS3909, CCDS56358, CCDS56359, CCDS56360, CCDS56361, CCDS56362

Canonical transcript exons

ENST00000618457 — 10 exons

Exon	Start	End
ENSE00001209814	35089551	35089663
ENSE00001267139	35118061	35118122
ENSE00001793279	35086208	35086340
ENSE00003490130	35068216	35068285
ENSE00003506299	35068779	35068878
ENSE00003587122	35070124	35070265
ENSE00003607697	35072575	35072744
ENSE00003718395	35230268	35230487
ENSE00003742082	35084470	35084639
ENSE00003850479	35055702	35066102

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 92.39.

FANTOM5 (CAGE): breadth broad, TPM avg 3.3165 / max 230.3872, expressed in 493 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61271	1.7771	341
61272	0.6139	214
61269	0.2880	127
61261	0.1217	13
61267	0.1015	19
61257	0.0940	44
61265	0.0814	38
61260	0.0574	12
61273	0.0506	22
61270	0.0457	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	92.39	gold quality
choroid plexus epithelium	UBERON:0003911	90.72	gold quality
seminal vesicle	UBERON:0000998	89.48	gold quality
endocervix	UBERON:0000458	85.03	gold quality
decidua	UBERON:0002450	83.02	gold quality
left adrenal gland	UBERON:0001234	82.90	gold quality
jejunal mucosa	UBERON:0000399	82.51	gold quality
right adrenal gland cortex	UBERON:0035827	82.45	gold quality
left adrenal gland cortex	UBERON:0035825	82.37	gold quality
right adrenal gland	UBERON:0001233	82.32	gold quality
adrenal cortex	UBERON:0001235	81.88	gold quality
ectocervix	UBERON:0012249	81.69	gold quality
body of uterus	UBERON:0009853	81.66	gold quality
endometrium	UBERON:0001295	81.47	gold quality
adrenal gland	UBERON:0002369	81.25	gold quality
uterus	UBERON:0000995	80.12	gold quality
mammary duct	UBERON:0001765	78.59	gold quality
adult mammalian kidney	UBERON:0000082	78.43	gold quality
myometrium	UBERON:0001296	78.33	gold quality
uterine cervix	UBERON:0000002	77.87	gold quality
epithelium of mammary gland	UBERON:0003244	77.51	gold quality
cauda epididymis	UBERON:0004360	77.07	gold quality
duodenum	UBERON:0002114	76.83	gold quality
rectum	UBERON:0001052	76.82	gold quality
corpus epididymis	UBERON:0004359	76.00	gold quality
kidney	UBERON:0002113	75.84	gold quality
thoracic mammary gland	UBERON:0005200	75.71	gold quality
mammary gland	UBERON:0001911	75.68	gold quality
liver	UBERON:0002107	75.59	gold quality
female reproductive system	UBERON:0000474	75.50	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-23	yes	2077.26
E-CURD-119	yes	31.53
E-ANND-3	yes	14.40

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FOXO3	Repression

Upstream regulators (CollecTRI, top): CEBPB, CEBPG, ESR1, HOXA1, NR1I2, NR5A1, SP1, SP3, STAT5A, STAT5B

miRNA regulators (miRDB)

438 targeting PRLR, 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-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684

Literature-anchored findings (GeneRIF, showing 40)

