Affinage

PRL

Prolactin · UniProt P01236

Round 2 corrected
Length
227 aa
Mass
25.9 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Prolactin (PRL) is a pituitary-derived peptide hormone that orchestrates lactation, reproductive function, metabolic homeostasis, and tissue remodeling through activation of the JAK2–STAT5 signaling axis and parallel MAPK and PI3K pathways. PRL is synthesized in the rough ER of lactotrophs, trafficked through the Golgi into secretory granules under tonic inhibitory control by dopamine acting via D2 receptors (PMID:743954, PMID:11739329); its secretion requires an intact C-terminal disulfide bond, as demonstrated by a human loss-of-function mutation (p.Arg220Ter) causing familial prolactin deficiency and alactogenesis (PMID:33770166). PRL binds the PRL receptor in a sequential 1:2 stoichiometry that activates constitutively associated JAK2, driving STAT5a/5b-dependent transcription of targets including cyclin D1 and β-casein, while the receptor's C-terminal cytoplasmic domain recruits phosphatases that negatively regulate MAPK output (PMID:22577091, PMID:11923474, PMID:10687859). Extrapituitary PRL expression from a Pit-1-independent upstream promoter activated by cAMP enables autocrine/paracrine functions in decidua, lymphocytes, and hair follicles, and cathepsin D cleavage of full-length PRL generates a 16 kDa antiangiogenic fragment that drives peripartum cardiomyopathy through exosomal miR-146a transfer to cardiomyocytes (PMID:8015553, PMID:17289576, PMID:23619365).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1978 High

    Defining the intracellular biosynthetic route of PRL—from ER synthesis through Golgi packaging to mature secretory granules—established the timeline and concentration steps underlying regulated hormone secretion from lactotrophs.

    Evidence Quantitative EM autoradiography with pulse-chase [³H]leucine labeling in dispersed rat pituitary cells

    PMID:743954

    Open questions at the time
    • Molecular machinery controlling granule maturation and sorting was not identified
    • No direct comparison between constitutive and regulated secretory pathways
  2. 1981 High

    Cloning and sequencing the human PRL cDNA and mapping the gene to chromosome 6 resolved the primary structure of pre-prolactin and established PRL as a single-locus gene distinct from GH/CS, providing the molecular foundation for all subsequent functional studies.

    Evidence cDNA cloning from pituitary prolactinoma mRNA and somatic cell hybrid chromosomal mapping

    PMID:6260780 PMID:7221563

    Open questions at the time
    • Three-dimensional structure of PRL itself was not yet determined
    • Receptor identity and binding mode remained unknown
  3. 1984 High

    Full genomic characterization revealed PRL as a single-copy ~10 kb gene with conserved intron–exon organization shared with GH, solidifying the gene duplication model and defining the transcriptional start site.

    Evidence Genomic library screening, restriction mapping, DNA sequencing, S1 nuclease mapping

    PMID:6325171

    Open questions at the time
    • Regulatory elements controlling pituitary-specific expression were not mapped
    • Alternative promoter usage was unknown
  4. 1986 High

    Demonstrating that PRL and dopamine inhibit PRL release from the same lactotroph subpopulation via distinct intracellular mechanisms resolved a key question about whether autocrine PRL feedback and dopaminergic inhibition are parallel or convergent pathways.

    Evidence Reverse hemolytic plaque assay on single rat pituitary cells with chloroquine dissection

    PMID:3093192

    Open questions at the time
    • Molecular identity of the PRL autocrine receptor pathway in lactotrophs was not defined
    • Signaling intermediates downstream of each inhibitory mechanism were not characterized
  5. 1990 High

    Discovery of an alternative upstream promoter ~6 kb 5' of the pituitary start site, producing the same mature PRL protein in decidua and lymphoblasts, explained how extrapituitary PRL expression is achieved independently of the pituitary transcription factor Pit-1.

    Evidence cDNA cloning, 5'-UTR sequencing, S1 mapping, and Northern blot from decidual and lymphoblast RNA

    PMID:1697858

    Open questions at the time
    • Transcription factors driving the extrapituitary promoter were not yet identified
  6. 1994 High

    Showing that the extrapituitary PRL promoter is activated by cAMP independently of Pit-1 and progesterone receptor identified the signaling pathway controlling decidual/lymphoid PRL expression and distinguished it mechanistically from pituitary regulation.

    Evidence Promoter-reporter transfection in multiple cell types with Pit-1 co-expression and cAMP stimulation

    PMID:8015553

    Open questions at the time
    • Specific cAMP-responsive transcription factors binding the extrapituitary promoter were not identified
    • In vivo validation of cAMP requirement was lacking
  7. 1994 High

    The crystal structure of hGH bound to the hPRLR extracellular domain revealed the structural basis for sequential receptor engagement and cross-reactivity between GH and PRL receptor families, establishing the two-site binding paradigm.

    Evidence X-ray crystallography of hGH–hPRLR ECD complex

    PMID:7984244

    Open questions at the time
    • A structure of PRL itself bound to PRLR was not yet available
    • Transmembrane and intracellular conformational changes upon dimerization were unknown
  8. 1996 High

    Mutagenesis of the Zn²⁺-binding site (H27A) demonstrated that Zn²⁺ promotes PRL self-association but is dispensable for receptor activation, separating storage/aggregation properties from signaling function.

    Evidence ⁶⁵Zn binding, Scatchard analysis, Nb2 bioassay, CD spectroscopy, and sedimentation equilibrium on WT and H27A PRL

    PMID:8833655

    Open questions at the time
    • Physiological significance of Zn²⁺-dependent aggregation in pituitary granules was not tested in vivo
  9. 1996 High

    Chimeric PRL receptor experiments demonstrated that different cytoplasmic domains (from IL-2Rβ or βc) all converge on STAT5 activation and β-casein transcription, establishing STAT5 as the obligate downstream effector regardless of the specific JAK kinase engaged.

