Affinage

PTH1R

Parathyroid hormone/parathyroid hormone-related peptide receptor · UniProt Q03431

Length
593 aa
Mass
66.4 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTH1R is a class B G protein-coupled receptor that transduces parathyroid hormone (PTH) and PTH-related peptide (PTHrP) signals to regulate bone formation, mineral ion homeostasis, and skeletal patterning through dual coupling to Gs/cAMP/PKA and Gq/PLC/calcium pathways (PMID:10497171, PMID:26620087). Agonist-induced phosphorylation of C-terminal tail residues Ser503/Thr504 drives β-arrestin recruitment, receptor internalization, and endosomal signaling, while ubiquitin-dependent sorting—modulated by the deubiquitinase USP2—determines whether the receptor recycles (via SNX27-retromer) or undergoes proteasomal degradation (PMID:27623777, PMID:21898592, PMID:26912788). β-Arrestin-biased agonism through PTH1R selectively stimulates trabecular bone anabolism without bone resorption, and receptor signaling is allosterically tuned by RAMP2, scaffolded by Kindlin-2/Gsα, negatively regulated by MMP14-mediated ectodomain cleavage, and subject to importin-α/β-dependent nuclear-cytoplasmic shuttling (PMID:20368153, PMID:35914163, PMID:33361757, PMID:36892459, PMID:17317770). Loss-of-function PTH1R mutations cause primary failure of eruption (PFE) and Eiken syndrome, while specific enchondromatosis-associated mutations impair ligand binding or surface expression (PMID:27898723, PMID:37268817, PMID:18559376).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Establishing that PTH1R dually couples to Gs (cAMP) and Gq (inositol phosphate) pathways resolved the fundamental question of which G-protein effectors transduce PTH/PTHrP binding into intracellular signals.

    Evidence Heterologous expression in COS-7 cells with radioligand binding and parallel cAMP/IP accumulation assays using zebrafish PTH1R ortholog

    PMID:10497171

    Open questions at the time
    • Relative contributions of Gs vs. Gq to specific physiological outputs were not dissected
    • No structural basis for dual coupling was provided
  2. 2006 Medium

    Demonstrating that PTH1R forms complexes with importin-α1/β and localizes to the nucleoplasm during specific cell-cycle stages revealed an unexpected non-canonical trafficking route for a GPCR, raising questions about nuclear functions.

    Evidence Immunoprecipitation, PTH-affinity chromatography, and deconvolution microscopy in osteoblast-like cells

    PMID:16574786

    Open questions at the time
    • Nuclear function of PTH1R was not established
    • Only one cell type examined
  3. 2007 High

    Identifying importin-α/β for nuclear import and CRM1 for nuclear export defined the molecular machinery controlling PTH1R nuclear-cytoplasmic shuttling and showed that serum/PTHrP availability regulates this partitioning.

    Evidence Importin-β siRNA, CRM1 inhibitor leptomycin B, co-IP, and nuclear fractionation

    PMID:17317770

    Open questions at the time
    • Biological consequence of nuclear PTH1R accumulation remains unknown
    • Mechanism by which PTHrP promotes cytoplasmic relocalization not resolved
  4. 2008 Medium

    Functional characterization of Ollier disease-associated PTHR1 mutations established that enchondromatosis arises from loss-of-function—reduced ligand binding or surface expression—rather than constitutive activation.

    Evidence Receptor-ligand affinity and cell-surface expression assays for G121E, A122T, R255H mutants

    PMID:18559376

    Open questions at the time
    • Only three mutations characterized; not all Ollier patients carry PTHR1 mutations
    • Downstream signaling of mutants not fully profiled
  5. 2009 High

    Engineered disulfide cross-linking across TM5 and TM6 revealed that agonist—but not antagonist—binding induces relative movement of these helices, providing the first physicochemical model of PTH1R activation conformational change.

