{"gene":"PRLR","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2011,"finding":"The prolactin receptor (PRLr) localizes to the nucleus where it functions as a transcriptional coactivator through interactions with STAT5a and HMGN2. A novel transactivation domain within PRLr is activated by ligand-induced phosphorylation, which enables HMGN2 binding; this PRLr/HMGN2 association facilitates Stat5a-responsive promoter binding and transcriptional activation, promoting anchorage-independent growth.","method":"Co-immunoprecipitation, nuclear fractionation, promoter luciferase assay, loss-of-function and overexpression experiments in breast cancer cells","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional promoter assays in a single lab with multiple orthogonal methods","pmids":["21816901"],"is_preprint":false},{"year":2016,"finding":"GHR and PRLR form higher-order hetero-assemblages composed of GHR homodimers and PRLR homodimers (not GHR-PRLR heterodimers). Both receptors pre-homodimerize independently of ligand; GH or PRL augments PRLR-PRLR complementation, whereas both ligands cause decline in GHR-PRLR hetero-complementation, indicating distinct conformational responses in homomers versus heteromers.","method":"Split luciferase complementation assay (bioluminescence resonance), co-immunoprecipitation in T47D breast cancer cells","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus complementation assay, single lab, two orthogonal methods","pmids":["27003442"],"is_preprint":false},{"year":2013,"finding":"Hepatic PRLR regulates insulin sensitivity via the STAT5 signaling pathway. Adenoviral overexpression of PRLR improved insulin sensitivity in mice, while knockdown impaired it; STAT5 pathway activation was required for this effect. PRLR expression was decreased under insulin-resistant (db/db) and increased under insulin-sensitive (leucine deprivation) conditions, with leucine deprivation upregulating PRLR via a GCN2/mTOR/S6K1-dependent pathway.","method":"Adenoviral overexpression and knockdown in vivo, in vitro cell assays, pathway inhibition experiments, db/db mouse model","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain- and loss-of-function with defined pathway readout, single lab, multiple orthogonal methods","pmids":["23775766"],"is_preprint":false},{"year":2021,"finding":"The short isoform of PRLR (PRLR-SF) suppresses the pentose phosphate pathway and nucleotide biosynthesis in pancreatic cancer by activating Hippo signaling. NEK9 directly interacts with PRLR-SF and acts as an intermediary between PRLR-SF and the Hippo pathway; downstream TEAD1 directly regulates expression of PPP rate-limiting enzymes G6PD and TKT.","method":"Co-immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation, promoter luciferase assay, 13C-labeled metabolite tracing, LC-MS, subcutaneous and orthotopic xenograft models","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including metabolic tracing, ChIP, PLA, and in vivo validation in a single rigorous study","pmids":["33664869"],"is_preprint":false},{"year":2019,"finding":"PRLR gene silencing inhibits hippocampal neuron apoptosis in a chronic mild stress depression model by inactivating the JAK2-STAT5 signaling pathway and elevating BDNF expression; conversely, PRLR overexpression promoted apoptosis through activation of JAK2-STAT5 and increased Caspase-3/Bax.","method":"Lentiviral shRNA knockdown and overexpression in vivo (CMS mouse model), western blot for pathway components, immunofluorescence for cleaved Caspase-3","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation with defined signaling readout, single lab","pmids":["31545956"],"is_preprint":false},{"year":2022,"finding":"AMPK activation promotes ubiquitination of PrlR through the E3 ligase β-TrCP, leading to lysosomal degradation of PrlR via endocytosis, which attenuates prolactin signaling and inhibits milk protein synthesis under energy-deficient conditions.","method":"Pharmacological AMPK activation/inhibition, ubiquitination assay, lysosomal inhibitor experiments, in vitro mammary cell and in vivo mouse lactation models","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay combined with endocytosis/lysosomal degradation experiments and in vivo validation, single lab","pmids":["35248054"],"is_preprint":false},{"year":2019,"finding":"miR-142-3p directly targets PRLR mRNA; knockdown of miR-142-3p increases PRLR expression and activates downstream mTOR, SREBP1, cyclin D1, and STAT5 signaling, promoting mammary epithelial cell proliferation and milk fat/protein synthesis, while overexpression of miR-142-3p has the opposite effects.","method":"miRNA knockdown and overexpression in vitro and in vivo (mouse mammary gland), western blot, flow cytometry for cell cycle/apoptosis, triglyceride and β-casein measurements","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with multiple signaling readouts in vitro and in vivo, single lab","pmids":["31369265"],"is_preprint":false},{"year":2019,"finding":"PRLR variant Asn492Ile (located in the intracellular domain) increases prolactin-induced pAkt signaling (>1.3-fold) and cellular proliferation (1.4-fold) compared to wild-type PRLR, without affecting pSTAT5 signaling. Treatment with an Akt1/2 inhibitor or everolimus reduced Asn492Ile signaling and proliferation to wild-type levels, identifying this as a gain-of-function variant selectively activating the PI3K-Akt pathway.","method":"In vitro transfection and signaling assays (western blot for pAkt and pSTAT5), cell proliferation assays, pharmacological pathway inhibition","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro mutagenesis with pathway-specific readouts and pharmacological confirmation, single lab","pmids":["30445560"],"is_preprint":false},{"year":2000,"finding":"Implantation and decidualization defects in PRLR-deficient mice are mediated by insufficient ovarian (luteal) progesterone production, not by absence of uterine PRLR. Progesterone administration rescued implantation failure and restored expression of implantation-specific genes (LIF, amphiregulin, HB-EGF, COX-1/2, PPARδ, Hoxa-10, cyclin-D3, VEGF, Flk-1, neuropilin-1) in PRLR-/- mice.","method":"PRLR knockout mouse model, hormone rescue experiments, in situ hybridization and immunolocalization, gene expression analysis","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with rescue experiment, multiple downstream gene readouts, mechanistic pathway placement","pmids":["10803598"],"is_preprint":false},{"year":2009,"finding":"PRL binding induces conformational change of a pre-existing PRLr dimer complex that is necessary for activation of PRLr-associated Jak2 kinase. Cyclophilin A (a prolyl isomerase) plays a role in ligand-induced activation of PRLr-associated Jak2.","method":"Biochemical/functional analyses of receptor dimerization and Jak2 activation reviewed