    Evidence Stable CHO cells expressing chimeric PRLR with IL-2Rβ or βc cytoplasmic domains; phospho-JAK/STAT Western blot, EMSA, β-casein reporter

    PMID:8721989

    Open questions at the time
    • Relative contributions of STAT5a vs. STAT5b to specific target gene activation were not resolved
  10. 1997 High

    Tissue-specific signaling outcomes of PRL were explained by showing that mammary gland (long-form PRLR dominant) activates JAK2/STAT5 in vivo while liver (short-form PRLR abundant) does not, implicating inactive heterodimers as a tissue-selective gating mechanism.

    Evidence In vivo PRL injection in ovario-hysterectomized rats with tissue-specific Co-IP, EMSA, and quantitative RT-PCR for receptor isoforms

    PMID:9314595

    Open questions at the time
    • Direct demonstration that short/long heterodimers are signaling-incompetent was not provided
    • Mechanism preventing JAK2 activation in heterodimers was unresolved
  11. 1998 High

    PRLR knockout mice established the non-redundant in vivo requirements for PRL signaling in female fertility, lactation, and pancreatic islet development, providing the definitive loss-of-function phenotypic framework.

    Evidence PRLR gene-targeted deletion in mice with reproductive, lactation, and islet phenotyping

    PMID:9626554

    Open questions at the time
    • Individual contributions of PRL vs. placental lactogen signaling through PRLR were not distinguished
    • CNS-mediated behavioral phenotypes were incompletely characterized
  12. 2000 Medium

    Identification of a negative regulatory role for the PRLR C-terminal domain on MAPK activation—through recruitment of tyrosine and serine/threonine phosphatases—revealed an intrinsic feedback mechanism that limits mitogenic signaling.

    Evidence PRLR truncation/deletion mutants in CHO cells with pharmacological phosphatase inhibitors and phospho-ERK Western blot

    PMID:10687859

    Open questions at the time
    • Specific phosphatases recruited to the C-terminal domain were not identified
    • In vivo significance of this feedback in mammary tissue was not tested
  13. 2002 High

    PRL was shown to transcriptionally activate cyclin D1 through a STAT5a/5b heterodimer binding a distal GAS element in the cyclin D1 promoter, directly linking PRL–STAT5 signaling to cell cycle progression in mammary carcinoma cells.

    Evidence Cyclin D1 promoter-luciferase reporters, EMSA with STAT5-specific supershifts, STAT5a/5b co-IP from nuclear extracts, proliferation assays in mammary carcinoma cells

    PMID:11923474

    Open questions at the time
    • Whether STAT5 heterodimer vs. homodimer usage differs between normal and malignant mammary cells was not addressed
  14. 2002 High

    Quantitative analysis of PRLR KO pancreata demonstrated that PRL/lactogenic signaling is required for normal islet density, beta-cell mass, and glucose-stimulated insulin secretion from early postnatal life, extending PRL's physiological roles beyond reproduction.

    Evidence PRLR knockout mouse morphometry, insulin mRNA quantification, static/dynamic insulin secretion assays, glucose tolerance testing

    PMID:11897695

    Open questions at the time
    • Whether PRL acts directly on beta cells or indirectly through islet vasculature/stroma was unresolved
    • Compensatory mechanisms from other growth factors were not excluded
  15. 2003 High

    Demonstration that PRL directly inhibits lipoprotein lipase activity in human white adipose tissue via functional PRLR isoforms established a direct metabolic action on lipid partitioning.

    Evidence LPL enzyme activity assay in PRL-treated human adipose tissue explants with PRLR expression confirmed by RT-PCR and immunoblot

    PMID:12679477

    Open questions at the time
    • Signaling pathway from PRLR to LPL inhibition was not delineated
    • In vivo metabolic consequences in humans were not measured
  16. 2005 High

    Mass spectrometric identification of Ser-163 and Ser-194 phosphorylation on human pituitary PRL, with Ser-163 dephosphorylated in circulating PRL, defined post-translational modifications that distinguish stored and secreted hormone forms.

    Evidence Mass spectrometry, 2D electrophoresis, Western blot on pituitary and serum PRL

    PMID:15687336

    Open questions at the time
    • Kinase(s) responsible for Ser-163/Ser-194 phosphorylation were not identified
    • Functional consequences of each phosphorylation event on receptor binding or bioactivity were not resolved
  17. 2006 High

    Showing that human hair follicles express both PRL and PRLR and that exogenous PRL induces premature catagen established PRL as an autocrine/paracrine catagen-promoting factor in human skin.

    Evidence RT-PCR and immunohistology for PRL/PRLR in scalp follicles; organ culture with PRL and Ki-67/TUNEL morphometry

    PMID:16507890

    Open questions at the time
    • Intracellular signaling pathway mediating catagen induction in follicular keratinocytes was not identified
    • Relative contribution of locally produced vs. circulating PRL was unknown
  18. 2007 High

    Discovery that cathepsin D cleaves PRL into a 16 kDa antiangiogenic fragment in the context of cardiac STAT3 deficiency, and that this fragment is both necessary and sufficient for peripartum cardiomyopathy (PPCM), identified a pathogenic proteolytic product of PRL and established a causal mechanism for PPCM.

    Evidence Cardiomyocyte-specific Stat3 KO mice, cathepsin D activity assay, forced 16 kDa PRL expression, bromocriptine rescue, human PPCM patient serum analysis

    PMID:17289576

    Open questions at the time
    • Endothelial receptor for 16 kDa PRL was not identified
    • Whether cathepsin D cleavage occurs intracellularly or extracellularly in the cardiac microenvironment was unclear
  19. 2013 High

    Elucidation of the 16 kDa PRL → miR-146a → exosome → cardiomyocyte axis provided the intercellular signaling mechanism by which the antiangiogenic PRL fragment damages the myocardium, identifying specific downstream targets (NRAS, Erbb4, Notch1, Irak1) in cardiomyocytes.