• Review: Prolactin receptor signal transduction (PMID:11721697)
• results presented are consistent with a role of the PRL-PRLR system in bone/cartilage formation/repair processes (PMID:11997178)
• Genomic regions containing exons for human prolactin receptor, and 5’-flanking and intronic sequences, were determined and their order was established in chromosome 5p14-13. (PMID:12021177)
• Given its apparent widespread expression, this PRLr isoform may contribute to PRL action. (PMID:12351696)
• Plasma prolactin elevated in exercise and correlated with total prolactin-receptor expression per B lymphocyte. Increase in prolactin-receptor per B lymphocyte in response to exercise. Increased circulating B lymphocytes expressing prolactin receptor. (PMID:12391112)
• Results demonstrate a stimulatory effect of estradiol on the expression of human prolactin receptor mRNA species with alternative exons-1, hE1(3) and hE1(N1)in breast cancer cells. (PMID:12477494)
• To evaluate a possible role of prolactin receptor genes in SLE & MS formed an association study of PRLR SNPs was done. No statistically significant difference in the prolactin allele distribution was observed for any of the tested variations. (PMID:12559630)
• the interaction between Cyclophilin A and the PRLR plays a differential regulatory role in the various signaling pathways leading from the PRLR. (PMID:12668872)
• results demonstrate a direct effect of prolactin, via functional prolactin receptors, in reducing the lipoprotein lipase activity in human adipose tissue (PMID:12679477)
• prolactin signaling is attenuated by phosphorylation of the prolactin receptor on Thr391 (PMID:12819209)
• expression in hepatocytes was maximum in secondary liver cancer, high in obstructive jaundice, and less in cholelithiasis; expression in cholangiocytes was higher than in hepatocytes and was maximum during obstructive jaundice (PMID:12937675)
• data indicate that the prolactin receptor is a novel SCF(beta-TrCP) substrate and implicate beta-TrCP as an important negative regulator of prolactin signaling and cellular responses to this hormone (PMID:15082796)
• A150C (Leu–>Ile) transversion at exon 6 of PRLR was detected.Polymorphism of prolactin receptors might play a role in mammary carcinogenesis (PMID:15119991)
• transactivation occurs through an indirect interaction between erbB2 and prolactin or leptin receptors (PMID:15135067)
• Data support an “induced-fit” model for prolactin receptor binding where binding of the first receptor to human prolactin induces a conformation change in the hormone creating the second receptor-binding site. (PMID:15504038)
• Prolactin receptor mediates the Vav2 and Nek3 interaction. (PMID:15618286)
• Responsiveness of ovarian carcinomas to prolactin suggest that the prolactin/prolactin receptor system may be a new therapeutic target of ovarian carcinomas. (PMID:15700312)
• prolactin binding initiates limited proteasomal cleavage of its receptor, generating a cell-associated fragment containing the extracellular domain; findings described new potential mediator of prolactin action (PMID:16103113)
• phosphorylation of prolactin receptor on Ser349 is decreased in breast cancer cells lines and primary cancer tissue that exhibit stabilization and accumulation of prolactin receptor (PMID:16278670)
• Prolactin acts on the preformed Long Form homodimer to induce active signal transduction, while Short Form heterodimer lacks cytoplasmic sequences essential for activation. (PMID:16556730)
• a novel Estradiol-regulated non-estrogen responsive element-dependent transcriptional mechanism that mediates hPRLR expression (PMID:16651265)
• The data suggest that prolactin synergistically augments epidermal growth factor signaling in T47D breast cancer cells at least in part by lessening EGF-induced epidermal growth factor receptor downregulation. (PMID:16785991)
• An analysis of changes in the the expression of the prolactin receptor in liver fibrosis and liver cirrhosis. (PMID:17177141)
• The data revealed a widespread expresion of PRLR in normal and neoplastic human thyroid tissues. (PMID:17525486)
• residual agonism can be abolished either by further disrupting hormone site 2-receptor contacts by N-terminal deletion, as in Del1-9-G129R-human prolactin (hPRL), or by stabilizing hPRL and constraining its intrinsic flexibility, as in G129V-hPRL (PMID:17785459)
• In this comprehensive analysis covering 59 kb of the PRL locus and 210 kb of the PRLR locus, we found no significant association between common variation in these candidate genes and breast cancer risk or plasma PRL levels. (PMID:18053149)
• Results demonstrate that altered extracellular domain conformation, and not just a change in bulk, produces altered conformation of the intracellular signaling region of the receptors. (PMID:18081308)
• The resulting pattern of findings confirmed the hypotheses of the significance of the genes involved in the development of affiliative behaviors in the manifestation of ASD, the strongest results were obtained for allelic associations with the PRLR genes. (PMID:18207134)
• Prolactin promotes phosphorylation of PRLr on Ser349 and accelerates endocytosis of PRLr. Prolactin stimulated PRLr phosphorylation, endocytosis, and degradation in Jak2-null cells reconstituted with wild type Jak2. (PMID:18252943)
• GSK3 beta is a bona fide PRLr kinase that phosphorylates PRLr on Ser(349) and is required for the recognition of PRLr by beta Trcp, as well as for PRLr ubiquitination and degradation (PMID:18316598)
• The results of experiments using forced expression of ubiquitin mutants indicate that PRLr polyubiquitination via K63-linked chains is important for efficient interaction of PRLr with AP2 as well as for efficient internalization. (PMID:18573876)
• Mechanisms controlling PRLR isoform expression in the fallopian tube. (PMID:18596217)
• Prolactin receptor is significantly more expressed in male breast carcinoma than in gynaecomastia, and with different patterns of reactivity, suggesting a role for prolactin in male breast carcinogenesis. (PMID:18613925)
• Autocrine prolactin appears to act as an inducible survival factor in a clonogenic subpopulation of breast cancer cells (PMID:18681966)
• a heterozygous single nucleotide polymorphism in exon 6 of the PrlR gene, encoding Ile(146)–>Leu substitution in its extracellular domain confers constitutive activity to the receptor variant (PMID:18779591)
• Data indicate that src family kinases are key mediators of ligand-initiated prolactin receptor internalization, down-regulation, and signal transduction in breast cancer cells. (PMID:19056863)
• Even a very low level of PRLR expression was found to be sufficient to mediate PRL responsiveness in breast cancer cell lines. (PMID:19153125)
• Results suggest that the prolactin receptor conformation as stabilized by S-S bonds is required for the inhibitory action of S1b on prolactin-induced LF-mediated function and JAK2 association. (PMID:19273600)
• Human mammary epithelial cells harboring degradation-resistant PRLr display accelerated proliferation and increased invasive growth. (PMID:19276348)
• Increased expression of short form 1b prolactin receptor in prostate cancer cells decreases cell growth and cell migration and reduced invasive capacity. (PMID:19739126)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	prlra	ENSDARG00000016570
danio_rerio	prlrb	ENSDARG00000045955
mus_musculus	Prlr	ENSMUSG00000005268
rattus_norvegicus	Prlr	ENSRNOG00000057557