from primary studies; cyclophilin A interaction studies","journal":"Trends in endocrinology and metabolism: TEM","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review summarizing primary data; specific experimental details of cyclophilin A interaction not fully detailed in abstract","pmids":["19535262"],"is_preprint":false},{"year":2021,"finding":"The slick-hair phenotype in cattle is caused by mutations in PRLR that truncate the C-terminal region of the protein involved in JAK2/STAT5 activation during prolactin signaling. CRISPR/Cas9-introduced SLICK1 variants conferred superior thermoregulation, growth, and scrotal circumference without deleterious effects on reproduction or carcass characteristics.","method":"CRISPR/Cas9 gene editing of PRLR in Angus and Jersey cattle, physiological measurements (vaginal/rectal temperature), growth and reproductive phenotyping","journal":"FASEB bioAdvances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene-editing with defined molecular mechanism (JAK2/STAT5 truncation) and multiple phenotypic readouts in vivo","pmids":["39114445"],"is_preprint":false},{"year":2021,"finding":"PRLR-mediated JAK2/STAT5 signaling promotes lipid (triglyceride) accumulation in adipocytes; PRLR overexpression in an insulin resistance cell model increased TG content and phosphorylated JAK2 and STAT5 levels. (Note: the companion paper PMID 38077883 was retracted; this finding from PMID 36238467 remains, though caution is warranted.)","method":"Western blot for PRLR, p-JAK2, p-STAT5; triglyceride colorimetric assay; PRLR overexpression in SW872 adipocytes with oleic acid-induced insulin resistance model","journal":"Computational and mathematical methods in medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell model, associated paper retracted; results uncertain","pmids":["36238467"],"is_preprint":false},{"year":2021,"finding":"In Chinese soft-shelled turtle, the membrane-proximal ligand-binding domain of PRLR is the critical domain for PRL binding and receptor activation; a PRLR mutant lacking the membrane-distal ligand-binding domain (PRLR-M2) could still be dose-dependently activated by recombinant PRL and trigger the intracellular JAK2-STAT5 signaling cascade.","method":"5× STAT5-luciferase reporter system with wild-type PRLR and domain-deletion mutant (PRLR-M2), recombinant PRL protein expressed in E. coli","journal":"General and comparative endocrinology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — functional reconstitution with deletion mutagenesis and reporter assay, single lab, non-mammalian ortholog","pmids":["34715089"],"is_preprint":false},{"year":2013,"finding":"The duplicated PRLR gene (dPRLR) at the chicken K locus encodes a functional PRL receptor lacking a 149-aa C-terminal tail; when expressed in HepG2 cells it can be activated by chicken PRL and couples to the intracellular STAT5 signaling pathway.","method":"5× STAT5-luciferase reporter system, western blot, RT-PCR expression analysis in HepG2 cells transfected with dPRLR","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional signaling assay with reporter and western blot, single lab, avian ortholog context","pmids":["23940279"],"is_preprint":false},{"year":2021,"finding":"PRLR gene silencing in a CMS depression model reduced JAK2-STAT5 pathway activity and decreased expression of Caspase-3 and Bax in hippocampal CA3 neurons, with increased BDNF and Bcl-2, establishing that PRLR signals through JAK2-STAT5 to regulate neuronal apoptosis in this context.","method":"Lentiviral PRLR shRNA and overexpression in CMS mouse model, western blot for pathway and apoptotic markers, immunofluorescence","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation with pathway and apoptosis readouts in vivo, single lab","pmids":["31545956"],"is_preprint":false},{"year":2021,"finding":"Bu-Shen-Zhu-Yun Decoction promotes PRLR deubiquitination via CSN5 (COP9 signalosome subunit 5), increasing PRLR protein levels and restoring JAK2/STAT5 phosphorylation and kisspeptin expression in hyperprolactinemia-treated GT1-7 cells. GATA1 transcriptionally regulates CSN5, and BSZY-D increases GATA1 binding to the CSN5 promoter.","method":"Co-immunoprecipitation, western blot, RT-PCR, renilla luciferase reporter assay, shRNA knockdown of CSN5, immunofluorescence","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, shRNA knockdown, and reporter assay with multiple orthogonal methods, single lab","pmids":["34424219"],"is_preprint":false},{"year":2023,"finding":"High prolactin concentrations induce apoptosis in ovine ovarian granulosa cells by downregulating both L-PRLR and S-PRLR, activating oxidative stress (increased ROS, decreased mitochondrial respiratory chain complex activity and ATP), and inducing autophagy (ATG7/ATG5 upregulation). Knockdown of either L-PRLR or S-PRLR further reduced mitochondrial function, while overexpression had the opposite effect.","method":"siRNA knockdown and overexpression of L-PRLR and S-PRLR in granulosa cells, ROS measurement, mitochondrial respiratory complex activity assay, ATP measurement, flow cytometry for apoptosis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional isoform-specific manipulation with multiple functional readouts, single lab","pmids":["37833858"],"is_preprint":false},{"year":2023,"finding":"In mandibular BM-MSCs, PRLR is a downstream target of miR-181a-5p; activation of JAK/STAT3 signaling occurs when PRLR is knocked down or when miR-181a-5p mimics are transfected, impairing immunomodulatory function. PRLR overexpression enhanced in vivo immunosuppressive properties of BM-MSCs in a periodontitis model, suggesting PRLR normally suppresses JAK/STAT3 in this context.","method":"siRNA and overexpression of PRLR in BM-MSCs, STAT3 inhibitor treatment, luciferase reporter assay for miR-181a-5p/PRLR interaction, in vivo periodontitis mouse model","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated miRNA-target interaction with functional rescue in vivo, single lab","pmids":["37490712"],"is_preprint":false}],"current_model":"PRLR is a class I cytokine receptor that pre-dimerizes at the cell surface; PRL binding induces conformational changes in the receptor complex that activate the associated JAK2 kinase, which phosphorylates STAT5 (and other STATs), AKT, and MAPK to regulate transcription, cell proliferation, differentiation, and metabolism. Beyond the canonical membrane signaling, nuclear-localized PRLr acts as a transcriptional coactivator by recruiting HMGN2 to facilitate STAT5a-driven gene expression. PRLR protein stability is regulated by ubiquitination (via β-TrCP) leading to lysosomal degradation, and by deubiquitination via CSN5. A short isoform (PRLR-SF) signals through NEK9 to activate the Hippo pathway, suppressing the pentose phosphate pathway and nucleotide biosynthesis. Gain-of-function intracellular domain variants (e.g., Asn492Ile) selectively hyperactivate PI3K-AKT signaling and are associated with prolactinoma formation, while C-terminal truncation mutations (slick-hair alleles) eliminate JAK2/STAT5 coupling and confer thermotolerance in cattle."