    Evidence Systematic double-cysteine mutagenesis with disulfide bond formation in cell membrane preparations

    PMID:19063682

    Open questions at the time
    • Full activation mechanism including intracellular conformational changes was not resolved
    • No high-resolution structure available at this time
  6. 2009 High

    A β-arrestin-biased agonist that activates β-arrestin2 but not G-protein signaling promoted trabecular bone formation without stimulating resorption, proving that PTH1R supports pathway-selective anabolic signaling in vivo.

    Evidence Biased agonist (D-Trp12,Tyr34)-PTH(7-34) in β-arrestin2 knockout mice with bone density measurements

    PMID:20368153

    Open questions at the time
    • Downstream effectors of β-arrestin2-dependent anabolism not identified
    • Whether biased signaling is translatable to humans was unknown
  7. 2010 High

    Demonstrating that PTH1R phosphorylation-deficient knock-in mice show sustained cyclin D1 downregulation and that PTHrP/PKA/PKC induces MKP-1 to dephosphorylate ERK1/2 established receptor phosphorylation and internalization as critical timers of intracellular signaling duration in osteoblasts.

    Evidence Phosphorylation-deficient PTH1R knock-in mouse calvarial osteoblasts; MKP-1 overexpression and immunodepletion with pERK1/2 dephosphorylation assays and PKA/PKC inhibitors

    PMID:19892016 PMID:20929987

    Open questions at the time
    • Identity of the kinase(s) phosphorylating PTH1R C-tail in vivo not established at this point
    • Relative contribution of ERK vs. other pathways to growth arrest not fully delineated
  8. 2011 High

    Discovery that PTH(1-34) triggers transient ubiquitination followed by USP2-mediated deubiquitination for receptor recycling, while PTH(7-34) causes sustained ubiquitination and proteasomal degradation, established ubiquitin editing as a ligand-dependent switch governing PTH1R fate.

    Evidence Ubiquitination assays, recycling/degradation assays, and USP2 overexpression rescue in cell lines

    PMID:21898592

    Open questions at the time
    • E3 ligase responsible for PTH1R ubiquitination not identified
    • Whether USP2 regulation occurs in vivo in bone was not shown
  9. 2015 High

    PTH1R was shown to function as a mechanosensor in osteocytes: fluid flow or hypotonic shock activated PTH1R-dependent calcium, PLC, PKA, β-catenin, and ERK signaling to prevent apoptosis, even without exogenous ligand, while conditional limb deletion caused symphalangism, revealing non-canonical ligand-independent activation and essential roles in digit segmentation.

    Evidence PTH1R siRNA/overexpression with calcium imaging and apoptosis assays in MLO-Y4 osteocytes; Prx1-Cre conditional PTH1R KO mice with skeletal phenotyping

    PMID:25529820 PMID:26620087

    Open questions at the time
    • Molecular mechanism by which mechanical force activates PTH1R without ligand not defined
    • Whether mechanosensory role is separable from IHH signaling axis in digit formation unclear
  10. 2016 High

    Mass spectrometry mapping of nine C-tail phosphosites and mutagenesis showing that Ser503/Thr504 account for ~70% of arrestin3 recruitment defined the phosphorylation code governing PTH1R-arrestin interaction, while SNX27-retromer was identified as the endosomal recycling machinery coupling PTH1R back to the surface in osteoblasts.

    Evidence MS phosphosite mapping with alanine mutagenesis and FRET/BRET arrestin recruitment; SNX27 PDZ-PTHR crystal structure, SNX27 KO osteoblasts with signaling and mineralization readouts

    PMID:26912788 PMID:27623777

    Open questions at the time
    • Whether phosphosite code differs between PTH and PTHrP stimulation not tested
    • How SNX27-retromer is regulated in response to different ligands unknown
  11. 2016 High

    PFE-causing mutations such as Gly452Glu were shown to be functionally inactive, retained intracellularly, and dominant-negative on wild-type PTH1R, while Pro415 was identified as critical for selective activation by the small-molecule agonist PCO371, defining both disease mechanisms and a novel pharmacological binding mode.

