Affinage

NPY4R

Neuropeptide Y receptor type 4 · UniProt P50391

Round 2 corrected
Length
375 aa
Mass
42.1 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

NPY4R (Y4 receptor) is a Gi/o-coupled GPCR that serves as the primary high-affinity receptor for pancreatic polypeptide (PP), mediating inhibition of cAMP production, regulation of intracellular calcium, and suppression of electrolyte secretion in the colon and glucagon release from pancreatic alpha-cells (PMID:7592911, PMID:10640301, PMID:11906964, PMID:25445712). Its PP-binding pocket is formed by residues in TM2 (Tyr2.64), TM6 (Asn6.55), and TM7 (Asn7.32, Phe7.35), it requires N-glycosylation for function, and it exhibits constitutive activity and notable resistance to agonist-promoted desensitization and internalization—properties governed by a C-terminal EESEHLPLSTVHTEVSKGS motif that controls arrestin-3 recruitment and endocytosis (PMID:24375409, PMID:21745157, PMID:27818291, PMID:10640301). Genetic studies in Y2/Y4 double-knockout mice reveal synergistic cooperation between Y2 and Y4 pathways in regulating adiposity and bone mass, and copy-number losses at the NPY4R locus and rare loss-of-function coding variants are associated with childhood obesity (PMID:12861009, PMID:26921218).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 High

    Cloning and functional reconstitution of NPY4R established it as a Gi-coupled GPCR with highest affinity for pancreatic polypeptide, resolving the molecular identity of the PP-preferring neuropeptide Y receptor subtype.

    Evidence Independent cloning from human genomic/cDNA libraries with radioligand binding, cAMP inhibition, and Ca²⁺ assays in transfected LMTK⁻ and CHO cells; Northern blot tissue profiling

    PMID:7493937 PMID:7592911

    Open questions at the time
    • Structural basis of PP selectivity over NPY/PYY unknown
    • In vivo physiological roles not yet addressed
    • G-protein coupling specificity (Gi subtypes) not resolved
  2. 1996 High

    Cloning of the rat ortholog and cross-species binding comparison showed 74% amino acid identity with human Y4R and confirmed species-dependent variation in PP affinity, indicating evolutionary divergence in ligand recognition.

    Evidence PCR cloning, stable HEK293 transfection, radioligand binding of human and rat receptors

    PMID:8643460

    Open questions at the time
    • Residues responsible for species selectivity not identified
    • Functional consequences of sequence divergence not tested
  3. 1997 High

    Chromosomal mapping placed the intronless NPY4R gene at human 10q11.2 and mouse chromosome 14, suggesting origin via retrotranspositional duplication from an ancestral Y1-like receptor.

    Evidence FISH and interspecific mouse backcross mapping

    PMID:9441761

    Open questions at the time
    • Regulatory elements controlling tissue-specific expression not characterized
  4. 2000 High

    Demonstration that Y4R is uniquely resistant to agonist-promoted desensitization and internalization—with preserved binding and signaling after prolonged PP exposure—distinguished it from other NPY receptor subtypes and raised questions about its regulatory mechanisms.

    Evidence Radioligand binding kinetics, cAMP assay, pertussis toxin block, and immunofluorescence after 24-h agonist exposure in stable CHO transfectants

    PMID:10640301

    Open questions at the time
    • Molecular determinants of desensitization resistance not identified
    • Phosphorylation and arrestin engagement not tested
  5. 2002 High

    Pharmacological dissection in native human colonic tissue established Y4R as the post-junctional mediator of PP-induced inhibition of electrolyte secretion, defining a gastrointestinal effector role.

    Evidence Ussing chamber electrophysiology with selective Y1, Y2, and TTX antagonists on human colon mucosa

    PMID:11906964

    Open questions at the time
    • Downstream ion channel/transporter targets not identified
    • Contribution of Y4R to colonic pathophysiology not tested
  6. 2003 High

    Y2/Y4 double-knockout mice revealed synergistic cooperation between Y2 and Y4 receptor pathways in controlling adiposity and bone mass, with double knockouts showing markedly reduced fat and threefold increased bone volume despite hyperphagia.