},"narrative":{"mechanistic_narrative":"PRLR is a prolactin receptor that couples ligand binding to intracellular signaling through a pre-formed receptor dimer: PRL binding induces a conformational change in the pre-existing PRLr dimer that activates the receptor-associated JAK2 kinase and drives STAT5 phosphorylation, the canonical output that governs cell proliferation, differentiation, apoptosis, and metabolism [PMID:34715089, PMID:23940279]. The membrane-proximal ligand-binding domain is the critical determinant of PRL binding and JAK2-STAT5 activation, and truncation of the C-terminal cytoplasmic region uncouples the receptor from JAK2/STAT5 signaling [PMID:39114445, PMID:34715089]. Beyond membrane signaling, nuclear-localized PRLr functions as a transcriptional coactivator: ligand-induced phosphorylation activates a transactivation domain that recruits HMGN2 to facilitate STAT5a promoter binding and transcription, promoting anchorage-independent growth [PMID:21816901]. Through JAK2-STAT5, PRLR regulates diverse physiological programs including hepatic insulin sensitivity [PMID:23775766], mammary epithelial proliferation and milk protein/fat synthesis [PMID:31369265], luteal progesterone production required for implantation and decidualization [PMID:10803598], and hippocampal neuronal apoptosis [PMID:31545956]. PRLR abundance is controlled post-translationally by opposing ubiquitination and deubiquitination: AMPK-driven, β-TrCP-mediated ubiquitination targets the receptor for endocytic lysosomal degradation under energy deficiency [PMID:35248054], while CSN5 deubiquitinates and stabilizes PRLR to restore JAK2/STAT5 output [PMID:34424219]; PRLR mRNA is additionally targeted by miR-142-3p [PMID:31369265]. A short isoform (PRLR-SF) signals non-canonically by directly engaging NEK9 to activate Hippo signaling, with downstream TEAD1 repressing the pentose phosphate pathway enzymes G6PD and TKT to suppress nucleotide biosynthesis in pancreatic cancer [PMID:33664869]. A gain-of-function intracellular-domain variant (Asn492Ile) selectively hyperactivates PI3K-Akt signaling and proliferation without affecting STAT5 [PMID:30445560].","teleology":[{"year":2000,"claim":"Established that the implantation and decidualization phenotype of PRLR loss is an endocrine, ovary-driven effect rather than a direct uterine receptor requirement, placing PRLR upstream of luteal progesterone.","evidence":"PRLR knockout mouse with progesterone rescue and downstream implantation-gene readouts","pmids":["10803598"],"confidence":"High","gaps":["Does not define the PRLR signaling pathway in luteal cells that drives progesterone production","Does not address direct uterine PRLR roles in other species"]},{"year":2009,"claim":"Defined the activation mechanism as conformational change within a pre-existing PRLr dimer triggering JAK2 activation, reframing receptor activation away from ligand-induced dimerization.","evidence":"Review of biochemical receptor dimerization/Jak2 activation studies and cyclophilin A interaction","pmids":["19535262"],"confidence":"Low","gaps":["Review summary; specific experimental detail of cyclophilin A interaction not given","Structural basis of the activating conformational change not resolved"]},{"year":2011,"claim":"Revealed a non-membrane function: nuclear PRLr acts as a STAT5a transcriptional coactivator via a ligand-activated transactivation domain recruiting HMGN2.","evidence":"Co-IP, nuclear fractionation, promoter luciferase, and gain/loss-of-function in breast cancer cells","pmids":["21816901"],"confidence":"Medium","gaps":["Mechanism of PRLr nuclear translocation not defined","Single-lab finding without independent replication"]},{"year":2013,"claim":"Connected PRLR-STAT5 signaling to systemic metabolism, showing hepatic PRLR controls insulin sensitivity and is itself regulated by nutrient sensing.","evidence":"Adenoviral overexpression/knockdown in vivo, db/db model, GCN2/mTOR/S6K1 pathway dissection","pmids":["23775766"],"confidence":"Medium","gaps":["Hepatocyte-specific STAT5 target genes mediating insulin sensitivity not identified","Relevance to human insulin resistance untested"]},{"year":2013,"claim":"Demonstrated that a C-terminally truncated PRLR isoform can still couple to STAT5, establishing that distal domains are dispensable for some signaling.","evidence":"STAT5-luciferase reporter and western blot in HepG2 cells with chicken dPRLR","pmids":["23940279"],"confidence":"Medium","gaps":["Avian ortholog; mammalian generalizability unclear","Functional consequences of the missing tail not characterized"]},{"year":2016,"claim":"Clarified receptor oligomerization, showing GHR and PRLR form higher-order assemblies of independent homodimers with distinct ligand-induced conformational responses.","evidence":"Split luciferase complementation and Co-IP in T47D cells","pmids":["27003442"],"confidence":"Medium","gaps":["Functional signaling consequence of GHR-PRLR hetero-assemblages not resolved","Single-lab finding"]},{"year":2019,"claim":"Identified a gain-of-function intracellular-domain variant that selectively biases PRLR toward PI3K-Akt rather than STAT5, linking PRLR to pathway-specific dysregulation.","evidence":"In vitro mutagenesis, pAkt/pSTAT5 western blots, proliferation assays, Akt/mTOR inhibitor rescue","pmids":["30445560"],"confidence":"Medium","gaps":["Structural basis for pathway-selective bias unknown","Disease causation established only by association, not in vivo"]},{"year":2019,"claim":"Defined miR-142-3p as a direct post-transcriptional regulator of PRLR controlling mammary proliferation and milk synthesis through mTOR/SREBP1/cyclin D1/STAT5.","evidence":"miRNA knockdown/overexpression in vitro and in vivo, western blot, cell cycle and lipid/protein readouts","pmids":["31369265"],"confidence":"Medium","gaps":["Direct miR-142-3p:PRLR 3'UTR binding site not detailed here","Crosstalk between the multiple downstream pathways not dissected"]},{"year":2019,"claim":"Placed PRLR-JAK2-STAT5 signaling in neuronal apoptosis, showing bidirectional control of hippocampal neuron death and BDNF in a depression model.","evidence":"Lentiviral knockdown/overexpression in CMS mouse model, western blot, cleaved Caspase-3 immunofluorescence","pmids":["31545956"],"confidence":"Medium","gaps":["Source and identity of the activating ligand in brain not defined","Single-lab, single disease model"]},{"year":2021,"claim":"Uncovered a non-canonical short-isoform pathway in which PRLR-SF engages NEK9 to activate Hippo signaling and suppress pentose phosphate flux via TEAD1-controlled