Paralogs (23): CRLF1 (ENSG00000006016), IL12RB2 (ENSG00000081985), IL5RA (ENSG00000091181), IL12RB1 (ENSG00000096996), IL27RA (ENSG00000104998), EBI3 (ENSG00000105246), GHR (ENSG00000112964), LIFR (ENSG00000113594), LEPR (ENSG00000116678), CSF3R (ENSG00000119535), CNTFR (ENSG00000122756), IL13RA2 (ENSG00000123496), IL13RA1 (ENSG00000131724), IL6ST (ENSG00000134352), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL2RG (ENSG00000147168), IL6R (ENSG00000160712), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CSF2RA (ENSG00000198223), CRLF2 (ENSG00000205755)

Protein

Protein identifiers

Prolactin receptor — P16471 (reviewed: P16471)

All UniProt accessions (8): P16471, D6R9E1, D6R9P5, D6R9V7, D6RAN9, D6RC67, D6RD41, D6RJC8

UniProt curated annotations — full annotation on UniProt →

Function. This is a receptor for the anterior pituitary hormone prolactin (PRL). Acts as a prosurvival factor for spermatozoa by inhibiting sperm capacitation through suppression of SRC kinase activation and stimulation of AKT. Isoform 4 is unable to transduce prolactin signaling. Isoform 6 is unable to transduce prolactin signaling.

Subunit / interactions. Homodimer upon hormone binding. Interacts with SMARCA1. Interacts with GH1. Interacts with CSH. Interacts with NEK3 and VAV2 and this interaction is prolactin-dependent.