    Evidence Genetic epistasis using single and double knockout mice with body composition analysis, bone histomorphometry, and plasma hormone measurements

    PMID:12861009

    Open questions at the time
    • Central versus peripheral site of action for adiposity/bone regulation unresolved
    • Downstream signaling pathways mediating bone effects unknown
  7. 2011 Medium

    Functional reconstitution with defined G-protein subunits showed Y4R couples optimally to Gαi2 and Gαo with RGS4, requires N-glycosylation for function, and exhibits moderate constitutive activity.

    Evidence Baculovirus co-expression of Y4R with Gi/Go subtypes and RGS proteins in Sf9 cells; steady-state GTPase assays; tunicamycin treatment

    PMID:21745157

    Open questions at the time
    • Constitutive activity not confirmed in mammalian cells
    • Glycosylation sites contributing to function not mapped
  8. 2013 High

    Systematic double-cycle mutagenesis and homology modeling defined the PP-binding pocket, identifying Tyr2.64, Asn6.55, Asn7.32, and Phe7.35 as critical contacts and explaining the molecular basis of PP selectivity.

    Evidence Site-directed and double-cycle mutagenesis, radioligand binding, and computational modeling of the Y4R–PP complex

    PMID:24375409

    Open questions at the time
    • No experimental 3D structure available
    • Activation-state conformational changes not resolved
  9. 2014 High

    Detection of Y4R protein and mRNA specifically in pancreatic alpha-cells, coupled with PP-mediated inhibition of glucagon secretion from isolated islets, established an endocrine axis for PP–Y4R signaling in glucose homeostasis.

    Evidence Immunoblotting, qRT-PCR on FACS-sorted islet fractions, immunohistochemistry, ex vivo glucagon secretion assay in mouse and human tissue

    PMID:25445712

    Open questions at the time
    • In vivo relevance using Y4R-knockout islets not tested
    • Signaling pathway linking Y4R activation to glucagon suppression not delineated
  10. 2016 High

    Identification of the C-terminal motif 7.78EESEHLPLSTVHTEVSKGS7.96 as the molecular determinant for arrestin-3 recruitment and receptor internalization resolved why Y4R normally resists desensitization and how endocytosis can be engaged.

    Evidence C-terminal deletion and point mutagenesis with BRET, fluorescence microscopy, binding, and inositol turnover assays

    PMID:27818291

    Open questions at the time
    • Phosphorylation events upstream of arrestin binding not mapped
    • Physiological context triggering this internalization pathway unknown
  11. 2016 Medium

    CNV losses at 10q11.22 encompassing NPY4R and functionally validated rare loss-of-function coding variants were enriched in obese children, linking NPY4R haploinsufficiency to human obesity.

    Evidence CNV analysis and mutation screening in obese vs. lean children with functional receptor assays for identified variants

    PMID:26921218

    Open questions at the time
    • Small cohort size limits generalizability
    • Mechanism connecting Y4R loss-of-function to increased adiposity not defined
    • Not replicated in independent populations
  12. 2021 Medium

    Discovery of the first selective Y4R allosteric antagonist (S)-VU0637120, binding a site within the transmembrane core below the orthosteric pocket, provided a pharmacological tool to probe Y4R function independently of PP competition.

    Evidence In vitro binding, ex vivo functional assays, computational docking, selectivity profiling against Y1R/Y2R/Y5R

    PMID:33595306

    Open questions at the time
    • In vivo efficacy and pharmacokinetics not reported
    • Allosteric site not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the lack of an experimental 3D structure of Y4R (free or PP-bound), the signaling cascades downstream of Gi that link Y4R to bone and adiposity regulation, whether RAMP interactions modulate Y4R pharmacology, and the precise mechanism connecting Y4R loss-of-function to obesity in humans.
  • No cryo-EM or crystal structure available
  • RAMP interaction with Y4R not functionally validated
  • Central versus peripheral contributions to metabolic phenotypes not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 2 R-HSA-8963743 Digestion and absorption 1
Partners
ARRB2GNAI2GNAO1PPRGS4