G6PD/TKT.","evidence":"Co-IP, PLA, ChIP, promoter luciferase, 13C metabolite tracing, LC-MS, xenografts","pmids":["33664869"],"confidence":"High","gaps":["How PRLR-SF activates NEK9 mechanistically is unresolved","Ligand dependence of the PRLR-SF/NEK9 axis unclear"]},{"year":2021,"claim":"Defined opposing post-translational stability control: CSN5-mediated deubiquitination stabilizes PRLR and restores JAK2/STAT5 output, under GATA1 transcriptional control.","evidence":"Co-IP, CSN5 shRNA, luciferase reporter, RT-PCR, immunofluorescence in GT1-7 cells","pmids":["34424219"],"confidence":"Medium","gaps":["Direct CSN5 deubiquitinase activity on PRLR not biochemically isolated","Studied in the context of a herbal decoction treatment"]},{"year":2021,"claim":"Mapped the membrane-proximal ligand-binding domain as the critical site for PRL binding and JAK2-STAT5 activation via domain-deletion.","evidence":"STAT5-luciferase reporter with wild-type and domain-deletion PRLR mutant, recombinant PRL, in turtle ortholog","pmids":["34715089"],"confidence":"Medium","gaps":["Non-mammalian ortholog; mammalian domain requirements may differ","Binding affinity not quantified"]},{"year":2021,"claim":"Linked PRLR-JAK2-STAT5 to adipocyte lipid accumulation in an insulin resistance model.","evidence":"PRLR overexpression in SW872 adipocytes, p-JAK2/p-STAT5 western blot, triglyceride assay","pmids":["36238467"],"confidence":"Low","gaps":["Companion paper retracted; results uncertain","Single cell model without in vivo validation"]},{"year":2021,"claim":"Established that C-terminal truncation of PRLR (slick-hair alleles) eliminates JAK2/STAT5 coupling and confers thermotolerance, demonstrating the physiological consequence of cytoplasmic-tail loss.","evidence":"CRISPR/Cas9 editing of PRLR in cattle with thermoregulation, growth, and reproductive phenotyping","pmids":["39114445"],"confidence":"Medium","gaps":["Molecular signaling profile of the truncated receptor not directly assayed in this study","Bovine context; human relevance unaddressed"]},{"year":2023,"claim":"Showed isoform-specific control of granulosa cell survival, where prolactin downregulation of both L- and S-PRLR drives oxidative stress, mitochondrial dysfunction, and autophagy-linked apoptosis.","evidence":"siRNA/overexpression of L- and S-PRLR, ROS, mitochondrial complex activity, ATP, apoptosis flow cytometry","pmids":["37833858"],"confidence":"Medium","gaps":["Signaling pathway linking PRLR isoforms to mitochondrial function not defined","Ovine ortholog context"]},{"year":2023,"claim":"Identified a context where PRLR suppresses JAK/STAT3 signaling, with PRLR as a miR-181a-5p target controlling MSC immunomodulation.","evidence":"siRNA/overexpression of PRLR, STAT3 inhibitor, luciferase reporter, in vivo periodontitis model","pmids":["37490712"],"confidence":"Medium","gaps":["Mechanism by which PRLR represses STAT3 not defined","Apparent opposition to canonical STAT activation unreconciled"]},{"year":null,"claim":"How PRLR balances canonical JAK2-STAT5, PI3K-Akt, nuclear coactivation, and short-isoform Hippo signaling within a single cell, and what determines pathway selection, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating ligand binding with pathway-selective output","Determinants of isoform- and context-specific signaling not defined","Mechanism of PRLr nuclear import not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,12,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,12,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,14,16]}],"complexes":[],"partners":["JAK2","STAT5A","HMGN2","NEK9","GHR","BTRC","CSN5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P16471","full_name":"Prolactin receptor","aliases":[],"length_aa":622,"mass_kda":69.5,"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","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P16471/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRLR","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRLR","total_profiled":1310},"omim":[{"mim_id":"615555","title":"HYPERPROLACTINEMIA; HPRL","url":"https://www.omim.org/entry/615555"},{"mim_id":"615554","title":"MULTIPLE FIBROADENOMAS OF THE BREAST; MFAB","url":"https://www.omim.org/entry/615554"},{"mim_id":"606756","title":"17-@BETA-HYDROXYSTEROID DEHYDROGENASE VII; HSD17B7","url":"https://www.omim.org/entry/606756"},{"mim_id":"603597","title":"SUPPRESSOR OF CYTOKINE SIGNALING 1; SOCS1","url":"https://www.omim.org/entry/603597"},{"mim_id":"601511","title":"SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5A; STAT5A","url":"https://www.omim.org/entry/601511"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":120.7},{"tissue":"parathyroid gland","ntpm":77.7},{"tissue":"placenta","ntpm":47.2}],"url":"https://www.proteinatlas.org/search/PRLR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P16471","domains":[{"cath_id":"2.60.40.10","chopping":"21-122","consensus_level":"high","plddt":93.1399,"start":21,"end":122},{"cath_id":"2.60.40.10","chopping":"130-234","consensus_level":"high","plddt":91.1242,"start":130,"end":234}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P16471","model_url":"https://alphafold.ebi.ac.uk/files/AF-P16471-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P16471-F1-predicted_aligned_error_v6.png","plddt_mean":61.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRLR","jax_strain_url":"https://www.jax.org/strain/search?query=PRLR"},"sequence":{"accession":"P16471","fasta_url":"https://rest.uniprot.org/uniprotkb/P16471.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P16471/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P16471"}},"corpus_meta":[{"pmid":"9748546","id":"PMC_9748546","title":"Ovarian steroids differentially regulate the expression of PRL-R in neuroendocrine dopaminergic neuron populations: a double label confocal microscopic study.","date":"1998","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9748546","citation_count":97,"is_preprint":false},{"pmid":"1537321","id":"PMC_1537321","title":"Detection of prolactin receptor (PRL-R) mRNA in the rat hypothalamus and pituitary gland.","date":"1992","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/1537321","citation_count":94,"is_preprint":false},{"pmid":"19535262","id":"PMC_19535262","title":"New mechanisms for PRLr action in breast cancer.","date":"2009","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/19535262","citation_count":80,"is_preprint":false},{"pmid":"18713476","id":"PMC_18713476","title":"Partial duplication of the PRLR and SPEF2 genes at the late feathering locus in chicken.","date":"2008","source":"BMC 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Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/19138903","citation_count":3,"is_preprint":false},{"pmid":"36830458","id":"PMC_36830458","title":"The Role of PRLR Gene Polymorphisms in Milk Production in European Wild Rabbit (Oryctolagus cuniculus).","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36830458","citation_count":2,"is_preprint":false},{"pmid":"36272045","id":"PMC_36272045","title":"4SC-202 exerts an anti-tumor effect in cervical cancer by targeting PRLR signaling pathway.","date":"2022","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/36272045","citation_count":2,"is_preprint":false},{"pmid":"40076589","id":"PMC_40076589","title":"Association of Genes TRH, PRL and PRLR with Milk Performance, Reproductive Traits and Heat Stress Response in Dairy Cattle.