Subcellular location. Membrane Secreted.

Tissue specificity. Expressed in breast, placenta, kidney, liver and pancreas.

Disease relevance. Multiple fibroadenomas of the breast (MFAB) [MIM:615554] A benign breast disease marked by lobuloalveolar growth with abnormally high proliferation of the epithelium, and characterized by the presence of more than 3 fibroadenomas in one breast. Fibroadenomas are adenomas containing fibrous tissue. The disease is caused by variants affecting the gene represented in this entry. Hyperprolactinemia (HPRL) [MIM:615555] A disorder characterized by increased levels of prolactin in the blood not associated with gestation or the puerperium. HPRL may result in infertility, hypogonadism, and galactorrhea. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is required for JAK interaction and/or activation.

Miscellaneous. Soluble isoform that appears specific for the BT-474 breast cancer cell line. Includes exon 11. Does not transduce prolactin signaling. Produced by deletion of part of exon 10 and frameshift. Does not transduce prolactin signaling. Splices from exon 7 to exon 11. SF1b with deletion of exon 4. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the type I cytokine receptor family. Type 1 subfamily.

Isoforms (9)

UniProt ID	Names	Canonical?
P16471-1	1	yes
P16471-2	2, Delta-S1
P16471-3	3
P16471-4	4, SF1a, Short form 1a
P16471-5	5, Intermediate
P16471-6	6, SF1b, Short form 1b
P16471-7	7, Delta 7/11
P16471-8	8, Delta 4-SF1b
P16471-9	9, SF1c, Short form 1c

RefSeq proteins (6): NP_000940, NP_001191243, NP_001191244, NP_001191245, NP_001191246, NP_001191247 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003528	Long_hematopoietin_rcpt_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015152	Growth/epo_recpt_lig-bind	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR050379	Type-I_Cytokine_Rcpt	Family

Pfam: PF09067

UniProt features (63 total): strand 20, splice variant 14, helix 4, glycosylation site 3, sequence variant 3, region of interest 3, short sequence motif 2, binding site 2, disulfide bond 2, topological domain 2, turn 2, domain 2, signal peptide 1, chain 1, compositionally biased region 1, transmembrane region 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
3N06	X-RAY DIFFRACTION	2
3NCE	X-RAY DIFFRACTION	2
3MZG	X-RAY DIFFRACTION	2.1
3N0P	X-RAY DIFFRACTION	2.1
3NCB	X-RAY DIFFRACTION	2.1
3D48	X-RAY DIFFRACTION	2.5
3NCC	X-RAY DIFFRACTION	2.5
3NCF	X-RAY DIFFRACTION	2.8
1BP3	X-RAY DIFFRACTION	2.9
4I18	X-RAY DIFFRACTION	3.24
2LFG	SOLUTION NMR
2N7I	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16471-F1	61.67	0.30

Antibody-complex structures (SAbDab): 1 — 4I18

Functional residue map

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

Ligand- & substrate-binding residues (2): 211; 212

Disulfide bonds (2): 36–46, 75–86

Glycosylation sites (3): 59, 104, 233

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1170546	Prolactin receptor signaling
R-HSA-982772	Growth hormone receptor signaling

MSigDB gene sets: 395 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOZGIT_ESR1_TARGETS_DN, GOBP_MAMMARY_GLAND_EPITHELIUM_DEVELOPMENT, GOBP_GROWTH, GOCC_CELL_SURFACE, GOBP_B_CELL_PROLIFERATION, GOBP_MAMMARY_GLAND_EPITHELIAL_CELL_DIFFERENTIATION