    Evidence miRNA profiling, NRAS 3'UTR luciferase reporter, exosome isolation/transfer, Stat3 KO mouse model, locked nucleic acid rescue, human PPCM plasma miR-146a measurement

    PMID:23619365

    Open questions at the time
    • Mechanism by which 16 kDa PRL induces miR-146a transcription in endothelial cells was not defined
    • Therapeutic window for anti-miR-146a or bromocriptine intervention was not established
  20. 2021 High

    A human stop-gain mutation (p.Arg220Ter) causing familial prolactin deficiency and alactogenesis demonstrated that the C-terminal disulfide bond is essential for PRL secretion, linking structural integrity to the secretory pathway and establishing a Mendelian form of PRL deficiency.

    Evidence Sanger sequencing, transfection of WT/mutant PRL, conditioned medium immunoassay and Nb2 bioassay for secretion

    PMID:33770166

    Open questions at the time
    • Mechanism by which C-terminal disulfide bond disruption blocks secretion (ER retention vs. degradation) was not resolved
    • Prevalence of PRL mutations in idiopathic lactation failure is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the atomic structure of the PRL–PRLR ternary complex, the identity of kinases phosphorylating Ser-163/Ser-194, the endothelial receptor mediating 16 kDa PRL effects, and whether PRL acts directly on pancreatic beta cells or through islet accessory cells.
  • No PRL:PRLR ternary complex structure available
  • Kinases for Ser-163/Ser-194 unidentified
  • 16 kDa PRL endothelial receptor unknown
  • Direct vs. indirect beta-cell action unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2
Partners
CTSDJAK2PRLRSTAT5ASTAT5B