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The human Y4 receptor (NPY4R) was cloned from a placental genomic library by homology screening with Y1 transmembrane probes. It encodes a 375-amino acid GPCR with highest affinity for human pancreatic polypeptide (PP; pKi ~10.25), followed by PYY and NPY. When expressed in LMTK- cells, human PP activation decreased cAMP and increased intracellular Ca2+, demonstrating coupling to both Gi and Gq-like pathways. cDNA cloning, radioligand binding (125I-PYY), cAMP and Ca2+ assays in transfected cells The Journal of biological chemistry High 7592911
1995 An independently cloned human NPY4R (designated PP1) was shown to bind PP with extremely high affinity (Ki ~14 pM), PYY with 1.44 nM, and NPY with 9.9 nM, establishing PP as the primary endogenous ligand. In stably transfected CHO cells, the receptor inhibited forskolin-stimulated cAMP synthesis. Northern blot detected mRNA in colon, small intestine, pancreas, and prostate. Homology cloning, radioligand binding, cAMP assay in stable CHO transfectants, Northern blot The Journal of biological chemistry High 7493937
1996 Human and rat NPY4R cDNAs were cloned and expressed in HEK293 cells. The human receptor bound 125I-labeled human PP with Kd = 2.8 nM; rank-order potency was human PP = bovine PP > [Pro34]PYY > rat PP > hPYY = hNPY. Northern blot showed mRNA most abundantly in skeletal muscle, with lesser expression in lung and brain. The rat ortholog shares 74% amino acid identity with human Y4R. PCR cloning, stable transfection, radioligand binding, Northern blot Proceedings of the National Academy of Sciences of the United States of America High 8643460
1997 [125I]Leu31,Pro34-PYY was identified as a high-affinity radioligand for rat PP1/Y4 receptor expressed in cell lines, demonstrating that this putative Y1-selective ligand also binds Y4 with high affinity. However, in rat brain sections this ligand does not label interpeduncular nucleus sites (high in [125I]-bPP binding), indicating heterogeneity among PP-recognizing receptors in brain versus peripheral tissues. Radioligand binding in transfected cell lines and rat brain autoradiography Peptides Medium 9145427
1997 The human Y4 receptor gene (PPYR1) was localized to chromosome 10q11.2 by nonisotopic in situ hybridization, and the mouse Y4 gene (Ppyr1) to chromosome 14 by interspecific backcross mapping. The gene contains no introns within its coding region, suggesting origin via an RNA-mediated transpositional event from an ancestral Y1-like receptor. Fluorescence in situ hybridization (FISH), interspecific mouse backcross mapping, genomic sequencing Genomics High 9441761
2000 Human Y4 receptor stably expressed in CHO cells showed one class of binding site (Kd = 0.26 nM for 125I-hPP). Signal transduction via Gi protein was demonstrated by pertussis toxin abolition of hPP-induced cAMP inhibition. Critically, 24-hour exposure to 10 nM hPP produced no change in binding capacity, affinity, or receptor potency, and immunofluorescence showed no receptor internalization, establishing that Y4R is resistant to agonist-promoted desensitization and internalization. Radioligand binding, cAMP assay, pertussis toxin treatment, immunofluorescence microscopy in stable CHO transfectants The Journal of pharmacology and experimental therapeutics High 10640301
2003 Using Y2(-/-)Y4(-/-) double knockout mice, synergistic interactions between Y2 and Y4 receptor pathways were demonstrated. Y4 single knockout produced a lean phenotype and elevated plasma PP. Despite hyperphagia, Y2/Y4 double knockouts showed markedly reduced adiposity and threefold increased bone volume with enhanced osteoblastic activity—effects more pronounced than Y2 single knockout alone—establishing that Y2 and Y4 pathways cooperate to regulate adiposity and bone mass. Genetic epistasis using double knockout mice, body composition analysis, bone histomorphometry, plasma hormone measurements Molecular and cellular biology High 12861009