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40076589","citation_count":2,"is_preprint":false},{"pmid":"38077883","id":"PMC_38077883","title":"Retracted: PRL/PRLR Can Promote Insulin Resistance by Activating the JAK2/STAT5 Signaling Pathway.","date":"2023","source":"Computational and mathematical methods in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38077883","citation_count":2,"is_preprint":false},{"pmid":"39201769","id":"PMC_39201769","title":"Aloperine Inhibits ASFV via Regulating PRLR/JAK2 Signaling Pathway In Vitro.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39201769","citation_count":1,"is_preprint":false},{"pmid":"40894210","id":"PMC_40894210","title":"Exercise ameliorates hepatic lipid accumulation via upregulating serum PRL and activating hepatic PRLR-mediated JAK2/STAT5 signaling pathway in NAFLD mice.","date":"2025","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40894210","citation_count":1,"is_preprint":false},{"pmid":"34077462","id":"PMC_34077462","title":"MICA-G129R: A bifunctional fusion protein increases PRLR-positive breast cancer cell death in co-culture with natural killer cells.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34077462","citation_count":1,"is_preprint":false},{"pmid":"39522661","id":"PMC_39522661","title":"The goat PRLR gene: mRNA expression, association analysis of InDel variants with body weight and growth traits.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/39522661","citation_count":1,"is_preprint":false},{"pmid":"17284423","id":"PMC_17284423","title":"[Preliminary study on the relationship between sow maternal behaviour during early lactation and polymorphism of PRLR gene].","date":"2007","source":"Yi chuan = 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A novel transactivation domain within PRLr is activated by ligand-induced phosphorylation, which enables HMGN2 binding; this PRLr/HMGN2 association facilitates Stat5a-responsive promoter binding and transcriptional activation, promoting anchorage-independent growth.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, promoter luciferase assay, loss-of-function and overexpression experiments in breast cancer cells\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional promoter assays in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21816901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GHR and PRLR form higher-order hetero-assemblages composed of GHR homodimers and PRLR homodimers (not GHR-PRLR heterodimers). Both receptors pre-homodimerize independently of ligand; GH or PRL augments PRLR-PRLR complementation, whereas both ligands cause decline in GHR-PRLR hetero-complementation, indicating distinct conformational responses in homomers versus heteromers.\",\n      \"method\": \"Split luciferase complementation assay (bioluminescence resonance), co-immunoprecipitation in T47D breast cancer cells\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus complementation assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"27003442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hepatic PRLR regulates insulin sensitivity via the STAT5 signaling pathway. Adenoviral overexpression of PRLR improved insulin sensitivity in mice, while knockdown impaired it; STAT5 pathway activation was required for this effect. PRLR expression was decreased under insulin-resistant (db/db) and increased under insulin-sensitive (leucine deprivation) conditions, with leucine deprivation upregulating PRLR via a GCN2/mTOR/S6K1-dependent pathway.\",\n      \"method\": \"Adenoviral overexpression and knockdown in vivo, in vitro cell assays, pathway inhibition experiments, db/db mouse model\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain- and loss-of-function with defined pathway readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23775766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The short isoform of PRLR (PRLR-SF) suppresses the pentose phosphate pathway and nucleotide biosynthesis in pancreatic cancer by activating Hippo signaling. NEK9 directly interacts with PRLR-SF and acts as an intermediary between PRLR-SF and the Hippo pathway; downstream TEAD1 directly regulates expression of PPP rate-limiting enzymes G6PD and TKT.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation, promoter luciferase assay, 13C-labeled metabolite tracing, LC-MS, subcutaneous and orthotopic xenograft models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including metabolic tracing, ChIP, PLA, and in vivo validation in a single rigorous study\",\n      \"pmids\": [\"33664869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRLR gene silencing inhibits hippocampal neuron apoptosis in a chronic mild stress depression model by inactivating the JAK2-STAT5 signaling pathway and elevating BDNF expression; conversely, PRLR overexpression promoted apoptosis through activation of JAK2-STAT5 and increased Caspase-3/Bax.\",\n      \"method\": \"Lentiviral shRNA knockdown and overexpression in vivo (CMS mouse model), western blot for pathway components, immunofluorescence for cleaved Caspase-3\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation with defined signaling readout, single lab\",\n      \"pmids\": [\"31545956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AMPK activation promotes ubiquitination of PrlR through the E3 ligase β-TrCP, leading to lysosomal degradation of PrlR via endocytosis, which attenuates prolactin signaling and inhibits milk protein synthesis under energy-deficient conditions.\",\n      \"method\": \"Pharmacological AMPK activation/inhibition, ubiquitination assay, lysosomal inhibitor experiments, in vitro mammary cell and in vivo mouse lactation models\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay combined with endocytosis/lysosomal degradation experiments and in vivo validation, single lab\",\n      \"pmids\": [\"35248054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-142-3p directly targets PRLR mRNA; knockdown of miR-142-3p increases PRLR expression and activates downstream mTOR, SREBP1, cyclin D1, and STAT5 signaling, promoting mammary epithelial cell proliferation and milk fat/protein synthesis, while overexpression of miR-142-3p has the opposite effects.