    Evidence cAMP/VASP assays, confocal microscopy, electrophysiology for PFE mutants; chimeric PTH1R/PTH2R analysis and in vivo validation for PCO371

    PMID:27857062 PMID:27898723

    Open questions at the time
    • Structural basis for dominant-negative effect not resolved
    • PCO371 binding site not visualized at atomic resolution
  12. 2019 High

    An ECD-binding antibody selectively blocked β-arrestin-2 recruitment without affecting Gs/cAMP signaling, demonstrating that the extracellular domain of PTH1R allosterically controls pathway selectivity and can be targeted for biased modulation.

    Evidence Phage display antibody with HDX-MS epitope mapping, parallel β-arrestin-2 and Gs signaling assays

    PMID:31594997

    Open questions at the time
    • In vivo consequence of ECD-selective inhibition not tested
    • Whether ECD antibody affects internalization kinetics not assessed
  13. 2020 High

    Kindlin-2 was identified as a scaffolding partner that binds both the PTH1R C-terminal domain and Gsα, and Kindlin-2 haploinsufficiency combined with Pth1r haploinsufficiency synergistically reduced bone mass, establishing Kindlin-2 as an intrinsic component of the PTH1R signaling complex in osteoblasts.

    Evidence Reciprocal co-IP, osteoblast-specific Kindlin-2 conditional KO, epistatic double-haploinsufficiency in mice, cAMP/CREB assays

    PMID:33361757

    Open questions at the time
    • Whether Kindlin-2 affects β-arrestin branch of PTH1R signaling not tested
    • Structural interface between Kindlin-2 and PTH1R not mapped at residue level
  14. 2021 High

    PTH1R was found to function in Leydig and epididymal epithelial cells, where abaloparatide-mediated anti-inflammatory effects required both Gq and β-arrestin-1, extending the receptor's physiological roles beyond bone and mineral metabolism.

    Evidence Gnaq heterozygous and Arrb1 knockout mouse models with inflammatory challenge

    PMID:34740971

    Open questions at the time
    • Downstream effectors of Gq/β-arrestin-1 anti-inflammatory signaling in reproductive tract not identified
    • Whether this is pharmacologically relevant in humans unknown
  15. 2022 High

    Cryo-EM structures of PTH- and ABL-bound PTH1R–Gs complexes revealed that PTH forms a more rigid complex with greater tolerance to ECD mutations, explaining the longer signaling duration of PTH versus abaloparatide, while RAMP2 was shown to allosterically shift PTH1R toward a preactivated state enhancing Gi3 sensitivity and β-arrestin2 recruitment.

    Evidence Cryo-EM with 3D variability analysis and site-directed mutagenesis; BRET/FRET optical biosensors for RAMP2 co-expression studies

    PMID:35914163 PMID:36271004

    Open questions at the time
    • Structure of RAMP2-PTH1R complex not determined
    • How RAMP2 modulates Gi3 coupling at the structural level is unknown
  16. 2023 High

    Eiken syndrome mutations were shown to increase basal cAMP or impair PTHrP-selective β-arrestin2 recruitment, while MMP14 was identified as a proteolytic negative regulator cleaving the PTH1R ectodomain in hypertrophic chondrocyte-derived osteoblasts, and a Zfp467-NFκB1 axis was found to transcriptionally upregulate Pth1r, revealing multiple layers of receptor regulation in skeletal cells.

    Evidence Signaling/binding assays for Eiken mutants; conditional Mmp14 KO with cleavage assay and bone phenotype; conditional Zfp467 KO with reporter assays and PKA inhibitors

    PMID:36892459 PMID:37159501 PMID:37268817

    Open questions at the time
    • MMP14 cleavage site on PTH1R ECD not mapped at residue resolution
    • Whether Zfp467-dependent transcriptional regulation operates in cell types beyond osteogenic precursors is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The nuclear function of PTH1R, the structural basis of RAMP2 allosteric modulation, the E3 ubiquitin ligase for PTH1R, and the mechanism of ligand-independent mechanosensory activation remain unresolved.
  • No function assigned to nuclear PTH1R despite established import/export machinery
  • E3 ligase for PTH1R ubiquitination not identified
  • Structural mechanism of mechanosensory activation without ligand not determined
  • RAMP2-PTH1R complex structure not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0140299 molecular sensor activity 1
Localization
GO:0005634 nucleus 2 GO:0005768 endosome 2 GO:0005886 plasma membrane 2 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-9609507 Protein localization 2
Partners
ARRB2FERMT2KPNA1KPNB1MMP14RAMP2SNX27USP2