2002 In isolated human colon mucosa in Ussing chambers, basolateral application of human PP (hPP) inhibited electrogenic ion transport. This inhibitory response was insensitive to Y1 antagonists (BIBP3226, BIBO3304) and Y2 antagonist (BIIE0246), and was not blocked by tetrodotoxin, establishing that Y4 receptors are the predominantly post-junctional mediators of PP-induced inhibition of colonic electrolyte secretion. Ussing chamber electrophysiology with selective receptor antagonists and TTX in human colonic tissue British journal of pharmacology High 11906964
2014 PPYR1 (Y4R) protein was detected by immunoblotting, qRT-PCR (enriched in FACS-sorted glucagon alpha-cell fraction), and immunohistochemistry on pancreatic sections in both mouse and human islets. Direct PP exposure to isolated mouse islets inhibited glucagon release, demonstrating that Y4R on alpha-cells mediates PP-dependent suppression of glucagon secretion. Immunoblotting, qRT-PCR on sorted islet cells, immunohistochemistry, ex vivo glucagon secretion assay in isolated islets Biochimica et biophysica acta High 25445712
2013 Double-cycle mutagenesis of hY4R combined with computational homology modeling of the hY4R–hPP complex identified residues Tyr2.64, Asp2.68, Asn6.55, Asn7.32, and Phe7.35 as critical for receptor activation by PP. The top of TM2 and TM6-TM7 form the core peptide-binding pocket, with Tyr2.64 making hydrophobic contact with Tyr27 of PP, Asn7.32 hydrogen-bonding Arg33 of PP, and Phe7.35 interacting with PP positions 33 and 36. Site-directed mutagenesis, radioligand binding, double-cycle mutagenesis, computational homology modeling The Journal of biological chemistry High 24375409
2016 The C-terminal motif 7.78EESEHLPLSTVHTEVSKGS7.96 of hY4R was identified as essential for receptor internalization and arrestin-3 recruitment. Deletion and point-mutation analysis showed glutamate, threonine, and serine residues within this motif are key determinants. This was established using fluorescence microscopy, binding assays, inositol turnover, and BRET assays, revealing the molecular basis for Y4R endocytosis. C-terminal deletion mutants, site-directed mutagenesis, fluorescence microscopy, BRET assays, binding assays, inositol turnover in transfected cells Cellular signalling High 27818291
2011 Human Y4R and Y2R were functionally reconstituted in Sf9 insect cells using baculovirus co-expression with Gi/Go proteins and RGS proteins. Steady-state GTPase assays showed hY4R couples optimally to Gαi2 and Gαo with RGS4. N-glycosylation was found to be essential for hY4R function, as tunicamycin treatment abolished receptor activity. Na+ sensitivity assays revealed moderate constitutive activity of hY4R. Baculovirus expression in Sf9 cells, steady-state GTPase assays, tunicamycin glycosylation inhibition, ion sensitivity assays Journal of receptor and signal transduction research Medium 21745157
2021 The first selective Y4R allosteric antagonist, (S)-VU0637120, was identified and characterized. In vitro, ex vivo, and in silico studies demonstrated it selectively inhibits native Y4R function by binding an allosteric site located below the endogenous PP-binding pocket within the core of the Y4R transmembrane domains, distinct from the orthosteric binding site. In vitro binding assays, ex vivo functional assays, computational modeling/docking, selectivity profiling against Y1R/Y2R/Y5R Journal of medicinal chemistry Medium 33595306
2024 Multiplexed screening of 215 GPCRs against all three RAMPs (receptor activity-modifying proteins) using suspension bead array immunoassays identified NPY4R (Y4R) among the 122 GPCRs showing strong evidence for interaction with at least one RAMP, identifying a potential regulatory complex for Y4R trafficking/pharmacology. Dual epitope-tagged GPCR library co-expressed with RAMPs 1-3, multiplexed suspension bead array immunoassays in three cell lines Science advances Low 39083597
2016 CNV analysis in obese children versus lean controls showed significantly higher frequency of NPY4R-containing 10q11.22 CNV loss in obese patients (p=0.0003) and CNV gain in controls (p=0.031). Mutation screening identified two rare non-synonymous heterozygous variants found only in obese patients for which receptor dysfunction was experimentally demonstrated. CNV analysis, coding region mutation screening, functional receptor assays for identified variants Obesity (Silver Spring, Md.) Medium 26921218