GO Biological Process (20): steroid biosynthetic process (GO:0006694), activation of transmembrane receptor protein tyrosine kinase activity (GO:0007171), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), embryo implantation (GO:0007566), lactation (GO:0007595), positive regulation of cell population proliferation (GO:0008284), response to bacterium (GO:0009617), cytokine-mediated signaling pathway (GO:0019221), regulation of cell adhesion (GO:0030155), regulation of epithelial cell differentiation (GO:0030856), positive regulation of B cell proliferation (GO:0030890), activation of Janus kinase activity (GO:0042976), negative regulation of apoptotic process (GO:0043066), mammary gland epithelial cell differentiation (GO:0060644), prostate gland growth (GO:0060736), mammary gland alveolus development (GO:0060749), cellular response to granulocyte macrophage colony-stimulating factor stimulus (GO:0097011), positive regulation of cold-induced thermogenesis (GO:0120162), prolactin signaling pathway (GO:0038161), mammary gland epithelium development (GO:0061180)

GO Molecular Function (8): prolactin receptor activity (GO:0004925), lipid binding (GO:0008289), peptide hormone binding (GO:0017046), protein kinase binding (GO:0019901), cytokine binding (GO:0019955), metal ion binding (GO:0046872), cytokine receptor activity (GO:0004896), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), endosome lumen (GO:0031904), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cytokine Signaling in Immune system	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
activation of protein kinase activity	2
mammary gland development	2
cellular response to cytokine stimulus	2
epithelial cell differentiation	2
cytokine-mediated signaling pathway	2
binding	2
steroid metabolic process	1
lipid biosynthetic process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
protein-containing complex assembly	1
cell surface receptor signaling pathway via STAT	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
body fluid secretion	1
milk ejection reflex	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
response to other organism	1
cell surface receptor signaling pathway	1
cell adhesion	1
regulation of cellular process	1
regulation of cell differentiation	1
regulation of multicellular organismal development	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of B cell activation	1
peptidyl-tyrosine phosphorylation	1
positive regulation of receptor signaling pathway via JAK-STAT	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
mammary gland epithelium development	1
developmental process involved in reproduction	1
prostate gland development	1
organ growth	1
anatomical structure development	1

Protein interactions and networks

STRING

942 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRLR	PRL	P01236	999
PRLR	JAK2	O60674	919
PRLR	CSH1	P01243	895
PRLR	CSH1	P01243	893
PRLR	STAT5A	P42229	870
PRLR	STAT5B	P51692	866
PRLR	CSN2	P05814	802
PRLR	EPO	P01588	730
PRLR	SRR	Q9GZT4	687
PRLR	SOCS1	O15524	668
PRLR	ESR1	P03372	643
PRLR	HSD17B7	P56937	631
PRLR	GH1	P01241	624
PRLR	SOCS2	O14508	613
PRLR	PGR	P06401	611

IntAct

13 interactions, top by confidence:

A	B	Type	Score
PLPP6	PRLR	psi-mi:“MI:0915”(physical association)	0.560
PRLR	PLPP6	psi-mi:“MI:0915”(physical association)	0.560
PRLR	INSIG2	psi-mi:“MI:0915”(physical association)	0.560
PRLR	YWHAZ	psi-mi:“MI:0915”(physical association)	0.400
PRLR	H1-1	psi-mi:“MI:0915”(physical association)	0.400
NEK3	PRLR	psi-mi:“MI:0915”(physical association)	0.400
VAV2	PRLR	psi-mi:“MI:0915”(physical association)	0.400
YWHAZ	PRLR	psi-mi:“MI:0915”(physical association)	0.400
INSIG2	PRLR	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): PRLR (Affinity Capture-RNA), PPIA (Affinity Capture-Western), PPIA (Reconstituted Complex), INSIG2 (Two-hybrid), PPAPDC2 (Two-hybrid), PRLR (Affinity Capture-Western), TEC (Affinity Capture-Western), PRLR (Affinity Capture-Western), VAV1 (Reconstituted Complex), TEC (Reconstituted Complex), PRLR (Affinity Capture-Western), VAV1 (Affinity Capture-Western), HIST1H1A (Proximity Label-MS), PRLR (Affinity Capture-Western), JAK2 (Affinity Capture-Western)