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1981 Human prolactin (PRL) cDNA was cloned and sequenced, revealing the complete coding sequence of pre-prolactin and establishing sequence homology with growth hormone, consistent with evolution from a common ancestral gene. The coding sequence predicts a signal peptide and mature hormone structure. cDNA cloning and nucleotide sequencing from pituitary prolactinoma mRNA The Journal of biological chemistry High 6260780
1981 The human prolactin gene was mapped to chromosome 6, distinct from the chromosomal locations of growth hormone and chorionic somatomammotropin genes, using somatic cell hybrid analysis. Somatic cell hybrid panel analysis with Southern blotting Science (New York, N.Y.) High 7221563
1984 The human PRL gene was isolated, shown to be a single-copy gene of ~10 kb containing four introns, three of which interrupt the coding sequence at positions conserved with GH and PRL genes, and the transcription origin was determined by S1 mapping. Genomic library screening, restriction mapping, DNA sequencing, S1 nuclease mapping The EMBO journal High 6325171
1978 Prolactin is synthesized in the rough endoplasmic reticulum (ER) of mammotrophs, rapidly transported to the Golgi (within 5–10 min), and sequentially packaged into immature then mature secretory granules over ~3 hours, with progressive ~20–150-fold concentration along the transport route. Quantitative electron microscopic autoradiography using pulse-chase [3H]leucine labeling of dispersed rat pituitary cells Endocrinology High 743954
1984 In intact female rats, rat GH (but not prolactin itself) induces upregulation of both GH and PRL receptors in the liver in a dose-dependent manner. PRL infusion caused slight downregulation of PRL receptors rather than induction, challenging the concept that PRL auto-induces its own hepatic receptors. Osmotic minipump infusion of recombinant hormones followed by radioligand binding assay and MgCl2 stripping on liver microsomal membranes Endocrinology High 6325135
1986 Ovine PRL and dopamine inhibit basal PRL release from the same subpopulation of rat mammotrophs, but by separate intracellular mechanisms: chloroquine (a lysosomotropic agent) reversed dopamine inhibition but not PRL-mediated inhibition, indicating distinct pathways converging on the same cells. Reverse hemolytic plaque assay on dispersed rat pituitary cells with pharmacological inhibitors Endocrinology High 3093192
1986 Antiidiotypic antibodies raised against anti-PRL antibodies specifically bind to PRL receptor-rich membrane preparations and competitively inhibit [125I]-PRL binding to its receptor, demonstrating that anti-PRL idiotypes share structural determinants with the PRL receptor binding site. Affinity chromatography purification of antibodies, [125I]-Protein A precipitation binding assay, competitive inhibition assays on tissue membrane preparations Endocrinology Medium 3002768
1988 In rat fetal pituitary, PRL mRNA (detectable from fetal day 18) is present at levels disproportionately higher than PRL protein content, and dopamine promotes PRL storage post-birth; in vitro, newborn pituitary cells store PRL when cultured with dopamine, indicating dopamine regulates PRL accumulation/storage rather than synthesis at the neonatal stage. Immunocytochemistry, in situ hybridization, cDNA probe hybridization quantification, in vitro dopamine treatment of primary pituitary cells, radioimmunoassay Molecular endocrinology (Baltimore, Md.) Medium 2464129
1990 Human PRL gene expression in extrapituitary sites (decidua and lymphoblasts) is initiated from an alternative promoter located ~6 kb upstream of the pituitary-specific start site, producing mRNA with a distinct 5'-noncoding exon; this extrapituitary transcript encodes the same mature PRL protein. cDNA cloning, 5'-UTR sequencing, S1 mapping, Northern blot analysis The Journal of biological chemistry High 1697858
1992 PRL receptor (PRL-R) mRNA, including both long and short isoforms, is expressed in the rat anterior pituitary, medial basal hypothalamus, and posterior pituitary — in addition to peripheral tissues — as demonstrated by RT-PCR, indicating PRL can feed back on its own secretion through receptors at both hypothalamic and pituitary levels. Reverse transcription-PCR with isoform-specific primers on RNA from multiple brain and peripheral tissues Endocrinology Medium 1537321
1994 The extrapituitary PRL promoter (decidual/lymphoid promoter) driving PRL gene expression in endometrial stroma and lymphocytes is independent of Pit-1 (the pituitary-specific transcription factor) and is not directly controlled by progesterone receptor, but is activated by cAMP signaling in endometrial stromal cells. Transfection of promoter-reporter constructs (3 kb 5'-flanking dPRL) into multiple cell types, Pit-1 co-expression experiments, pharmacological cAMP stimulation Molecular endocrinology (Baltimore, Md.) High 8015553
1994 The crystal structure of hGH bound to the extracellular domain of the human PRL receptor (hPRLR) at 1:1 stoichiometry was solved, revealing the structural basis for how hGH binds to two distinct receptor types (hGHR and hPRLR) through overlapping but non-identical receptor-binding surfaces. X-ray crystallography of hGH–hPRLR extracellular domain complex Nature High 7984244
1996 Human PRL binds Zn²⁺ at a site involving histidine-27 (H27); the H27A mutant shows greatly reduced Zn²⁺ binding but retains normal biological activity and fold, demonstrating that Zn²⁺ binding to the high-affinity site is not required for receptor activation but promotes concentration-dependent self-association/aggregation of PRL. 65Zn binding assays, Scatchard analysis, Nb2 cell bioassay, circular dichroism spectroscopy, dynamic light scattering, sedimentation equilibrium analysis Molecular endocrinology (Baltimore, Md.) High 8833655