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
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2005 Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. The European journal of neuroscience 616 16262633
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2010 The extended PP1 toolkit: designed to create specificity. Trends in biochemical sciences 419 20399103
2017 Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nature biotechnology 378 28319085
1995 Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY. The Journal of biological chemistry 333 7592911
2012 Phosphoregulation of Spc105 by Mps1 and PP1 regulates Bub1 localization to kinetochores. Current biology : CB 298 22521787
1995 Cloning of a human receptor of the NPY receptor family with high affinity for pancreatic polypeptide and peptide YY. The Journal of biological chemistry 274 7493937
1988 Presence of three distinct molecular species of Gi protein alpha subunit. Structure of rat cDNAs and human genomic DNAs. The Journal of biological chemistry 256 2834384
2002 MLO-Y4 osteocyte-like cells support osteoclast formation and activation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 229 12412815
2006 Repo-Man recruits PP1 gamma to chromatin and is essential for cell viability. The Journal of cell biology 213 16492807
2009 PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation. Nature cell biology 189 19396163
2011 KNL1/Spc105 recruits PP1 to silence the spindle assembly checkpoint. Current biology : CB 184 21640906
2006 Condensin and Repo-Man-PP1 co-operate in the regulation of chromosome architecture during mitosis. Nature cell biology 178 16998479
2019 Control of RNA Pol II Speed by PNUTS-PP1 and Spt5 Dephosphorylation Facilitates Termination by a "Sitting Duck Torpedo" Mechanism. Molecular cell 171 31677974
2002 The Src-selective kinase inhibitor PP1 also inhibits Kit and Bcr-Abl tyrosine kinases. The Journal of biological chemistry 159 12475982
2014 Ki-67 is a PP1-interacting protein that organises the mitotic chromosome periphery. eLife 156 24867636
2001 Expression of functional gap junctions and regulation by fluid flow in osteocyte-like MLO-Y4 cells. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 154 11204425
2018 A Cdk9-PP1 switch regulates the elongation-termination transition of RNA polymerase II. Nature 127 29899453
2002 The kinase inhibitor PP1 blocks tumorigenesis induced by RET oncogenes. Cancer research 127 11861385
2003 Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis. Biochimie 126 14585537
2015 Structural and Functional Analysis of the GADD34:PP1 eIF2α Phosphatase. Cell reports 122 26095357
2010 PP1 cooperates with ASPP2 to dephosphorylate and activate TAZ. The Journal of biological chemistry 117 21189257
2010 Identification and characterization of a novel human PP1 phosphatase complex. The Journal of biological chemistry 111 20516061
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
1999 Establishment and characterization of an osteocyte-like cell line, MLO-Y4. Journal of bone and mineral metabolism 106 10084404
2002 Structure and receptor binding of PYY analogs. Peptides 93 11825645
2017 Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/β-catenin pathway. JBMR plus 92 29104955
2012 PP1 and PP2A phosphatases--cooperating partners in modulating retinoblastoma protein activation. The FEBS journal 89 22299668
2015 Kinetochore-localized PP1-Sds22 couples chromosome segregation to polar relaxation. Nature 86 26168397
2004 Recovery from DNA damage checkpoint arrest by PP1-mediated inhibition of Chk1. The EMBO journal 86 14765108
2003 Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. Molecular and cellular biology 86 12861009
2002 PP1 binds Sara and negatively regulates Dpp signaling in Drosophila melanogaster. Nature genetics 80 12134149
2014 hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling. Nucleic acids research 78 25324306
2019 The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis. Nature communications 74 31586073
2010 ALDH1L1 inhibits cell motility via dephosphorylation of cofilin by PP1 and PP2A. Oncogene 73 20729910