ESM2 similar proteins: A0MSX9, A5HJM1, C8AW46, C8AW47, K9JA28, O02671, O35664, O46561, O70458, P05710, P14787, P15260, P15261, P16297, P16471, P16871, P16872, P16882, P26896, P48356, P48357, P48551, P97378, Q08501, Q13651, Q28172, Q28235, Q38IC7, Q38J85, Q3SYS8, Q4W815, Q5VWK5, Q61727, Q62959, Q63257, Q65Z14, Q6JTA8, Q6PHB0, Q80VH0, Q80XZ4

Diamond homologs: O02671, P16471, P48356, P48357, Q62959, Q9MYL0, O46561, O46600, O75462, P05710, P10912, P14787, P16310, P16882, P19756, P19941, P79108, P79194, Q02092, Q04594, Q08501, Q28172, Q28235, Q28575, Q6JTA8, Q90374, Q90375, Q91094, Q91513, Q95JF2, Q95ML5, Q9JI97, Q9JM58, Q9XSZ1, Q9TU69, P40189, P78552

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GH1	up-regulates	PRLR	binding
PRL	up-regulates	PRLR	binding
PRLR	“down-regulates quantity by repression”	FOXO3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	68
Likely benign	10
Benign	3

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
599315	NM_000949.7(PRLR):c.511C>T (p.Arg171Ter)	Pathogenic
599316	NM_000949.7(PRLR):c.806C>T (p.Pro269Leu)	Pathogenic
89027	NM_000949.7(PRLR):c.635A>G (p.His212Arg)	Pathogenic
929748	NM_000949.7(PRLR):c.851T>G (p.Leu284Trp)	Likely pathogenic

SpliceAI

2803 predictions. Top by Δscore:

Variant	Effect	Δscore
5:35066098:CCCTT:C	acceptor_gain	1.0000
5:35066099:CCTTC:C	acceptor_gain	1.0000
5:35066100:CTT:C	acceptor_gain	1.0000
5:35066101:TTC:T	acceptor_loss	1.0000
5:35066103:C:CC	acceptor_gain	1.0000
5:35066106:T:TC	acceptor_gain	1.0000
5:35068781:ATAG:A	donor_gain	1.0000
5:35068781:ATAGC:A	donor_gain	1.0000
5:35070118:GCTCA:G	donor_loss	1.0000
5:35070119:CTCAC:C	donor_loss	1.0000
5:35070120:TCA:T	donor_loss	1.0000
5:35070121:CAC:C	donor_loss	1.0000
5:35070122:A:AC	donor_gain	1.0000
5:35070122:A:C	donor_loss	1.0000
5:35070123:C:CC	donor_gain	1.0000
5:35070123:C:CG	donor_loss	1.0000
5:35070123:CCA:C	donor_gain	1.0000
5:35070123:CCACT:C	donor_gain	1.0000
5:35070261:TGGAT:T	acceptor_gain	1.0000
5:35070262:GGAT:G	acceptor_gain	1.0000
5:35070263:GAT:G	acceptor_gain	1.0000
5:35070265:TCT:T	acceptor_loss	1.0000
5:35070266:C:CA	acceptor_loss	1.0000
5:35070266:C:CC	acceptor_gain	1.0000
5:35070271:G:C	acceptor_gain	1.0000
5:35070271:G:GC	acceptor_gain	1.0000
5:35072570:CTCA:C	donor_loss	1.0000
5:35072571:TCA:T	donor_loss	1.0000
5:35072572:CAC:C	donor_loss	1.0000
5:35072573:A:T	donor_loss	1.0000