1996 Chimeric PRL receptors bearing the transmembrane/cytoplasmic domains of IL-2Rβ or βc cytokine receptor subunits transduce PRL signals through Jak1 and Jak2 respectively, both leading to Stat5 tyrosine phosphorylation, DNA binding, and β-casein promoter activation, demonstrating that distinct cytoplasmic domains converge on the same Stat5-dependent transcriptional output and that Stat5 activation is not dependent on a specific JAK kinase. Stably transfected CHO cells expressing chimeric receptors, Western blotting for phospho-Jak1/Jak2/Stat5, EMSA with LHRR probe, luciferase reporter assay Molecular endocrinology (Baltimore, Md.) High 8721989
1997 During in vivo lactogenesis in rats, PRL activates JAK2 and STAT5 in mammary gland (but not in liver) despite the PRL receptor being constitutively associated with JAK2 in both tissues. The long-form PRL-R predominates in mammary gland, while the short form is abundant in liver and may form inactive heterodimers with the long form, explaining tissue-specific signal activation. In vivo PRL injection in ovario-hysterectomized rats, immunoprecipitation/Western blot for phospho-JAK2 and phospho-PRLR, EMSA for STAT5 binding using β-casein probe, quantitative RT-PCR for receptor isoforms Biology of reproduction High 9314595
1997 Anti-PRL IgG autoantibodies form non-covalent complexes with 23 kDa monomeric PRL (which retains full bioactivity in vitro), and the IgG-PRL complex is cleared more slowly from rat circulation than free PRL, explaining macroprolactinemia as a result of delayed metabolic clearance rather than increased secretion. Enzyme immunoassay, Nb2-cell bioassay, gel chromatography, affinity chromatography, SDS-PAGE under non-reducing conditions, pharmacokinetic clearance studies in anesthetized rats The Journal of clinical endocrinology and metabolism High 9284753
1998 PRL receptor (PRLR) knockout mice display: infertility in homozygous females (due to ovulation of premeiotic oocytes, reduced fertilization, lack of implantation), near-complete failure to lactate in heterozygous females after first pregnancy, and reduced islet/beta-cell function, establishing the physiological roles of PRL/lactogen signaling through the PRLR in reproductive function and lactation. Targeted gene deletion in mice (PRLR knockout), phenotypic analysis of reproductive outcomes, histology, hormone assays Endocrine reviews High 9626554
2000 The C-terminal cytoplasmic domain of the PRL receptor exerts a negative regulatory role on PRL-induced MAPK (ERK) activation; MAPK activation by PRL requires both MEK-dependent and PI3K-dependent pathways, and the negative regulation by the C-terminal domain involves tyrosine phosphatases and serine/threonine phosphatases recruited by the last 141 residues. Transient transfection of PRL-R cytoplasmic domain deletion/truncation mutants in CHO cells, pharmacological inhibitors (pervanadate, PAO, okadaic acid, MEK inhibitor, PI3K inhibitor), Western blot for phospho-ERK Molecular and cellular endocrinology Medium 10687859
2001 Dopamine suppresses PRL secretion from pituitary lactotrophs by binding D2 dopamine receptors coupled to membrane ion channels and G proteins, controlling calcium fluxes and activating intracellular signaling pathways, while also suppressing PRL gene expression and lactotroph proliferation. PRL homeostasis is determined by this inhibitory dopamine tone balanced against multiple stimulatory factors. Review integrating pharmacological, transgenic animal, and clinical studies; calcium flux measurements, receptor characterization, gene expression assays Endocrine reviews High 11739329
2001 S179D-human PRL (designed to mimic phospho-S179 PRL) acts as an agonist, not an antagonist, at the human PRL receptor: it stimulates Nb2 cell proliferation, T-47D cell proliferation, transcriptional activation of lactogenic response element reporters, and activates JAK/STAT and MAPK pathways, albeit with slightly reduced affinity due to local alteration of receptor binding site 1. Nb2 lymphoma cell proliferation bioassay, T-47D human mammary tumor cell proliferation assay, lactogenic hormone response element-luciferase reporter assay, Western blot for JAK2/STAT5/MAPK phosphorylation Endocrinology High 11517174
2002 PRL-receptor-deficient (PRLR KO) mice exhibit 26–42% reductions in islet density and beta-cell mass from as early as 3 weeks of age, with reduced pancreatic insulin mRNA, lower islet insulin content, blunted glucose-stimulated insulin secretion both in vivo and in vitro, and impaired glucose tolerance, establishing a physiological role for lactogenic hormones in islet development and beta-cell function. PRLR knockout mouse model, morphometric analysis of islet density and beta-cell mass, pancreatic insulin mRNA quantification, static and dynamic glucose-stimulated insulin secretion assays, intraperitoneal glucose tolerance test Endocrinology High 11897695
2002 PRL significantly increases proliferation of mammary carcinoma cells and upregulates cyclin D1 mRNA/protein levels via transcriptional activation of the cyclin D1 promoter through the JAK2/STAT5 pathway. PRL-induced Stat5a and Stat5b bind as a heterodimer to a distal GAS site in the cyclin D1 promoter; disruption of this distal GAS site abolishes PRL-induced promoter activity. Cell proliferation assays, cyclin D1 protein immunoblot, actinomycin D transcription block, cyclin D1 promoter-luciferase reporter assay in CHO cells, EMSA demonstrating STAT5 binding to GAS sites, co-immunoprecipitation of STAT5a/5b heterodimers from nuclear extracts Molecular endocrinology (Baltimore, Md.) High 11923474