2003 The pp60c-Src inhibitor PP1 is non-competitive against ATP. FEBS letters 73 12606029
2012 Glucose-induced posttranslational activation of protein phosphatases PP2A and PP1 in yeast. Cell research 71 22290422
2002 Neuropeptide Y receptors as targets for anti-obesity drug development: perspective and current status. European journal of pharmacology 71 12007534
2018 SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 69 30348783
2008 Dissociation of heterotrimeric g proteins in cells. Science signaling 69 18577758
2000 Protein phosphatases PP1 and PP2A are located in distinct positions in the Chlamydomonas flagellar axoneme. Journal of cell science 69 10591628
1996 Cloning and functional expression of cDNAs encoding human and rat pancreatic polypeptide receptors. Proceedings of the National Academy of Sciences of the United States of America 67 8643460
2001 NPY regulates catecholamine secretion from human adrenal chromaffin cells. The Journal of clinical endocrinology and metabolism 64 11739470
2009 Genome-wide association study suggested copy number variation may be associated with body mass index in the Chinese population. Journal of human genetics 62 19229253
2011 Expression of muscle anabolic and metabolic factors in mechanically loaded MLO-Y4 osteocytes. American journal of physiology. Endocrinology and metabolism 59 22114022
2014 Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A. Nature communications 56 25048371
2008 Displacement affinity chromatography of protein phosphatase one (PP1) complexes. BMC biochemistry 56 19000314
2005 PNUTS enhances in vitro chromosome decondensation in a PP1-dependent manner. The Biochemical journal 56 15907195
2017 Microcystins: Synthesis and structure-activity relationship studies toward PP1 and PP2A. Bioorganic & medicinal chemistry 54 28893598
2002 Neuropeptide Y, Y1, Y2 and Y4 receptors mediate Y agonist responses in isolated human colon mucosa. British journal of pharmacology 54 11906964
2002 Clinical potentials of neuropeptide Y family of hormones. American journal of surgery 54 11975932
2020 Dissecting the sequence determinants for dephosphorylation by the catalytic subunits of phosphatases PP1 and PP2A. Nature communications 53 32681005
1997 [125I]Leu31, Pro34-PYY is a high affinity radioligand for rat PP1/Y4 and Y1 receptors: evidence for heterogeneity in pancreatic polypeptide receptors. Peptides 53 9145427
2018 MYC dephosphorylation by the PP1/PNUTS phosphatase complex regulates chromatin binding and protein stability. Nature communications 52 30158517
2016 Greatwall dephosphorylation and inactivation upon mitotic exit is triggered by PP1. Journal of cell science 52 26906418
2011 Spindle checkpoint silencing: PP1 tips the balance. Current biology : CB 51 22075433
2021 Bisphenol A induces pyroptotic cell death via ROS/NLRP3/Caspase-1 pathway in osteocytes MLO-Y4. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 50 34929351
2017 Physiological and Pathological Roles of CaMKII-PP1 Signaling in the Brain. International journal of molecular sciences 49 29271887
2013 Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5. The Journal of cell biology 49 24189275
1997 KLP38B: a mitotic kinesin-related protein that binds PP1. The Journal of cell biology 46 9230081
2019 ASPP proteins discriminate between PP1 catalytic subunits through their SH3 domain and the PP1 C-tail. Nature communications 45 30770806
2007 Protein phosphatase PP1 gamma 2 in sperm morphogenesis and epididymal initiation of sperm motility. Asian journal of andrology 44 17589781
2019 The RIF1-PP1 Axis Controls Abscission Timing in Human Cells. Current biology : CB 43 30905608
2017 Estrogen deficiency attenuates fluid flow-induced [Ca2+]i oscillations and mechanoresponsiveness of MLO-Y4 osteocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 43 28363954
2014 Pancreatic polypeptide regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-cells. Biochimica et biophysica acta 43 25445712
2009 Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions. Oncogene 43 19581931
2018 KNL1 Binding to PP1 and Microtubules Is Mutually Exclusive. Structure (London, England : 1993) 42 30100357