\",\n      \"method\": \"miRNA knockdown and overexpression in vitro and in vivo (mouse mammary gland), western blot, flow cytometry for cell cycle/apoptosis, triglyceride and β-casein measurements\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with multiple signaling readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"31369265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRLR variant Asn492Ile (located in the intracellular domain) increases prolactin-induced pAkt signaling (>1.3-fold) and cellular proliferation (1.4-fold) compared to wild-type PRLR, without affecting pSTAT5 signaling. Treatment with an Akt1/2 inhibitor or everolimus reduced Asn492Ile signaling and proliferation to wild-type levels, identifying this as a gain-of-function variant selectively activating the PI3K-Akt pathway.\",\n      \"method\": \"In vitro transfection and signaling assays (western blot for pAkt and pSTAT5), cell proliferation assays, pharmacological pathway inhibition\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro mutagenesis with pathway-specific readouts and pharmacological confirmation, single lab\",\n      \"pmids\": [\"30445560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Implantation and decidualization defects in PRLR-deficient mice are mediated by insufficient ovarian (luteal) progesterone production, not by absence of uterine PRLR. Progesterone administration rescued implantation failure and restored expression of implantation-specific genes (LIF, amphiregulin, HB-EGF, COX-1/2, PPARδ, Hoxa-10, cyclin-D3, VEGF, Flk-1, neuropilin-1) in PRLR-/- mice.\",\n      \"method\": \"PRLR knockout mouse model, hormone rescue experiments, in situ hybridization and immunolocalization, gene expression analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with rescue experiment, multiple downstream gene readouts, mechanistic pathway placement\",\n      \"pmids\": [\"10803598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PRL binding induces conformational change of a pre-existing PRLr dimer complex that is necessary for activation of PRLr-associated Jak2 kinase. Cyclophilin A (a prolyl isomerase) plays a role in ligand-induced activation of PRLr-associated Jak2.\",\n      \"method\": \"Biochemical/functional analyses of receptor dimerization and Jak2 activation reviewed from primary studies; cyclophilin A interaction studies\",\n      \"journal\": \"Trends in endocrinology and metabolism: TEM\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review summarizing primary data; specific experimental details of cyclophilin A interaction not fully detailed in abstract\",\n      \"pmids\": [\"19535262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The slick-hair phenotype in cattle is caused by mutations in PRLR that truncate the C-terminal region of the protein involved in JAK2/STAT5 activation during prolactin signaling. CRISPR/Cas9-introduced SLICK1 variants conferred superior thermoregulation, growth, and scrotal circumference without deleterious effects on reproduction or carcass characteristics.\",\n      \"method\": \"CRISPR/Cas9 gene editing of PRLR in Angus and Jersey cattle, physiological measurements (vaginal/rectal temperature), growth and reproductive phenotyping\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene-editing with defined molecular mechanism (JAK2/STAT5 truncation) and multiple phenotypic readouts in vivo\",\n      \"pmids\": [\"39114445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRLR-mediated JAK2/STAT5 signaling promotes lipid (triglyceride) accumulation in adipocytes; PRLR overexpression in an insulin resistance cell model increased TG content and phosphorylated JAK2 and STAT5 levels. (Note: the companion paper PMID 38077883 was retracted; this finding from PMID 36238467 remains, though caution is warranted.)\",\n      \"method\": \"Western blot for PRLR, p-JAK2, p-STAT5; triglyceride colorimetric assay; PRLR overexpression in SW872 adipocytes with oleic acid-induced insulin resistance model\",\n      \"journal\": \"Computational and mathematical methods in medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell model, associated paper retracted; results uncertain\",\n      \"pmids\": [\"36238467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Chinese soft-shelled turtle, the membrane-proximal ligand-binding domain of PRLR is the critical domain for PRL binding and receptor activation; a PRLR mutant lacking the membrane-distal ligand-binding domain (PRLR-M2) could still be dose-dependently activated by recombinant PRL and trigger the intracellular JAK2-STAT5 signaling cascade.\",\n      \"method\": \"5× STAT5-luciferase reporter system with wild-type PRLR and domain-deletion mutant (PRLR-M2), recombinant PRL protein expressed in E. coli\",\n      \"journal\": \"General and comparative endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — functional reconstitution with deletion mutagenesis and reporter assay, single lab, non-mammalian ortholog\",\n      \"pmids\": [\"34715089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The duplicated PRLR gene (dPRLR) at the chicken K locus encodes a functional PRL receptor lacking a 149-aa C-terminal tail; when expressed in HepG2 cells it can be activated by chicken PRL and couples to the intracellular STAT5 signaling pathway.\",\n      \"method\": \"5× STAT5-luciferase reporter system, western blot, RT-PCR expression analysis in HepG2 cells transfected with dPRLR\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional signaling assay with reporter and western blot, single lab, avian ortholog context\",\n      \"pmids\": [\"23940279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRLR gene silencing in a CMS depression model reduced JAK2-STAT5 pathway activity and decreased expression of Caspase-3 and Bax in hippocampal CA3 neurons, with increased BDNF and Bcl-2, establishing that PRLR signals through JAK2-STAT5 to regulate neuronal apoptosis in this context.\",\n      \"method\": \"Lentiviral PRLR shRNA and overexpression in CMS mouse model, western blot for pathway and apoptotic markers, immunofluorescence\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation with pathway and apoptosis readouts in vivo, single lab\",\n      \"pmids\": [\"31545956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Bu-Shen-Zhu-Yun Decoction promotes PRLR deubiquitination via CSN5 (COP9 signalosome subunit 5), increasing PRLR protein levels and restoring JAK2/STAT5 phosphorylation and kisspeptin expression in hyperprolactinemia-treated GT1-7 cells. GATA1 transcriptionally regulates CSN5, and BSZY-D increases GATA1 binding to the CSN5 promoter.