AlphaMissense

4099 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:35086267:C:A	W48C	1.000
5:35086267:C:G	W48C	1.000
5:35084586:C:G	C86S	0.998
5:35084587:A:T	C86S	0.998
5:35072667:A:G	W151R	0.997
5:35072667:A:T	W151R	0.997
5:35084580:A:C	F88C	0.997
5:35084619:C:G	C75S	0.997
5:35084620:A:T	C75S	0.997
5:35086269:A:G	W48R	0.997
5:35086269:A:T	W48R	0.997
5:35086304:C:G	C36S	0.997
5:35086305:A:T	C36S	0.997
5:35070189:C:G	R207P	0.996
5:35084580:A:G	F88S	0.996
5:35084585:G:C	C86W	0.996
5:35084586:C:T	C86Y	0.996
5:35072665:C:A	W151C	0.995
5:35072665:C:G	W151C	0.995
5:35084530:C:G	A105P	0.995
5:35084555:C:A	W96C	0.995
5:35084555:C:G	W96C	0.995
5:35084579:A:C	F88L	0.995
5:35084579:A:T	F88L	0.995
5:35084581:A:G	F88L	0.995
5:35086274:C:G	C46S	0.995
5:35086275:A:T	C46S	0.995
5:35086280:A:G	F44S	0.995
5:35086301:C:G	R37P	0.995
5:35070161:A:C	S216R	0.994

dbSNP variants (sampled 300 via entrez): RS1000003658 (5:35098890 A>C), RS1000004965 (5:35054632 G>A,T), RS1000016688 (5:35078478 C>G,T), RS1000024071 (5:35068551 G>A,C), RS1000029959 (5:35146126 C>T), RS1000100061 (5:35204769 T>C), RS1000100177 (5:35118159 A>G,T), RS1000101683 (5:35146387 G>T), RS1000105672 (5:35104193 G>A), RS1000114111 (5:35116454 C>T), RS1000152711 (5:35117921 C>T), RS1000210293 (5:35102139 C>A), RS1000224304 (5:35207502 G>T), RS1000244433 (5:35171554 C>G), RS1000250091 (5:35175327 T>C,G)

Disease associations

OMIM: gene MIM:176761 | disease phenotypes: MIM:614307, MIM:615555, MIM:181500, MIM:615554

GenCC curated gene-disease

Disease	Classification	Inheritance
familial hyperprolactinemia	Supportive	Autosomal dominant

Mondo (5): alpha-methylacyl-CoA racemase deficiency (MONDO:0013681), familial hyperprolactinemia (MONDO:0014250), schizophrenia (MONDO:0005090), multiple fibroadenoma of the breast (MONDO:0014249), primary ovarian failure (MONDO:0005387)

Orphanet (5): Congenital bile acid synthesis defect type 4 (Orphanet:79095), Familial hyperprolactinemia (Orphanet:397685), OBSOLETE: Multiple fibroadenoma of the breast (Orphanet:50920), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

16 total (17 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000134	Female hypogonadism
HP:0000141	Amenorrhea
HP:0000789	Infertility
HP:0000870	Increased circulating prolactin concentration
HP:0000876	Oligomenorrhea
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0008222	Female infertility
HP:0010619	Fibroadenoma of the breast
HP:0011462	Young adult onset
HP:0012886	Hemorrhagic ovarian cyst
HP:0031109	Agalactia
HP:0100829	Galactorrhea
HP:0100753	Schizophrenia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003219_22	Advanced age-related macular degeneration	2.000000e-08
GCST004251_4	Paneth cell defects in Crohn’s disease	2.000000e-06
GCST006248_11	Response to lurasidone in schizophrenia	8.000000e-06
GCST007576_135	Chronotype	2.000000e-09
GCST008895_2	Psychotic experience	3.000000e-08
GCST009391_1689	Metabolite levels	8.000000e-06
GCST009391_1912	Metabolite levels	6.000000e-83
GCST009391_765	Metabolite levels	9.000000e-06
GCST90000025_26	Appendicular lean mass	1.000000e-13
GCST90093090_3	DHEAS levels	2.000000e-07

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0007963	abnormal paneth cell measurement
EFO:0008328	chronotype measurement
EFO:0005940	psychotic symptoms
EFO:0010343	cholesteryl ester 18:0 measurement
EFO:0010464	beta-aminoisobutyric acid measurement
EFO:0010391	sphingomyelin 16:0 measurement
EFO:0004980	appendicular lean mass
EFO:0007001	dehydroepiandrosterone sulphate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C565768	Alpha-Methylacyl-CoA Racemase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5588 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Prolactin receptor family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
prolactin	Agonist	8.05	pKd