2014 Phosphatase holoenzyme PP1/GADD34 negatively regulates TLR response by inhibiting TAK1 serine 412 phosphorylation. Journal of immunology (Baltimore, Md. : 1950) 42 24534530
2018 cAMP regulation of protein phosphatases PP1 and PP2A in brain. Biochimica et biophysica acta. Molecular cell research 41 30401536
2017 Repo-Man/PP1 regulates heterochromatin formation in interphase. Nature communications 41 28091603
2017 Mouse Rif1 is a regulatory subunit of protein phosphatase 1 (PP1). Scientific reports 41 28522851
2010 Structural signature of the MYPT1-PP1 interaction. Journal of the American Chemical Society 41 21142030
2020 Co-option of Plasmodium falciparum PP1 for egress from host erythrocytes. Nature communications 40 32669539
2015 KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR. Nature communications 40 26081938
2006 Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells. Oncogene 39 16732323
2016 Aurkb/PP1-mediated resetting of Oct4 during the cell cycle determines the identity of embryonic stem cells. eLife 38 26880562
2018 A substrate-trapping strategy for protein phosphatase PP1 holoenzymes using hypoactive subunit fusions. The Journal of biological chemistry 37 30115685
2019 SDS22 selectively recognizes and traps metal-deficient inactive PP1. Proceedings of the National Academy of Sciences of the United States of America 35 31548429
2010 RRP1B targets PP1 to mammalian cell nucleoli and is associated with Pre-60S ribosomal subunits. Molecular biology of the cell 35 20926688
2006 Identification of a hydrogen peroxide-induced PP1-JNK1-Sp1 signaling pathway for gene regulation. American journal of physiology. Lung cellular and molecular physiology 33 16815888
2000 Functional and molecular properties of the human recombinant Y4 receptor: resistance to agonist-promoted desensitization. The Journal of pharmacology and experimental therapeutics 33 10640301
2023 Primary cilia are WNT-transducing organelles whose biogenesis is controlled by a WNT-PP1 axis. Developmental cell 32 36693320
2017 Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation. Basic research in cardiology 31 28597249
2012 The WNK/SPAK and IRBIT/PP1 pathways in epithelial fluid and electrolyte transport. Physiology (Bethesda, Md.) 31 23026752
2023 Structural basis of ubiquitin-independent PP1 complex disassembly by p97. The EMBO journal 30 37264685
2019 NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR Synaptic Content. Cell reports 30 31291571
2016 Increased NEK2 in hepatocellular carcinoma promotes cancer progression and drug resistance by promoting PP1/Akt and Wnt activation. Oncology reports 30 27509921
2016 CNV analysis and mutation screening indicate an important role for the NPY4R gene in human obesity. Obesity (Silver Spring, Md.) 29 26921218
2009 Sds22, a PP1 phosphatase regulatory subunit, regulates epithelial cell polarity and shape [Sds22 in epithelial morphology]. BMC developmental biology 29 19228425
2020 Controlling Ser/Thr protein phosphatase PP1 activity and function through interaction with regulatory subunits. Advances in protein chemistry and structural biology 28 32951813
2020 Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme. eLife 28 32975518
2013 Pancreatic polypeptide is recognized by two hydrophobic domains of the human Y4 receptor binding pocket. The Journal of biological chemistry 28 24375409
2015 Drosophila Rif1 is an essential gene and controls late developmental events by direct interaction with PP1-87B. Scientific reports 27 26022086
2020 Streptococcus pneumoniae Infection Promotes Histone H3 Dephosphorylation by Modulating Host PP1 Phosphatase. Cell reports 26 32209465
2008 Protein phosphatase PP1 is required for normal DNA methylation in Neurospora. Genes & development 26 19141471
2007 The interaction of PP1 with BRCA1 and analysis of their expression in breast tumors. BMC cancer 26 17511879
2001 Purification and properties of Arabidopsis thaliana type 1 protein phosphatase (PP1). Biochimica et biophysica acta 26 11738087
2012 Repo-Man-PP1: a link between chromatin remodelling and nuclear envelope reassembly. Nucleus (Austin, Tex.) 25 22555598