\",\n      \"method\": \"Co-immunoprecipitation, western blot, RT-PCR, renilla luciferase reporter assay, shRNA knockdown of CSN5, immunofluorescence\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, shRNA knockdown, and reporter assay with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34424219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"High prolactin concentrations induce apoptosis in ovine ovarian granulosa cells by downregulating both L-PRLR and S-PRLR, activating oxidative stress (increased ROS, decreased mitochondrial respiratory chain complex activity and ATP), and inducing autophagy (ATG7/ATG5 upregulation). Knockdown of either L-PRLR or S-PRLR further reduced mitochondrial function, while overexpression had the opposite effect.\",\n      \"method\": \"siRNA knockdown and overexpression of L-PRLR and S-PRLR in granulosa cells, ROS measurement, mitochondrial respiratory complex activity assay, ATP measurement, flow cytometry for apoptosis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional isoform-specific manipulation with multiple functional readouts, single lab\",\n      \"pmids\": [\"37833858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In mandibular BM-MSCs, PRLR is a downstream target of miR-181a-5p; activation of JAK/STAT3 signaling occurs when PRLR is knocked down or when miR-181a-5p mimics are transfected, impairing immunomodulatory function. PRLR overexpression enhanced in vivo immunosuppressive properties of BM-MSCs in a periodontitis model, suggesting PRLR normally suppresses JAK/STAT3 in this context.\",\n      \"method\": \"siRNA and overexpression of PRLR in BM-MSCs, STAT3 inhibitor treatment, luciferase reporter assay for miR-181a-5p/PRLR interaction, in vivo periodontitis mouse model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated miRNA-target interaction with functional rescue in vivo, single lab\",\n      \"pmids\": [\"37490712\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRLR is a class I cytokine receptor that pre-dimerizes at the cell surface; PRL binding induces conformational changes in the receptor complex that activate the associated JAK2 kinase, which phosphorylates STAT5 (and other STATs), AKT, and MAPK to regulate transcription, cell proliferation, differentiation, and metabolism. Beyond the canonical membrane signaling, nuclear-localized PRLr acts as a transcriptional coactivator by recruiting HMGN2 to facilitate STAT5a-driven gene expression. PRLR protein stability is regulated by ubiquitination (via β-TrCP) leading to lysosomal degradation, and by deubiquitination via CSN5. A short isoform (PRLR-SF) signals through NEK9 to activate the Hippo pathway, suppressing the pentose phosphate pathway and nucleotide biosynthesis. Gain-of-function intracellular domain variants (e.g., Asn492Ile) selectively hyperactivate PI3K-AKT signaling and are associated with prolactinoma formation, while C-terminal truncation mutations (slick-hair alleles) eliminate JAK2/STAT5 coupling and confer thermotolerance in cattle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRLR is a prolactin receptor that couples ligand binding to intracellular signaling through a pre-formed receptor dimer: PRL binding induces a conformational change in the pre-existing PRLr dimer that activates the receptor-associated JAK2 kinase and drives STAT5 phosphorylation, the canonical output that governs cell proliferation, differentiation, apoptosis, and metabolism [#12, #13]. The membrane-proximal ligand-binding domain is the critical determinant of PRL binding and JAK2-STAT5 activation, and truncation of the C-terminal cytoplasmic region uncouples the receptor from JAK2/STAT5 signaling [#10, #12]. Beyond membrane signaling, nuclear-localized PRLr functions as a transcriptional coactivator: ligand-induced phosphorylation activates a transactivation domain that recruits HMGN2 to facilitate STAT5a promoter binding and transcription, promoting anchorage-independent growth [#0]. Through JAK2-STAT5, PRLR regulates diverse physiological programs including hepatic insulin sensitivity [#2], mammary epithelial proliferation and milk protein/fat synthesis [#6], luteal progesterone production required for implantation and decidualization [#8], and hippocampal neuronal apoptosis [#4, #14]. PRLR abundance is controlled post-translationally by opposing ubiquitination and deubiquitination: AMPK-driven, β-TrCP-mediated ubiquitination targets the receptor for endocytic lysosomal degradation under energy deficiency [#5], while CSN5 deubiquitinates and stabilizes PRLR to restore JAK2/STAT5 output [#15]; PRLR mRNA is additionally targeted by miR-142-3p [#6]. A short isoform (PRLR-SF) signals non-canonically by directly engaging NEK9 to activate Hippo signaling, with downstream TEAD1 repressing the pentose phosphate pathway enzymes G6PD and TKT to suppress nucleotide biosynthesis in pancreatic cancer [#3]. A gain-of-function intracellular-domain variant (Asn492Ile) selectively hyperactivates PI3K-Akt signaling and proliferation without affecting STAT5 [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that the implantation and decidualization phenotype of PRLR loss is an endocrine, ovary-driven effect rather than a direct uterine receptor requirement, placing PRLR upstream of luteal progesterone.\",\n      \"evidence\": \"PRLR knockout mouse with progesterone rescue and downstream implantation-gene readouts\",\n      \"pmids\": [\"10803598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the PRLR signaling pathway in luteal cells that drives progesterone production\", \"Does not address direct uterine PRLR roles in other species\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the activation mechanism as conformational change within a pre-existing PRLr dimer triggering JAK2 activation, reframing receptor activation away from ligand-induced dimerization.\",\n      \"evidence\": \"Review of biochemical receptor dimerization/Jak2 activation studies and cyclophilin A interaction\",\n      \"pmids\": [\"19535262\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Review summary; specific experimental detail of cyclophilin A interaction not given\", \"Structural basis of the activating conformational change not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a non-membrane function: nuclear PRLr acts as a STAT5a transcriptional coactivator via a ligand-activated transactivation domain recruiting HMGN2.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, promoter luciferase, and gain/loss-of-function in breast cancer cells\",\n      \"pmids\": [\"21816901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PRLr nuclear translocation not defined\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected PRLR-STAT5 signaling to systemic metabolism, showing hepatic PRLR controls insulin sensitivity and is itself regulated by nutrient sensing.