2003 PRL directly inhibits lipoprotein lipase (LPL) activity in human white adipose tissue to ~31% of control via functional PRL receptors (long and intermediate isoforms expressed in adipose tissue), demonstrating a direct metabolic action of PRL on lipid metabolism in humans. RT-PCR/Southern blot and immunoblot for PRLR isoforms in human adipose tissue, in vitro culture of human adipose tissue with PRL/GH/cortisol, LPL enzyme activity assay The Journal of clinical endocrinology and metabolism High 12679477
2005 Human pituitary PRL is phosphorylated at serine 194 and serine 163; serine 163 is dephosphorylated in serum PRL. Acidic PRL isoforms (with distinct pI) are enriched in macroprolactinemic patients with anti-PRL autoantibodies and may contribute to chronic antigen stimulation (IgG4-predominant response). Western blot, mass spectrometry, two-dimensional electrophoresis, enzyme immunoassay for IgG subclasses The Journal of clinical endocrinology and metabolism High 15687336
2006 Human scalp hair follicles express both PRL and PRL receptors at mRNA and protein level, and treatment of organ-cultured human hair follicles with high-dose PRL (400 ng/ml) inhibits hair shaft elongation, promotes premature catagen development, reduces keratinocyte proliferation, and increases apoptosis, demonstrating PRL acts as an autocrine/paracrine catagen-promoting factor in human skin. RT-PCR, immunohistology for PRL and PRL-R, organ culture of human scalp hair follicles with PRL, Ki-67/TUNEL immunohistomorphometry The American journal of pathology High 16507890
2007 In mice with cardiomyocyte-specific STAT3 deletion, enhanced cardiac cathepsin D (CD) activity cleaves full-length prolactin into an antiangiogenic/proapoptotic 16 kDa N-terminal fragment that impairs cardiac capillary network and function, causing postpartum cardiomyopathy (PPCM). Bromocriptine (prolactin secretion inhibitor) prevents PPCM, and forced cardiac generation of 16 kDa PRL recapitulates the PPCM phenotype. Cardiomyocyte-specific Stat3 knockout mice, cathepsin D activity assay, Western blot for 16 kDa PRL fragment, bromocriptine treatment, forced myocardial 16 kDa PRL overexpression, cardiac function/capillary network assessment, measurement of serum CD and 16 kDa PRL in human PPCM patients Cell High 17289576
2008 The PRL/JAK2/STAT5 signaling pathway is enhanced in estrogen receptor-positive (ER+) breast cancer cells (T47D, MCF7) compared with ER-negative lines, as measured by a highly sensitive pGL4-CISH luciferase reporter; overexpression of STAT5 further amplifies PRL-driven CISH reporter activation. Luciferase reporter assay (pGL4-CISH) in multiple cell lines, STAT5 overexpression, comparison across ER+ and ER- cell lines BMC biotechnology Medium 18254957
2012 Prolactin receptor activation and signaling involve: (1) sequential two-step binding where site 1 on PRL binds one receptor molecule, then site 2 binds a second receptor to form a 1:2 (PRL:PRLR) homodimer; (2) receptor dimerization activates associated JAK2 kinase (no intrinsic kinase domain in PRLR), leading to phosphorylation of JAK2 and the receptor; (3) downstream activation of STAT5, Ras/Raf/MAPK, IRS-1/PI3K, SHP-2, PLCγ, and PKC pathways. Three human hormones (PRL, GH, placental lactogen) can activate the PRLR through structurally distinct mechanisms. Comprehensive mechanistic review integrating structural, biochemical, and genetic studies Endocrine reviews High 22577091
2013 The 16 kDa N-terminal PRL fragment induces microRNA-146a (miR-146a) expression in endothelial cells (ECs), which attenuates angiogenesis by downregulating NRAS. 16K PRL stimulates secretion of miR-146a-loaded exosomes from ECs; these exosomes are absorbed by cardiomyocytes, raising miR-146a levels and decreasing metabolic activity and expression of Erbb4, Notch1, and Irak1, thereby contributing to PPCM pathogenesis. miRNA expression profiling, luciferase reporter for NRAS 3'UTR, exosome isolation and transfer experiments, cardiomyocyte-specific Stat3 KO mouse model, locked nucleic acid/antago-miR treatment, measurement of miR-146a in PPCM patient plasma and hearts The Journal of clinical investigation High 23619365
2013 Stiff collagen matrices shift prolactin signaling in luminal breast cancer cells from STAT5-mediated physiological outcomes to SRC family kinase-dependent FAK phosphorylation (pY925), FAK-GRB2 association, and ERK1/2 activation, promoting matrix metalloproteinase-dependent invasion. Co-localization of PRL receptors with integrin-activated FAK increases in stiff matrices, implicating altered spatial receptor organization. Three-dimensional collagen I matrix culture with defined stiffness, Western blot for phospho-STAT5/FAK/ERK, matrix metalloproteinase invasion assay, pharmacological SRC inhibitors, immunofluorescence co-localization of PRLR and FAK The Journal of biological chemistry Medium 23530035
2021 A heterozygous stop-gain mutation in PRL exon 5 (p.Arg220Ter, c.658C>T) causes familial prolactin deficiency and alactogenesis. Transfection of the mutant PRL produces normal intracellular prolactin levels but fails to secrete immunoactive or bioactive prolactin; deletion of the terminal cysteine (p.Lys218Ter) also impairs secretion and cannot be rescued by removing the penultimate cysteine, indicating the C-terminal disulfide bond is essential for PRL secretion. Sanger sequencing of PRL exons, transfection of wild-type and mutant PRL constructs, conditioned medium immunoassay for secreted PRL, Nb2-cell bioassay for bioactive PRL The Journal of clinical endocrinology and metabolism High 33770166