2011 Sds22/PP1 links epithelial integrity and tumor suppression via regulation of myosin II and JNK signaling. Oncogene 25 21399659
2006 ATM regulates ionizing radiation-induced disruption of HDAC1:PP1:Rb complexes. Cellular signalling 24 17008050
2021 Modulation of serine/threonine-protein phosphatase 1 (PP1) complexes: A promising approach in cancer treatment. Drug discovery today 23 34390863
2019 Molecular mechanism of TMEM16A regulation: role of CaMKII and PP1/PP2A. American journal of physiology. Cell physiology 23 31461344
2016 Protein 4.1N acts as a potential tumor suppressor linking PP1 to JNK-c-Jun pathway regulation in NSCLC. Oncotarget 23 26575790
2009 DCP-LA stimulates AMPA receptor exocytosis through CaMKII activation due to PP-1 inhibition. Journal of cellular physiology 23 19492412
2008 Mutually exclusive binding of PP1 and RNA to AKAP149 affects the mitochondrial network. Human molecular genetics 23 19074462
2020 PP1 promotes cyclin B destruction and the metaphase-anaphase transition by dephosphorylating CDC20. Molecular biology of the cell 22 32755477
2010 TLRR (lrrc67) interacts with PP1 and is associated with a cytoskeletal complex in the testis. Biology of the cell 22 19886865
2014 Acetylcholine affects osteocytic MLO-Y4 cells via acetylcholine receptors. Molecular and cellular endocrinology 21 24508663
2021 Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO-Y4: Involvement of ROS-mediated mTOR/ULK1 pathway. Ecotoxicology and environmental safety 20 34954677
2019 Delineating the contribution of Spc105-bound PP1 to spindle checkpoint silencing and kinetochore microtubule attachment regulation. The Journal of cell biology 20 31649151
2016 Fin1-PP1 Helps Clear Spindle Assembly Checkpoint Protein Bub1 from Kinetochores in Anaphase. Cell reports 20 26832405
2021 Targeted substrate loop insertion by VCP/p97 during PP1 complex disassembly. Nature structural & molecular biology 19 34824462
2022 Piezo1-mediated fluid shear stress promotes OPG and inhibits RANKL via NOTCH3 in MLO-Y4 osteocytes. Channels (Austin, Tex.) 18 35754337
2021 Highly Selective Y4 Receptor Antagonist Binds in an Allosteric Binding Pocket. Journal of medicinal chemistry 18 33595306
2018 Overexpression of PP1-NIPP1 limits the capacity of cells to repair DNA double-strand breaks. Journal of cell science 18 29898919
2007 Visualization of intracellular PP1 targeting through transiently and stably expressed fluorescent protein fusions. Methods in molecular biology (Clifton, N.J.) 18 17200560
2018 Copy number of pancreatic polypeptide receptor gene NPY4R correlates with body mass index and waist circumference. PloS one 17 29621259
2018 Interrogating PP1 Activity in the MAPK Pathway with Optimized PP1-Disrupting Peptides. Chembiochem : a European journal of chemical biology 17 30338897
2010 Flexibility in the PP1:spinophilin holoenzyme. FEBS letters 17 21094159
2011 Functional reconstitution of human neuropeptide Y (NPY) Y(2) and Y(4) receptors in Sf9 insect cells. Journal of receptor and signal transduction research 10 21745157
2016 C-terminal motif of human neuropeptide Y4 receptor determines internalization and arrestin recruitment. Cellular signalling 8 27818291
2008 Protein phosphatase-1 is targeted to DNA polymerase delta via an interaction with the p68 subunit. Biochemistry 7 18826257
1997 Assignment of the Y4 receptor gene (PPYR1) to human chromosome 10q11.2 and mouse chromosome 14. Genomics 7 9441761
2012 Comparison of fragments comprising the first two helices of the human Y4 and the yeast Ste2p G-protein-coupled receptors. Biophysical journal 6 22947943
2021 Theoretical study of the interactions between peptide tyrosine tyrosine [PYY (1-36)], a newly identified modulator in type 2 diabetes pathophysiology, with receptors NPY1R and NPY4R. Hormones (Athens, Greece) 5 33782920
1997 Neuropeptide Y receptor genes mapped in human and mouse: receptors with high affinity for pancreatic polypeptide are not clustered with receptors specific for neuropeptide Y and peptide YY. Genomics 5 9417917
2024 Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins. Science advances 3 39083597
2009 Cloning and characterization of rabbit neuropeptide Y receptor subtypes. Peptides 2 19481128