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 A beta-arrestin-biased agonist (D-Trp12,Tyr34)-PTH(7-34) selectively activates beta-arrestin2 but not G protein signaling through PTH1R, and in beta-arrestin2-null mice the anabolic bone formation evoked by this biased agonist is ablated, demonstrating that PTH1R can signal through a distinct beta-arrestin2-dependent pathway to promote trabecular bone formation without stimulating bone resorption. Biased agonist pharmacology in vivo; beta-arrestin2 knockout mice with bone mineral density measurement Science translational medicine High 20368153
2016 SNX27 binds directly to the C-terminal PDZ-binding motif of PTH1R and couples it to the retromer trafficking complex for endosomal sorting; depletion of SNX27 or retromer augments intracellular PTH1R signaling in endosomes and impairs bone mineralization in osteoblasts lacking SNX27. Direct binding assay, crystal structure of SNX27-PTHR PDZ motif complex, SNX27 KO osteoblasts with signaling and mineralization readouts, SNX27-KO mouse skeletal phenotype Molecular biology of the cell High 26912788
2011 PTH(1-34) stimulation induces transient PTHR ubiquitination followed by deubiquitination mediated by the PTHR-specific deubiquitinating enzyme USP2, enabling receptor recycling; in contrast, PTH(7-34) induces sustained PTHR ubiquitination without USP2 induction, leading to proteasomal degradation of the receptor. Ubiquitination assays, recycling/degradation assays, USP2 overexpression rescue, ligand treatment in cell lines Journal of bone and mineral research High 21898592
2016 Mass spectrometry identified nine phosphorylation sites in the C-terminal tail of PTH1R; two clusters (Ser489-Ser495 and Ser501-Thr506) are responsible for PTH(1-34)-induced phosphorylation. Ser503 and Thr504 in the second cluster account for ~70% of arrestin3 recruitment and are key determinants for arrestin3 interaction with the receptor, as shown by FRET and BRET assays. Mass spectrometry phosphosite mapping, alanine mutagenesis, FRET/BRET arrestin3 recruitment assays The Biochemical journal High 27623777
2006 PTH1R forms a complex with importin alpha1 and importin beta in osteoblast-like cells, as demonstrated by immunoprecipitation and PTH-affinity chromatography, indicating that these transport proteins mediate nuclear import of PTH1R. Nuclear PTH1R localization is restricted to the nucleoplasm and is associated with specific stages of the cell cycle. Immunoprecipitation, affinity chromatography, immunofluorescence/deconvolution microscopy Endocrinology Medium 16574786
2007 PTH1R nuclear-cytoplasmic shuttling depends on importin-alpha/beta for nuclear import and CRM1/exportin1 for nuclear export; importin-beta siRNA knockdown reduces nuclear PTH1R, and leptomycin B (CRM1 inhibitor) causes nuclear accumulation. Serum starvation favors nuclear localization, while PTHrP or serum re-addition promotes cytoplasmic localization. siRNA knockdown, CRM1 inhibitor (leptomycin B), co-immunoprecipitation, immunofluorescence microscopy, nuclear fractionation Endocrinology High 17317770
2009 PTH agonist and antagonist induce distinct conformational changes at the extracellular-facing interface of transmembrane domains TM5 and TM6 of PTH1R; engineered disulfide bond formation showed TM5/TM6 move relative to each other upon agonist binding but not antagonist binding, providing physicochemical evidence for the receptor activation mechanism. Engineered disulfide bond cross-linking strategy, cell membrane preparations, 18 double-cysteine PTHR1 mutants Journal of bone and mineral research High 19063682