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1998 Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocrine reviews 1425 9626554
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2001 Dopamine as a prolactin (PRL) inhibitor. Endocrine reviews 712 11739329
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2007 A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 645 17289576
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2013 MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. The Journal of clinical investigation 385 23619365
1994 The X-ray structure of a growth hormone-prolactin receptor complex. Nature 341 7984244
1981 Human prolactin. cDNA structural analysis and evolutionary comparisons. The Journal of biological chemistry 277 6260780
1994 PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth. Molecular and cellular biology 247 8196618
2007 PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. Cancer research 226 17409395
1994 Nonpituitary human prolactin gene transcription is independent of Pit-1 and differentially controlled in lymphocytes and in endometrial stroma. Molecular endocrinology (Baltimore, Md.) 212 8015553
2002 Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance. Endocrinology 198 11897695
2007 Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Annals of the New York Academy of Sciences 189 17785327
2008 PRL PTPs: mediators and markers of cancer progression. Cancer metastasis reviews 174 18224294
2003 Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Proceedings of the National Academy of Sciences of the United States of America 174 12552091
2006 PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility. Cancer research 165 16540666
1990 The sec and prl genes of Escherichia coli. Journal of bioenergetics and biomembranes 157 2202721
2010 PCBP1 suppresses the translation of metastasis-associated PRL-3 phosphatase. Cancer cell 153 20609352
1978 Intracellular transport and packaging of prolactin: a quantitative electron microscope autoradiographic study of mammotrophs dissociated from rat pituitaries. Endocrinology 151 743954
2002 PRL activates the cyclin D1 promoter via the Jak2/Stat pathway. Molecular endocrinology (Baltimore, Md.) 141 11923474
2008 Genes controlling affiliative behavior as candidate genes for autism. Biological psychiatry 126 18207134
1984 Isolation and characterization of the human prolactin gene. The EMBO journal 124 6325171
2003 Frequent misdiagnosis and mismanagement of hyperprolactinemic patients before the introduction of macroprolactin screening: application of a new strict laboratory definition of macroprolactinemia. Clinical chemistry 123 12928232
2011 Genome-wide association identifies three new susceptibility loci for Paget's disease of bone. Nature genetics 122 21623375
2012 Molecular mechanisms of prolactin and its receptor. Endocrine reviews 120 22577091
2012 Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. PLoS genetics 120 23284291
1981 The prolactin gene is located on chromosome 6 in humans. Science (New York, N.Y.) 120 7221563
2006 Human scalp hair follicles are both a target and a source of prolactin, which serves as an autocrine and/or paracrine promoter of apoptosis-driven hair follicle regression. The American journal of pathology 114 16507890
2003 Identification of functional prolactin (PRL) receptor gene expression: PRL inhibits lipoprotein lipase activity in human white adipose tissue. The Journal of clinical endocrinology and metabolism 114 12679477
1990 Human prolactin gene expression. The use of an alternative noncoding exon in decidua and the IM-9-P3 lymphoblast cell line. The Journal of biological chemistry 113 1697858
2010 PRL-3 phosphatase and cancer metastasis. Journal of cellular biochemistry 108 21053359
2004 Expression of PRL-3 phosphatase in human gastric carcinomas: close correlation with invasion and metastasis. Pathobiology : journal of immunopathology, molecular and cellular biology 108 15263806
2013 Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells. The Journal of biological chemistry 106 23530035
2010 A large-scale candidate gene association study of age at menarche and age at natural menopause. Human genetics 106 20734064
2013 CBFβ stabilizes HIV Vif to counteract APOBEC3 at the expense of RUNX1 target gene expression. Molecular cell 102 23333304
2009 Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population. Journal of human genetics 102 19851340
2008 The metastasis-associated gene Prl-3 is a p53 target involved in cell-cycle regulation. Molecular cell 102 18471976
2014 The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis. Oncogene 100 24632616
2010 Prolactin, Oxytocin, and the development of paternal behavior across the first six months of fatherhood. Hormones and behavior 98 20399783
1997 Anti-prolactin (PRL) autoantibodies cause asymptomatic hyperprolactinemia: bioassay and clearance studies of PRL-immunoglobulin G complex. The Journal of clinical endocrinology and metabolism 97 9284753
1984 Rat growth hormone (GH) but not prolactin (PRL) induces both GH and PRL receptors in female rat liver. Endocrinology 95 6325135
1992 Detection of prolactin receptor (PRL-R) mRNA in the rat hypothalamus and pituitary gland. Endocrinology 94 1537321
2007 Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells. Blood 88 17934070
2006 PRL-3 initiates tumor angiogenesis by recruiting endothelial cells in vitro and in vivo. Cancer research 86 17018620
2015 Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis. Cancer research 85 26669864
2003 Enhanced cell cycle progression and down regulation of p21(Cip1/Waf1) by PRL tyrosine phosphatases. Cancer letters 75 14643450
2016 Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis. EMBO reports 68 27856537
2005 Trimeric structure of PRL-1 phosphatase reveals an active enzyme conformation and regulation mechanisms. Journal of molecular biology 65 15571731
2013 Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells. The Journal of clinical investigation 64 23867504
2007 Ezrin is a specific and direct target of protein tyrosine phosphatase PRL-3. Biochimica et biophysica acta 63 18078820
2006 Identification of integrin alpha1 as an interacting protein of protein tyrosine phosphatase PRL-3. Biochemical and biophysical research communications 62 16472776
2008 Monoclonal antibodies target intracellular PRL phosphatases to inhibit cancer metastases in mice. Cancer biology & therapy 59 18364570
2004 Structure of human PRL-3, the phosphatase associated with cancer metastasis. FEBS letters 58 15135076
1997 In vivo study of prolactin (PRL) intracellular signalling during lactogenesis in the rat: JAK/STAT pathway is activated by PRL in the mammary gland but not in the liver. Biology of reproduction 57 9314595
2019 Increased anxiety and decreased sociability induced by paternal deprivation involve the PVN-PrL OTergic pathway. eLife 55 31084703
2018 Physiological and oncogenic roles of the PRL phosphatases. The FEBS journal 55 29770564
2011 The metastasis-promoting phosphatase PRL-3 shows activity toward phosphoinositides. Biochemistry 53 21806020
2005 Generation of PRL-3- and PRL-1-specific monoclonal antibodies as potential diagnostic markers for cancer metastases. Clinical cancer research : an official journal of the American Association for Cancer Research 52 15788667
2006 mRNA expression patterns for GH, PRL, SL, IGF-I and IGF-II during altered feeding status in rabbitfish, Siganus guttatus. General and comparative endocrinology 50 16978626
2013 KCNN4 channels participate in the EMT induced by PRL-3 in colorectal cancer. Medical oncology (Northwood, London, England) 49 23572150
2019 Magnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolism. Proceedings of the National Academy of Sciences of the United States of America 48 30718434
2016 Inhibition of PRL-2·CNNM3 Protein Complex Formation Decreases Breast Cancer Proliferation and Tumor Growth. The Journal of biological chemistry 47 26969161
2013 Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia. EMBO molecular medicine 42 23929599
2012 An epigenetic role for PRL-3 as a regulator of H3K9 methylation in colorectal cancer. Gut 41 22345654
2008 New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53. Oncogene 40 18997816
2020 The Oncogenic PRL Protein Causes Acid Addiction of Cells by Stimulating Lysosomal Exocytosis. Developmental cell 39 32918875
1988 Discrepancy between prolactin (PRL) messenger ribonucleic acid and PRL content in rat fetal pituitary cells: possible role of dopamine. Molecular endocrinology (Baltimore, Md.) 39 2464129