\",\n      \"evidence\": \"Adenoviral overexpression/knockdown in vivo, db/db model, GCN2/mTOR/S6K1 pathway dissection\",\n      \"pmids\": [\"23775766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hepatocyte-specific STAT5 target genes mediating insulin sensitivity not identified\", \"Relevance to human insulin resistance untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that a C-terminally truncated PRLR isoform can still couple to STAT5, establishing that distal domains are dispensable for some signaling.\",\n      \"evidence\": \"STAT5-luciferase reporter and western blot in HepG2 cells with chicken dPRLR\",\n      \"pmids\": [\"23940279\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Avian ortholog; mammalian generalizability unclear\", \"Functional consequences of the missing tail not characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Clarified receptor oligomerization, showing GHR and PRLR form higher-order assemblies of independent homodimers with distinct ligand-induced conformational responses.\",\n      \"evidence\": \"Split luciferase complementation and Co-IP in T47D cells\",\n      \"pmids\": [\"27003442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional signaling consequence of GHR-PRLR hetero-assemblages not resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a gain-of-function intracellular-domain variant that selectively biases PRLR toward PI3K-Akt rather than STAT5, linking PRLR to pathway-specific dysregulation.\",\n      \"evidence\": \"In vitro mutagenesis, pAkt/pSTAT5 western blots, proliferation assays, Akt/mTOR inhibitor rescue\",\n      \"pmids\": [\"30445560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for pathway-selective bias unknown\", \"Disease causation established only by association, not in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined miR-142-3p as a direct post-transcriptional regulator of PRLR controlling mammary proliferation and milk synthesis through mTOR/SREBP1/cyclin D1/STAT5.\",\n      \"evidence\": \"miRNA knockdown/overexpression in vitro and in vivo, western blot, cell cycle and lipid/protein readouts\",\n      \"pmids\": [\"31369265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miR-142-3p:PRLR 3'UTR binding site not detailed here\", \"Crosstalk between the multiple downstream pathways not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed PRLR-JAK2-STAT5 signaling in neuronal apoptosis, showing bidirectional control of hippocampal neuron death and BDNF in a depression model.\",\n      \"evidence\": \"Lentiviral knockdown/overexpression in CMS mouse model, western blot, cleaved Caspase-3 immunofluorescence\",\n      \"pmids\": [\"31545956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source and identity of the activating ligand in brain not defined\", \"Single-lab, single disease model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a non-canonical short-isoform pathway in which PRLR-SF engages NEK9 to activate Hippo signaling and suppress pentose phosphate flux via TEAD1-controlled G6PD/TKT.\",\n      \"evidence\": \"Co-IP, PLA, ChIP, promoter luciferase, 13C metabolite tracing, LC-MS, xenografts\",\n      \"pmids\": [\"33664869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PRLR-SF activates NEK9 mechanistically is unresolved\", \"Ligand dependence of the PRLR-SF/NEK9 axis unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined opposing post-translational stability control: CSN5-mediated deubiquitination stabilizes PRLR and restores JAK2/STAT5 output, under GATA1 transcriptional control.\",\n      \"evidence\": \"Co-IP, CSN5 shRNA, luciferase reporter, RT-PCR, immunofluorescence in GT1-7 cells\",\n      \"pmids\": [\"34424219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CSN5 deubiquitinase activity on PRLR not biochemically isolated\", \"Studied in the context of a herbal decoction treatment\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the membrane-proximal ligand-binding domain as the critical site for PRL binding and JAK2-STAT5 activation via domain-deletion.\",\n      \"evidence\": \"STAT5-luciferase reporter with wild-type and domain-deletion PRLR mutant, recombinant PRL, in turtle ortholog\",\n      \"pmids\": [\"34715089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-mammalian ortholog; mammalian domain requirements may differ\", \"Binding affinity not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PRLR-JAK2-STAT5 to adipocyte lipid accumulation in an insulin resistance model.\",\n      \"evidence\": \"PRLR overexpression in SW872 adipocytes, p-JAK2/p-STAT5 western blot, triglyceride assay\",\n      \"pmids\": [\"36238467\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Companion paper retracted; results uncertain\", \"Single cell model without in vivo validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that C-terminal truncation of PRLR (slick-hair alleles) eliminates JAK2/STAT5 coupling and confers thermotolerance, demonstrating the physiological consequence of cytoplasmic-tail loss.\",\n      \"evidence\": \"CRISPR/Cas9 editing of PRLR in cattle with thermoregulation, growth, and reproductive phenotyping\",\n      \"pmids\": [\"39114445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signaling profile of the truncated receptor not directly assayed in this study\", \"Bovine context; human relevance unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed isoform-specific control of granulosa cell survival, where prolactin downregulation of both L- and S-PRLR drives oxidative stress, mitochondrial dysfunction, and autophagy-linked apoptosis.\",\n      \"evidence\": \"siRNA/overexpression of L- and S-PRLR, ROS, mitochondrial complex activity, ATP, apoptosis flow cytometry\",\n      \"pmids\": [\"37833858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway linking PRLR isoforms to mitochondrial function not defined\", \"Ovine ortholog context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a context where PRLR suppresses JAK/STAT3 signaling, with PRLR as a miR-181a-5p target controlling MSC immunomodulation.\",\n      \"evidence\": \"siRNA/overexpression of PRLR, STAT3 inhibitor, luciferase reporter, in vivo periodontitis model\",\n      \"pmids\": [\"37490712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PRLR represses STAT3 not defined\", \"Apparent opposition to canonical STAT activation unreconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRLR balances canonical JAK2-STAT5, PI3K-Akt, nuclear coactivation, and short-isoform Hippo signaling within a single cell, and what determines pathway selection, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating ligand binding with pathway-selective output\", \"Determinants of isoform- and context-specific signaling not defined\", \"Mechanism of PRLr nuclear import not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 12, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 14, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JAK2\", \"STAT5A\", \"HMGN2\", \"NEK9\", \"GHR\", \"BTRC\", \"CSN5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}