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.70	Kd	2000	nM	CHEMBL504608
5.52	Kd	3000	nM	CHEMBL486199

PubChem BioAssay actives

2 with measured affinity, of 3 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[(2S,5S,8S,11S,14S,17S,20S,23S)-14-(3-amino-3-oxopropyl)-8,20-bis[3-(diaminomethylideneamino)propyl]-17-(hydroxymethyl)-11-[(4-hydroxyphenyl)methyl]-5-methyl-3,6,9,12,15,18,21,24-octaoxo-23-propan-2-yl-1,4,7,10,13,16,19,22-octazacyclotetracos-2-yl]propanoic acid	366992: Binding affinity to human prolactin receptor extracellular binding domain by surface plasmon response	kd	2.0000	uM
3-[(2S,5R,8R,11S,14S,17S,20S,23S)-20-[3-(diaminomethylideneamino)propyl]-14-(hydroxymethyl)-11,17-bis[(4-hydroxyphenyl)methyl]-5-methyl-8-(2-methylpropyl)-3,6,9,12,15,18,21,24-octaoxo-23-propan-2-yl-1,4,7,10,13,16,19,22-octazacyclotetracos-2-yl]propanoic acid	366992: Binding affinity to human prolactin receptor extracellular binding domain by surface plasmon response	kd	3.0000	uM

CTD chemical–gene interactions

52 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, increases expression	7
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Progesterone	affects cotreatment, decreases expression, increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression, increases expression	2
(+)-JQ1 compound	decreases expression	2
Formaldehyde	increases expression	2
Testosterone	increases expression	2
Particulate Matter	decreases expression, increases abundance	2
methyleugenol	decreases expression	1
bisphenol A	increases expression	1
arsenite	increases methylation	1
methylparaben	increases expression	1
o,p’-DDT	decreases expression	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
latrunculin A	decreases uptake	1
butylparaben	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
glycidamide	decreases expression	1
chromium hexavalent ion	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
azaspiracid	decreases uptake	1
clothianidin	decreases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
Acetaminophen	decreases expression	1
Glyphosate	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL980832	Binding	Binding affinity to human prolactin receptor extracellular binding domain by surface plasmon response	Synthesis and screening of a cyclic peptide library: discovery of small-molecule ligands against human prolactin receptor. — Bioorg Med Chem

Cellosaurus cell lines

7 cell lines: 3 transformed cell line, 2 cancer cell line, 1 spontaneously immortalized cell line, 1 factor-dependent cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E6RI	Genomeditech CHO-K1 H_PRLR	Spontaneously immortalized cell line	Female
CVCL_E7I6	HEK293 HL5	Transformed cell line	Female
CVCL_E7I7	HEK293 HL10	Transformed cell line	Female
CVCL_E7I8	HEK293 HL21	Transformed cell line	Female
CVCL_E7I9	Ba/F3-LP	Factor-dependent cell line
CVCL_TH10	HAP1 PRLR (-) 1	Cancer cell line	Male
CVCL_TH11	HAP1 PRLR (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00541554	PHASE4	UNKNOWN	Reversal of Antipsychotic-Induced Hyperprolactinemia, Weight Gain, Hyperglycemia and Dyslipidemia
NCT00625950	PHASE4	COMPLETED	Endometriosis Patients Undergoing Quinagolide Treatment
NCT00889512	PHASE4	TERMINATED	The Luveris In Vitro Fertilization Trial
NCT01085383	PHASE4	COMPLETED	Aripiprazole and Prolactin Study
NCT01742390	PHASE4	UNKNOWN	A Multicenter Study to Evaluate the Effects of Switching to Aripiprazole 12 Weeks on the Sexual Dysfunction From Risperidone or Paliperidone in Patients With Schizophrenia Spectrum Disorders or Bipolar Spectrum Disorders
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia