Affinage

NPRL3

GATOR1 complex protein NPRL3 · UniProt Q12980

Round 2 corrected
Length
569 aa
Mass
63.6 kDa
Annotated
2026-04-29
130 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPRL3 is a core subunit of the GATOR1 complex that functions as a negative regulator of mTORC1 signaling by promoting GTP hydrolysis on RagA/RagB GTPases at the lysosomal surface in response to amino acid deprivation. Within GATOR1, the NPRL2–NPRL3 heterodimer executes the GAP catalytic activity toward RagA, while DEPDC5 serves as the Rag-contacting inhibitory module, and the entire complex is recruited to lysosomes by the KICSTOR scaffold (PMID:23723238, PMID:29590090, PMID:28199306). Loss of NPRL3 locks mTORC1 in a constitutively active lysosomal conformation irrespective of nutrient status, causing neuronal hypertrophy, cortical lamination defects, and seizures that are reversible by rapamycin (PMID:35136953, PMID:34965576). Germline loss-of-function mutations in NPRL3 cause familial focal epilepsy with variable foci, accompanied by mTOR pathway hyperactivation in patient brain tissue (PMID:26285051, PMID:26505888).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2009 High

    Establishing that NPRL2 and NPRL3 orthologs form an evolutionarily conserved heterodimer required for TORC1 inactivation during amino acid starvation answered the question of how cells relay amino acid insufficiency upstream of TOR.

    Evidence Genome-wide reverse genetic screen in yeast combined with co-immunoprecipitation of human NPRL2–NPRL3

    PMID:19521502

    Open questions at the time
    • Mechanism of TORC1 inhibition (direct GAP or indirect) was unknown
    • Whether a third subunit existed was not determined
    • Mammalian functional data limited to co-IP
  2. 2011 High

    Demonstrating that the yeast Iml1p–Npr2p–Npr3p complex is required for non-nitrogen-starvation autophagy linked NPRL3-containing complexes to autophagosome formation, expanding their role beyond TORC1 signaling per se.

    Evidence Fluorescence microscopy and EM of yeast deletion mutants under selective starvation conditions

    PMID:21900499

    Open questions at the time
    • Whether the autophagy function is conserved in mammals was untested
    • Whether autophagy induction is a direct consequence of TORC1 inhibition or a parallel function was unclear
  3. 2013 High

    Biochemical reconstitution of GATOR1 as a trimeric complex (NPRL3–NPRL2–DEPDC5) with direct GAP activity toward RagA/RagB GTPases established the molecular mechanism by which NPRL3 suppresses mTORC1, and revealed that GATOR1-mutant cancer cells are hypersensitive to rapamycin.

    Evidence Affinity purification/mass spectrometry, in vitro GAP activity assay, RNAi, amino acid starvation in human cells

    PMID:23723238

    Open questions at the time
    • Which subunit(s) catalyze GAP activity was not resolved
    • Structural basis of the complex was unknown
    • How GATOR1 is recruited to the lysosomal membrane was undefined
  4. 2014 High

    Genetic epistasis in yeast and Drosophila confirmed that NPRL2–NPRL3 act upstream of Rag GTPases to inactivate TORC1 and established in vivo physiological consequences of NPRL3 loss, including failed autophagy and apoptosis during starvation.

    Evidence Yeast GTPase mutant epistasis, Drosophila oogenesis genetic analysis, TORC1 localization and autophagy flux assays

    PMID:24786828 PMID:25046117

    Open questions at the time
    • Mammalian in vivo phenotypes of NPRL3 loss were still uncharacterized
    • Whether NPRL3 has functions independent of Rag GAP activity was not addressed
  5. 2015 Medium

    Human genetic studies identified loss-of-function NPRL3 mutations as a cause of familial focal epilepsy, with patient brain tissue showing mTOR pathway hyperactivation, linking GATOR1 dysfunction to a Mendelian neurological disease.

    Evidence Exome sequencing and linkage analysis in epilepsy families, phospho-S6 immunohistochemistry on resected brain tissue

    PMID:26285051 PMID:26505888

    Open questions at the time
    • Causal proof via rescue or functional reconstitution in human neurons was lacking
    • Genotype–phenotype correlations across GATOR1 genes were not established
    • Mechanism of cortical malformation was not elucidated
  6. 2017 High

    Discovery that KICSTOR recruits GATOR1 to the lysosomal surface resolved how NPRL3-containing complexes access their Rag GTPase substrates, explaining a key spatial prerequisite for mTORC1 regulation.

    Evidence Reciprocal co-immunoprecipitation, lysosomal fractionation, mTORC1 activity assays, SZT2 knockout mice

    PMID:28199306

    Open questions at the time
    • Whether KICSTOR–GATOR1 interaction is regulated by nutrients was not fully resolved
    • Structural basis of the KICSTOR–GATOR1 interface was unknown
  7. 2018 High

    Cryo-EM structures of GATOR1 and GATOR1–Rag complexes revealed that NPRL2–NPRL3 heterodimer executes the catalytic GAP step toward RagA, while DEPDC5 contacts and inhibits Rag GTPases in a separate binding mode, resolving the long-standing question of subunit-specific roles.

    Evidence Cryo-electron microscopy at sub-nanometer resolution with mutagenesis-validated GAP activity assays

    PMID:29590090

    Open questions at the time
    • Atomic details of the catalytic mechanism (arginine finger) were not fully resolved
    • Structural basis for GATOR2-mediated regulation of GATOR1 was not determined
  8. 2021 Medium

    Identification of post-translational and translational regulatory mechanisms for NPRL3 (FKBP39-dependent proteolysis, uORF-mediated translational repression) revealed that NPRL3 protein levels are dynamically tuned by nutrient status, adding a feed-forward layer to TORC1 control.

    Evidence Drosophila fkbp39 mutants, protein stability assays, uORF reporter assays, TORC1 and autophagy readouts

    PMID:34078879

    Open questions at the time
    • Whether these regulatory mechanisms are conserved in mammals is unknown
    • Identity of the E3 ligase mediating NPRL3 degradation was not established
  9. 2022 High

    In vivo mouse models (focal and conditional cortex-wide Nprl3 knockout) demonstrated that NPRL3 loss decouples mTOR from nutrient sensing at the lysosome, causes cortical malformations and spontaneous epilepsy, and that rapamycin rescues lamination defects and seizures, providing direct causal proof for the NPRL3–mTORC1–epilepsy axis.

    Evidence CRISPR/Cas9 knockout in neuronal cells, in utero electroporation, conditional knockout mice, EEG monitoring, rapamycin rescue, mTOR lysosomal localization under starvation

    PMID:34965576 PMID:35136953

    Open questions at the time
    • Why rapamycin benefit is less durable after withdrawal in Nprl3-cKO versus Depdc5-cKO is unexplained
    • Cell-type-specific requirements for NPRL3 in the brain are not resolved
    • Whether NPRL3 loss contributes to epileptogenesis through mTOR-independent mechanisms is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full atomic-resolution catalytic mechanism for NPRL2–NPRL3-mediated GAP activity, the structural basis of GATOR2-to-GATOR1 signal relay, and whether NPRL3 has mTORC1-independent functions in inflammation or other contexts remain open questions.
  • Catalytic residues and arginine finger for GAP activity not definitively identified
  • GATOR2–GATOR1 structural interface unresolved
  • NPRL3 role in microglial inflammation (ARRB1/ARRB2 axis) not independently replicated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005764 lysosome 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 3
Partners
DEPDC5FKBP39NPRL2RRAGARRAGBSZT2
Complex memberships
GATOR1

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 NPRL3 (together with DEPDC5 and NPRL2) is a subunit of the GATOR1 complex, which has GTPase-activating protein (GAP) activity for RagA and RagB GTPases, thereby negatively regulating mTORC1 signaling. Inhibition of NPRL3 makes mTORC1 signaling resistant to amino acid deprivation, and cancer cells with inactivating GATOR1 mutations show mTOR hyperactivity and hypersensitivity to rapamycin. Affinity purification/mass spectrometry, RNAi knockdown, in vitro GAP activity assay, amino acid starvation experiments, epistasis analysis Science High 23723238
2009 Yeast Npr2 and Npr3 (orthologs of human NPRL2 and NPRL3) form a heterodimer and are required to inactivate TORC1 in response to amino acid starvation. The human homologs NPRL2 and NPRL3 also co-immunoprecipitate, indicating the heterodimer interaction is evolutionarily conserved. Genome-wide reverse genetic screen, biochemical purification, co-immunoprecipitation, TORC1 activity reporters PLoS genetics High 19521502
2011 In yeast, the Iml1p-Npr2p-Npr3p complex (ortholog of mammalian GATOR1) is selectively required for non-nitrogen-starvation (NNS)-induced autophagy. The complex is required for autophagosome formation under NNS conditions, and Iml1p localizes to preautophagosomal structures (PAS). A conserved domain in Iml1p is required for both NNS-induced autophagy and complex formation. Visual screen, yeast deletion mutants, fluorescence microscopy, ultrastructural analysis (EM), domain mutagenesis Molecular biology of the cell High 21900499
2014 In yeast, Npr2-Npr3 function upstream of Gtr1-Gtr2 (Rag GTPase orthologs). Npr2-Npr3 promote GTP hydrolysis on Gtr1 (converting it to GDP-bound state), which is required to inactivate TORC1 and induce autophagy. Loss of Npr2 or expression of constitutively GTP-bound Gtr1 both suppress autophagy and increase Tor1 vacuole localization. Mammalian NPRL2 and NPRL3 were also shown to regulate autophagy. Yeast genome-wide deletion screen, GTPase mutant analysis, TORC1 localization assay, autophagy flux assays in yeast and mammalian cells Autophagy High 25046117
2014 In Drosophila, Nprl2 and Nprl3 physically interact and co-localize to lysosomes and autolysosomes. They inhibit TORC1 signaling in the female germline in response to amino acid starvation, and work in concert with Tsc1/2 to fine-tune TORC1 activity. Failure to downregulate TORC1 in nprl2/nprl3 mutants during amino acid starvation triggers apoptosis in oogenesis. Co-immunoprecipitation, subcellular localization (immunofluorescence), genetic loss-of-function in Drosophila oogenesis, TORC1 activity assays, epistasis with Tsc1/2 Cell death and differentiation High 24786828
2018 Cryo-EM structures of the human GATOR1 complex and GATOR1-Rag GTPase complexes revealed that GATOR1 adopts an extended architecture where NPRL2 links DEPDC5 and NPRL3. The NPRL2-NPRL3 heterodimer executes GAP activity toward RAGA, while DEPDC5 contacts the Rag GTPase heterodimer and inhibits GAP activity when directly bound to RAGA. Thus at least two binding modes exist between Rag GTPases and GATOR1. Cryo-electron microscopy, biochemical GAP activity assays, mutagenesis Nature High 29590090
2016 In fission yeast, loss of Npr2 or Npr3 (Nprl2/Nprl3 orthologs) disinhibits TORC1 activity under nitrogen depletion and diminishes vacuolar localization and protein levels of Gtr1 and Gtr2 (Rag GTPase orthologs). Lam2 (LAMTOR2 ortholog) physically interacts with Npr2 and Gtr1, and Lam2-Npr2-Npr3 function together to tether GDP-bound Gtr1 to the vacuolar membrane to suppress TORC1 activity. Yeast genetics, co-immunoprecipitation, subcellular localization imaging, TORC1 activity (Rps6 phosphorylation), genetic rescue experiments PloS one Medium 27227887
2015 Mutations in NPRL3 cause familial focal epilepsy (including cases with focal cortical dysplasia). Immunostaining of resected brain tissue from patients with NPRL3 mutations demonstrated mTOR pathway hyperactivation (phospho-S6 immunoreactivity), linking loss-of-function NPRL3 mutations to mTORC1 dysregulation in human brain. Exome sequencing, linkage analysis, immunohistochemistry for mTOR activation markers in resected brain tissue Annals of neurology Medium 26285051
2015 NPRL3 mutations identified in focal epilepsy patients act through the mTOR-signaling pathway; NPRL3 is established as a focal epilepsy gene together with NPRL2 and DEPDC5 (all GATOR1 complex genes). Targeted capture next-generation sequencing, exome sequencing, linkage analysis of epilepsy families Annals of neurology Medium 26505888
2022 CRISPR/Cas9 knockout of Nprl3 in Neuro2a cells causes mTOR pathway hyperactivation (phospho-S6 and 4E-BP1), cell soma enlargement, and cellular aggregation. mTOR remains constitutively localized to the lysosome in an active conformation even under amino acid-free starvation, demonstrating that Nprl3 loss decouples mTOR activation from nutrient status. In vivo focal Nprl3 knockout in fetal mouse cortex (in utero electroporation) caused altered cortical lamination and white matter heterotopic neurons, both prevented by rapamycin treatment. EEG recordings showed network hyperexcitability and reduced seizure threshold. CRISPR/Cas9 knockout, immunofluorescence for mTOR localization, Western blot for mTOR substrates, time-lapse imaging, rapamycin rescue, in utero electroporation, EEG recordings Brain High 35136953
2021 In Drosophila, Nprl3 protein stability is regulated by the FKBP39-dependent proteolytic destruction pathway and the Unassembled Soluble Complex Proteins Degradation (USPD) pathway. Under nutrient-replete conditions, FKBP39 promotes Nprl3 degradation to keep levels low; nutrient starvation abrogates this degradation, allowing rapid Nprl3 accumulation. Loss of fkbp39 decreases TORC1 activity and increases autophagy. Additionally, the 5'UTR of nprl3 transcripts contains a functional upstream open reading frame (uORF) that inhibits main ORF translation. Genetic loss-of-function (fkbp39 mutants), protein stability assays, TORC1 activity measurements, autophagy assays, uORF reporter assays Cell death & disease Medium 34078879
2021 NPRL3 mediates the opposing functions of β-arrestin 1 (ARRB1) and β-arrestin 2 (ARRB2) in microglial inflammatory responses. RNA sequencing revealed that ARRB1 and ARRB2 differentially regulate Nprl3 expression, and gain/loss-of-function studies demonstrated that Nprl3 mediates ARRB effects on microglia inflammatory responses (STAT1 and NF-κB pathways) and Parkinson's disease pathology. RNA sequencing, gain/loss-of-function studies, primary microglia culture, in vivo PD mouse models, STAT1/NF-κB pathway assays Cell death and differentiation Medium 33686256
2022 Conditional dorsal telencephalon-specific Nprl3 knockout mice (Emx1cre/+; Nprl3f/f) develop spontaneous seizures and dysmorphic enlarged neurons with increased mTORC1 signaling, similar to Depdc5-cKO mice. Chronic postnatal rapamycin administration prolonged survival and inhibited seizures but not enlarged neuronal cells. The benefit of rapamycin after withdrawal was less durable in Nprl3-cKO compared with Depdc5-cKO mice. Conditional knockout mice, EEG/seizure monitoring, rapamycin treatment, immunohistochemistry for mTORC1 signaling markers, comparative phenotype analysis Human molecular genetics High 34965576
2021 A loss-of-function NPRL3 mutation (c316C>T; p.Q106*) in familial focal epilepsy with variable foci leads to decreased NPRL3 mRNA and protein expression in peripheral blood cells, with consequent increased phospho-p70 S6 kinase (P-S6K), confirming that NPRL3 loss-of-function causes mTORC1 pathway hyperactivation. Whole exome sequencing, PCR, Western blotting, immunohistochemistry in peripheral blood cells from family members Frontiers in genetics Medium 34868250
2017 KICSTOR (including SZT2) recruits GATOR1 to the lysosomal surface and is required for GATOR1 to interact with its substrates the Rag GTPases; NPRL3 (as part of GATOR1) is thereby positioned at the lysosome to regulate mTORC1 in response to nutrient signals. Co-immunoprecipitation, subcellular localization, lysosomal fractionation, mTORC1 activity assays, mouse knockout Nature High 28199306

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
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
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2013 A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science (New York, N.Y.) 884 23723238
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 Opposite Roles of Salicylic Acid Receptors NPR1 and NPR3/NPR4 in Transcriptional Regulation of Plant Immunity. Cell 518 29656896
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2017 Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nature biotechnology 378 28319085
2014 The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell reports 353 25263562
2017 KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 270 28199306
2012 Seventy-five genetic loci influencing the human red blood cell. Nature 266 23222517
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2006 A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science (New York, N.Y.) 212 16728641
2018 The landscape of epilepsy-related GATOR1 variants. Genetics in medicine : official journal of the American College of Medical Genetics 183 30093711
2015 Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Annals of neurology 176 26505888
2009 Clinical and subclinical endometritis in the mare: both threats to fertility. Reproduction in domestic animals = Zuchthygiene 165 19660076
2017 SZT2 dictates GATOR control of mTORC1 signalling. Nature 159 28199315
2018 Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes. Nature 158 29590090
2020 A Cellular Mechanism to Detect and Alleviate Reductive Stress. Cell 156 32941802
2011 The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle. The Journal of biological chemistry 148 21555518
2016 Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 140 27173016
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2004 The sequence and analysis of duplication-rich human chromosome 16. Nature 130 15616553
2020 Diverse Roles of the Salicylic Acid Receptors NPR1 and NPR3/NPR4 in Plant Immunity. The Plant cell 129 33037144
2009 A genome-wide screen for regulators of TORC1 in response to amino acid starvation reveals a conserved Npr2/3 complex. PLoS genetics 126 19521502
1999 Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3). Proceedings of the National Academy of Sciences of the United States of America 111 10468599
2015 Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. Annals of neurology 108 26285051
2015 The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation. Molecular cell 104 25936802
1979 Biological and binding activities of equine pituitary gonadotrophins and pregnant mare serum gonadotrophin. The Journal of endocrinology 101 536667
2019 Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy. Epilepsia open 92 31440721
2020 Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer. Nature communications 90 32814769
2012 GWAS of blood cell traits identifies novel associated loci and epistatic interactions in Caucasian and African-American children. Human molecular genetics 83 23263863
2014 Regulation of ACVR1 and ID2 by cell-secreted exosomes during follicle maturation in the mare. Reproductive biology and endocrinology : RB&E 78 24884710
2011 Selective regulation of autophagy by the Iml1-Npr2-Npr3 complex in the absence of nitrogen starvation. Molecular biology of the cell 78 21900499
2009 Chromosome looping at the human alpha-globin locus is mediated via the major upstream regulatory element (HS -40). Blood 77 19696202
2015 Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino-Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1. Molecular cell 76 26051179
2015 Effects of age on follicular fluid exosomal microRNAs and granulosa cell transforming growth factor-β signalling during follicle development in the mare. Reproduction, fertility, and development 70 25945781
2022 Structure of the nutrient-sensing hub GATOR2. Nature 69 35831510
2001 Luteal deficiency and embryo mortality in the mare. Reproduction in domestic animals = Zuchthygiene 65 11555357
2014 Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3 inactivates TORC1 and induces autophagy. Autophagy 61 25046117
2021 Opposing functions of β-arrestin 1 and 2 in Parkinson's disease via microglia inflammation and Nprl3. Cell death and differentiation 49 33686256
2018 Long Noncoding RNA BCYRN1 Promotes the Proliferation of Colorectal Cancer Cells via Up-Regulating NPR3 Expression. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 49 30114690
2017 Identification of dipeptidyl peptidase-IV inhibitory peptides from mare whey protein hydrolysates. Journal of dairy science 47 28711271
2016 Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3. Epilepsia 46 26786403
1984 Quantitation of the immunoglobulins in reproductive tract secretions of the mare. Research in veterinary science 46 6522826
2015 Integrating data on the Arabidopsis NPR1/NPR3/NPR4 salicylic acid receptors; a differentiating argument. Frontiers in plant science 45 25914712
2014 The TORC1 inhibitors Nprl2 and Nprl3 mediate an adaptive response to amino-acid starvation in Drosophila. Cell death and differentiation 45 24786828
2016 The Mare Model to Study the Effects of Ovarian Dynamics on Preantral Follicle Features. PloS one 43 26900687
1995 Targeted inactivation of the major positive regulatory element (HS-40) of the human alpha-globin gene locus. Blood 43 7620173
1995 Transforming growth factor beta 1 expression in the endometrium of the mare during placentation. Molecular reproduction and development 42 8562058
2014 Physiopathologic mechanisms involved in mare endometrosis. Reproduction in domestic animals = Zuchthygiene 41 25277436
1980 Pancreatic beta-cell function in the fetal foal and mare. The Journal of endocrinology 39 7000958
2012 The salicylic acid receptor NPR3 is a negative regulator of the transcriptional defense response during early flower development in Arabidopsis. Molecular plant 37 22986789
1993 Transcriptional activation of human zeta 2 globin promoter by the alpha globin regulatory element (HS-40): functional role of specific nuclear factor-DNA complexes. Molecular and cellular biology 37 8455611
2007 Suppression of behavioural and physiological oestrus in the mare by vaccination against GnRH. Australian veterinary journal 36 17300452
2021 Mare's Milk: Composition, Properties, and Application in Medicine. Archives of Razi Institute 35 35096348
2016 Salicylic Acid Regulates Pollen Tip Growth through an NPR3/NPR4-Independent Pathway. Molecular plant 35 27575693
2015 Effect of pregnancy on endometrial expression of luteolytic pathway components in the mare. Reproduction, fertility, and development 34 24679480
2020 LncRNA FENDRR Upregulation Promotes Hepatic Carcinoma Cells Apoptosis by Targeting miR-362-5p Via NPR3 and p38-MAPK Pathway. Cancer biotherapy & radiopharmaceuticals 30 32251605
2020 miR-146a regulates insulin sensitivity via NPR3. Cellular and molecular life sciences : CMLS 30 33206203
2019 Steroids in the establishment and maintenance of pregnancy and at parturition in the mare. Reproduction (Cambridge, England) 30 31252409
2015 Natriuretic peptide receptor 3 (NPR3) is regulated by microRNA-100. Journal of molecular and cellular cardiology 30 25736855
2003 Encephalitozoon cuniculi placentitis and abortion in a quarterhorse mare. Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc 30 12580298
2022 UBP12/UBP13-mediated deubiquitination of salicylic acid receptor NPR3 suppresses plant immunity. Molecular plant 29 36415131
2018 Kinetics of the chromosome 14 microRNA cluster ortholog and its potential role during placental development in the pregnant mare. BMC genomics 29 30572819
2022 NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold. Brain : a journal of neurology 28 35136953
2020 Prostaglandins effect on matrix metallopeptidases and collagen in mare endometrial fibroblasts. Theriogenology 28 32442743
2016 Progestin withdrawal at parturition in the mare. Reproduction (Cambridge, England) 26 27568209
2020 Chemical composition and lipid profile of mare colostrum and milk of the quarter horse breed. PloS one 24 32925944
2020 Hormone-responsive organoids from domestic mare and endangered Przewalski's horse endometrium. Reproduction (Cambridge, England) 24 33112764
1984 Beta-adrenergic receptor concentration in corpora lutea of different ages obtained from pregnant mare serum gonadotropin-treated rats. Endocrinology 24 6327235
2020 Cow, Goat, and Mare Milk Diets Differentially Modulated the Immune System and Gut Microbiota of Mice Colonized by Healthy Infant Feces. Journal of agricultural and food chemistry 23 33300339
2011 Impact of natriuretic peptide clearance receptor (NPR3) gene variants on blood pressure in type 2 diabetes. Diabetes care 23 21464461
1993 An immunohistological study of MHC class II expression and T lymphocytes in the endometrium of the mare. Equine veterinary journal 23 8467770
2022 Metformin combats high glucose-induced damage to the osteogenic differentiation of human periodontal ligament stem cells via inhibition of the NPR3-mediated MAPK pathway. Stem cell research & therapy 22 35841070
2021 NPR3, transcriptionally regulated by POU2F1, inhibits osteosarcoma cell growth through blocking the PI3K/AKT pathway. Cellular signalling 22 34229087
1991 Influence of pregnancy on diurnal and seasonal changes in cortisol, T3 and T4 levels in the mare blood serum. Comparative biochemistry and physiology. A, Comparative physiology 22 1673372
2022 Genetic Diversity, Biofilm Formation, and Antibiotic Resistance of Pseudomonas aeruginosa Isolated from Cow, Camel, and Mare with Clinical Endometritis. Veterinary sciences 20 35622767
2020 Expression of genes involved in the NF-κB-dependent pathway of the fibrosis in the mare endometrium. Theriogenology 20 32074495
2020 The Inhibition of Cathepsin G on Endometrial Explants With Endometrosis in the Mare. Frontiers in veterinary science 20 33195599
2016 Early pregnancy in the mare: old concepts revisited. Domestic animal endocrinology 20 27345319
2009 Histomorphological and immunohistochemical study of angiogenesis and angiogenic factors in the ovary of the mare. Research in veterinary science 20 19447455
2024 Minimal aromatic aldehyde reduction (MARE) yeast platform for engineering vanillin production. Biotechnology for biofuels and bioproducts 19 38184607
2022 Dorsal telencephalon-specific Nprl2- and Nprl3-knockout mice: novel mouse models for GATORopathy. Human molecular genetics 19 34965576
2019 Cell type-specific endometrial transcriptome changes during initial recognition of pregnancy in the mare. Reproduction, fertility, and development 19 30253121
2019 Characterization of the placental transcriptome through mid to late gestation in the mare. PloS one 19 31725741
2016 Dorsal root ganglion axon bifurcation tolerates increased cyclic GMP levels: the role of phosphodiesterase 2A and scavenger receptor Npr3. The European journal of neuroscience 19 27740716
2024 Potential role of camel, mare milk, and their products in inflammatory rheumatic diseases. Rheumatology international 17 38183445
2020 Complete genome analysis of Glutamicibacter creatinolyticus from mare abscess and comparative genomics provide insight of diversity and adaptation for Glutamicibacter. Gene 17 32171826
2019 Cellular and molecular mechanisms of the preovulatory follicle differenciation and ovulation: What do we know in the mare relative to other species. Theriogenology 17 30921545
2016 The role of relaxin in mare reproductive physiology: A comparative review with other species. Theriogenology 17 27158127
2016 NPR3 protects cardiomyocytes from apoptosis through inhibition of cytosolic BRCA1 and TNF-α. Cell cycle (Georgetown, Tex.) 17 27494651
1988 Chromosome anomalies and infertility in the mare. Equine veterinary journal 17 3371327
1975 Selected pathological changes of the mare uterus and ovary. Journal of reproduction and fertility. Supplement 17 1060802
2023 Comparative Analysis of Protein Digestion Characteristics in Human, Cow, Goat, Sheep, Mare, and Camel Milk under Simulated Infant Condition. Journal of agricultural and food chemistry 16 37801409
2022 Impact of different dietary regimens on the lipidomic profile of mare's milk. Food research international (Ottawa, Ont.) 16 35651065
2014 Protamine mRNA ratio in stallion spermatozoa correlates with mare fecundity. Andrology 16 24711287
2022 Dystocia in the Standardbred Mare: A Retrospective Study from 2004 to 2020. Animals : an open access journal from MDPI 15 35739823
2021 Hemimegalencephaly and intractable seizures associated with the NPRL3 gene variant in a newborn: A case report. American journal of medical genetics. Part A 15 33749980
2021 Enzymes Present in Neutrophil Extracellular Traps May Stimulate the Fibrogenic PGF2α Pathway in the Mare Endometrium. Animals : an open access journal from MDPI 15 34573581
2019 Inclusion of hemimegalencephaly into the phenotypic spectrum of NPRL3 pathogenic variants in familial focal epilepsy with variable foci. Epilepsia 15 31111464
2015 Production of a bacteriocin-like inhibitory substance by Leuconostoc mesenteroides subsp. dextranicum 213M0 isolated from Mongolian fermented mare milk, airag. Animal science journal = Nihon chikusan Gakkaiho 15 26388181
1994 Isolation of cell populations from the mare corpus luteum: comparison of mechanical and collagenase dissociation. Journal of reproduction and fertility 15 7799328
1978 Formation of steroids by the pregnant mare. VI. Metabolism of [14C]farnesyl pyrophosphate and [3H]dehydroepiandrosterone injected into the fetus. Endocrinology 15 155006
2023 Transcriptomic profiling of mare endometrium at different stages of endometrosis. Scientific reports 14 37758834
2019 Collagens and DNA methyltransferases in mare endometrosis. Reproduction in domestic animals = Zuchthygiene 14 31512314
2017 Evaluation of circulating miRNAs during late pregnancy in the mare. PloS one 14 28388652
2015 Pregnancy Recognition and Implantation of the Conceptus in the Mare. Advances in anatomy, embryology, and cell biology 14 26450499
2012 Association of a single nucleotide polymorphism of the NPR3 gene promoter with early onset ischemic stroke in an Italian cohort. European journal of internal medicine 14 22995222
1989 Dimethyl sulfoxide intrauterine therapy in the mare: effects upon endometrial histological features and biopsy classification. Theriogenology 14 16726673
2016 Localisation of epidermal growth factor (EGF), its specific receptor (EGF-R) and aromatase at the materno-fetal interface during placentation in the pregnant mare. Placenta 13 28161062
2015 Nodal Promotes Functional Luteolysis via Down-Regulation of Progesterone and Prostaglandins E2 and Promotion of PGF2α Synthetic Pathways in Mare Corpus Luteum. Endocrinology 13 26653568
2015 In vitro screening of mare's milk antimicrobial effect and antiproliverative activity. FEMS microbiology letters 13 26656278
2002 Genetic polymorphism of the major regulatory element HS-40 upstream of the human alpha-globin gene cluster. British journal of haematology 13 12437670
1990 Relationships of total protein, specific gravity, viscosity, refractive index and latex agglutination to immunoglobulin G concentration in mare colostrum. Equine veterinary journal 12 2105210
2023 Clinical phenotypic and genotypic characterization of NPRL3-related epilepsy. Frontiers in neurology 11 36937533
2021 A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci. Frontiers in genetics 11 34868250
2020 Analysis of rare thalassemia caused by HS-40 regulatory site deletion. Hematology (Amsterdam, Netherlands) 11 32720864
2016 Expression of leukaemia inhibitory factor at the conceptus-maternal interface during preimplantation development and in the endometrium during the oestrous cycle in the mare. Reproduction, fertility, and development 11 25881292
1997 Expression and localization of relaxin in the ovary of the mare. Journal of reproduction and fertility 11 9306987
2023 Identification and comparison of milk fat globule membrane and whey proteins from Selle Français, Welsh pony, and Tieling Draft horse mare's milk. Food chemistry 10 37931453
2022 Uterine extracellular vesicles as multi-signal messengers during maternal recognition of pregnancy in the mare. Scientific reports 10 36114358
2021 Myeloperoxidase Inhibition Decreases the Expression of Collagen and Metallopeptidase in Mare Endometria under In Vitro Conditions. Animals : an open access journal from MDPI 10 33467081
2023 Refining the electroclinical spectrum of NPRL3-related epilepsy: A novel multiplex family and literature review. Epilepsia open 9 37491868
2021 FKBP39 controls nutrient dependent Nprl3 expression and TORC1 activity in Drosophila. Cell death & disease 9 34078879
2020 MPG and NPRL3 Polymorphisms are Associated with Ischemic Stroke Susceptibility and Post-Stroke Mortality. Diagnostics (Basel, Switzerland) 9 33202874
2016 The Loss of Lam2 and Npr2-Npr3 Diminishes the Vacuolar Localization of Gtr1-Gtr2 and Disinhibits TORC1 Activity in Fission Yeast. PloS one 9 27227887