2005 Up-regulation of Prl, a subtilisin-like protease, during conidiation in the insect pathogen Metarhizium anisopliae. Mycological research 37 15912947
1984 The effect of ketanserin, a specific serotonin antagonist on the PRL, GH, ACTH and cortisol responses to hypoglycaemia in normal subjects. Clinical endocrinology 36 6325044
2018 PRL-3 Promotes Ubiquitination and Degradation of AURKA and Colorectal Cancer Progression via Dephosphorylation of FZR1. Cancer research 35 30498084
1995 Laminin decreases PRL and IGFBP-1 expression during in vitro decidualization of human endometrial stromal cells. Journal of cellular physiology 35 7534770
1986 Ovine prolactin (PRL) and dopamine preferentially inhibit PRL release from the same subpopulation of rat mammotropes. Endocrinology 35 3093192
2014 Independent oncogenic and therapeutic significance of phosphatase PRL-3 in FLT3-ITD-negative acute myeloid leukemia. Cancer 34 24737397
2011 Metastasis-associated phosphatase PRL-2 regulates tumor cell migration and invasion. Oncogene 34 21765462
2007 Characterization of a PRL protein tyrosine phosphatase from Plasmodium falciparum. Molecular and biochemical parasitology 34 18096253
2001 S179D-human PRL, a pseudophosphorylated human PRL analog, is an agonist and not an antagonist. Endocrinology 34 11517174
2019 Branch-restricted localization of phosphatase Prl-1 specifies axonal synaptogenesis domains. Science (New York, N.Y.) 32 31048465
2016 LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML. Molecular cancer research : MCR 32 28011885
2008 Quantification of PRL/Stat5 signaling with a novel pGL4-CISH reporter. BMC biotechnology 32 18254957
2005 Immunoglobulin G subclasses and prolactin (PRL) isoforms in macroprolactinemia due to anti-PRL autoantibodies. The Journal of clinical endocrinology and metabolism 32 15687336
2012 The posterior chamber phakic refractive lens (PRL): a review. Eye (London, England) 31 23222559
1986 Antiidiotypic antibodies raised against anti-prolactin (PRL) antibodies recognize the PRL receptor. Endocrinology 31 3002768
2001 Interaction of farnesylated PRL-2, a protein-tyrosine phosphatase, with the beta-subunit of geranylgeranyltransferase II. The Journal of biological chemistry 30 11447212
2013 Thioredoxin-related protein 32 (TRP32) specifically reduces oxidized phosphatase of regenerating liver (PRL). The Journal of biological chemistry 29 23362275
1986 Prolactin (PRL), follicle-stimulating hormone, and luteinizing hormone are regulators of testicular PRL receptors in golden hamsters. Endocrinology 29 3002766
2014 LEO1 is regulated by PRL-3 and mediates its oncogenic properties in acute myelogenous leukemia. Cancer research 28 24686170
2012 PRL-3 activates NF-κB signaling pathway by interacting with RAP1. Biochemical and biophysical research communications 28 23178297
2019 The Phosphatase PRL-3 Is Involved in Key Steps of Cancer Metastasis. Journal of molecular biology 27 31207239
2011 Therapeutic potential of PRL-3 targeting and clinical significance of PRL-3 genomic amplification in gastric cancer. BMC cancer 27 21466710
1996 Properties of human prolactin (PRL) and H27A-PRL, a mutant that does not bind Zn++. Molecular endocrinology (Baltimore, Md.) 26 8833655
2016 Elevated phosphatase of regenerating liver 3 (PRL-3) promotes cytoskeleton reorganization, cell migration and invasion in endometrial stromal cells from endometrioma. Human reproduction (Oxford, England) 25 26874360
2016 Phosphatase of regenerating liver 3 (PRL-3) is overexpressed in human prostate cancer tissue and promotes growth and migration. Journal of translational medicine 25 26975394
2007 Oxidative stress-induced expression and modulation of Phosphatase of Regenerating Liver-1 (PRL-1) in mammalian retina. Biochimica et biophysica acta 25 17673310
2015 Plasticity of the prolactin (PRL) axis: mechanisms underlying regulation of output in female mice. Advances in experimental medicine and biology 24 25472537
1997 Lactogenic hormones of the placenta and pituitary inhibit suckling-induced prolactin (PRL) release but not the ante-partum PRL surge. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 24 9083259
2021 The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2. iScience 23 35036882
2016 Regulatory mechanisms of phosphatase of regenerating liver (PRL)-3. Biochemical Society transactions 23 27911713
2011 DGAT1, GH, GHR, PRL and PRLR polymorphism in water buffalo (Bubalus bubalis). Reproduction in domestic animals = Zuchthygiene 23 21883511
2013 Reversible oxidation of PRL family protein-tyrosine phosphatases. Methods (San Diego, Calif.) 22 23831336
2000 PRL-1 PTPase expression is developmentally regulated with tissue-specific patterns in epithelial tissues. American journal of physiology. Gastrointestinal and liver physiology 22 10960362
2017 PRL-3 promotes telomere deprotection and chromosomal instability. Nucleic acids research 21 28482095
2005 Induction of GH, PRL, and TSH beta mRNA by transfection of Pit-1 in a human pituitary adenoma-derived cell line. Cell and tissue research 21 16133148
1999 Urethane-induced somatostatin mediated inhibition of gastric acid: reversal by the somatostatin 2 receptor antagonist, PRL-2903. Life sciences 21 10499878
2021 PRL Mutation Causing Alactogenesis: Insights Into Prolactin Structure and Function Relationships. The Journal of clinical endocrinology and metabolism 20 33770166
2020 lncRNA PCBP1-AS1 Aggravates the Progression of Hepatocellular Carcinoma via Regulating PCBP1/PRL-3/AKT Pathway. Cancer management and research 20 32753957
2020 Indel variants within the PRL and GHR genes associated with sheep litter size. Reproduction in domestic animals = Zuchthygiene 20 32762057
2010 HLA class II, MICA and PRL gene polymorphisms: the common contribution to the systemic lupus erythematosus development in Czech population. Rheumatology international 20 20352225
2009 The PRL -1149 G/T polymorphism and rheumatoid arthritis susceptibility. Arthritis and rheumatism 20 19404952
1999 Prolactin (PRL)-like protein J, a novel member of the PRL/growth hormone family, is exclusively expressed in maternal decidua. Endocrinology 20 10537137
1996 Immunocytochemical and morphometric study on the changes of TSH, PRL, GH and ACTH cells during the development of Bufo arenarum. Cell and tissue research 20 8581952
1995 Immunocytochemical and morphometric study of TSH, PRL, GH, and ACTH cells in Bufo arenarum larvae with inhibited thyroid function. General and comparative endocrinology 20 7635270
2018 Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia. Oncogene 19 30305722
2014 A prl mutation in SecY suppresses secretion and virulence defects of Listeria monocytogenes secA2 mutants. Journal of bacteriology 19 25535272
2019 Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) promotes the aggressiveness of human uveal melanoma through dephosphorylation of CRMP2. Scientific reports 18 30816227
2018 Glial cells as mediators of protective actions of prolactin (PRL) in the CNS. General and comparative endocrinology 18 29378204
2015 PRL-3 mediates the protein maturation of ULBP2 by regulating the tyrosine phosphorylation of HSP60. Journal of immunology (Baltimore, Md. : 1950) 18 25687758
2010 Single nucleotide polymorphisms in bovine PRL gene and their associations with milk production traits in Chinese Holsteins. Molecular biology reports 18 19714484
1996 Convergence of signaling transduced by prolactin (PRL)/cytokine chimeric receptors on PRL-responsive gene transcription. Molecular endocrinology (Baltimore, Md.) 18 8721989
2020 PRL-3 facilitates Hepatocellular Carcinoma progression by co-amplifying with and activating FAK. Theranostics 17 32929353
2009 Novel SNP of the goat prolactin gene (PRL) associated with cashmere traits. Journal of applied genetics 17 19193983
2008 Analysis of molecular determinants of PRL-3. Journal of cellular and molecular medicine 17 19040419
2005 Cloning of duck PRL cDNA and genomic DNA. General and comparative endocrinology 17 15707601
2000 Effect of PRL on MAPK activation: negative regulatory role of the C-terminal part of the PRL receptor. Molecular and cellular endocrinology 17 10687859
2017 Antibody Array Revealed PRL-3 Affects Protein Phosphorylation and Cytokine Secretion. PloS one 16 28068414
2014 Anti-cytomegalovirus activity of the anthraquinone atanyl blue PRL. Antiviral research 16 25499125
2000 Increase in prolactin receptor (PRL-R) mRNA level in the mammary gland after hormonal induction of lactation in virgin ewes. Domestic animal endocrinology 16 10701763