2016 An orally active small-molecule agonist (PCO371) acts as a full agonist of PTH1R but not PTH2R; chimeric receptor analysis identified Pro415 of PTH1R as critical for PCO371-mediated activation, indicating a distinct binding mode from peptide ligands. PTH1R-PTHR2 chimeric receptor analysis, cAMP assays, in vivo rat models Nature communications High 27857062
2022 Cryo-EM structures of PTH- and ABL-bound PTH1R-Gs complexes reveal similar overall conformations but notable differences in the receptor ECD regions and peptide C-terminal portions; 3D variability analysis and site-directed mutagenesis show PTH-bound complexes display less motion and greater tolerance to mutations, providing molecular basis for the longer signaling duration of teriparatide (PTH) vs. abaloparatide (ABL). Cryo-EM structure determination, 3D variability analysis, site-directed mutagenesis, signaling assays Nature communications High 36271004
2022 RAMP2 acts as a specific allosteric modulator of PTH1R, shifting it to a preactivated state that permits faster ligand-dependent activation; RAMP2 modulates PTH1R downstream signaling in an agonist-dependent manner, increasing PTH-mediated Gi3 signaling sensitivity and enhancing β-arrestin2 recruitment by both PTH and PTHrP. Optical biosensors (BRET/FRET), homology modeling, co-expression of RAMP2 with PTH1R Proceedings of the National Academy of Sciences of the United States of America High 35914163
2023 MMP14 cleaves the extracellular domain of PTH1R in hypertrophic chondrocyte-derived osteoblasts, dampening PTH signaling; in HC lineage-specific Mmp14 null mice, PTH1R signaling is enhanced and bone formation is increased, demonstrating MMP14 as a negative regulator of PTH1R signaling intensity in the osteoblast lineage. HC lineage-specific Mmp14 conditional knockout, single-cell transcriptomics, in vitro cleavage assay, PTH 1-34 treatment in mutant mice eLife High 36892459
2019 An ECD-binding antibody (ECD-scFvhFc) targeting the α1 helix of the PTH1R extracellular domain potently inhibits β-arrestin-2 recruitment after PTH(1-34) activation without affecting Gs-mediated cAMP signaling, representing pathway-selective inhibition of PTH1R signaling. Phage display antibody generation, hydrogen-deuterium exchange mass spectrometry epitope mapping, β-arrestin-2 recruitment assay, Gs signaling assay Scientific reports High 31594997
2020 Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via residues aa 474-475 and with Gsα, functioning as an intrinsic component of the PTH1R signaling complex; Kindlin-2 loss suppresses PTH-induced cAMP production and CREB phosphorylation in osteoblasts, and haploinsufficiency of both Kindlin-2 and Pth1r significantly decreases bone mass. Co-immunoprecipitation, haploinsufficiency double-mutant epistasis in mice, cAMP/CREB signaling assays in osteoblasts, osteoblast-specific conditional KO Signal transduction and targeted therapy High 33361757
2022 Mechanical stimulation (fluid flow) causes redistribution of PTH1R along the entire primary cilium of osteocytic MLO-Y4 cells; PTH1R and primary cilia signaling are both required for FF-mediated inhibition of osteoclast recruitment and differentiation via modulation of CXCL5 and IL-6 secretion from osteocytes. siRNA knockdown of PTH1R and primary cilia, fluid flow stimulation, proteomic analysis, live imaging, neutralizing antibodies, osteoclast migration/differentiation assays Journal of cellular physiology High 35933642
2015 Mechanical stimulation (hypotonic shock or pulsatile fluid flow) activates PTH1R-dependent signaling in osteocytic MLO-Y4 cells to prevent apoptosis; this involves calcium signaling (blocked by verapamil), PLC (blocked by U73122), and PKA, as well as β-catenin stabilization and nuclear ERK translocation. Hypotonic shock rapidly stimulates Ca2+ transients in PTH1R-overexpressing HEK-293 cells even in the absence of PTHrP ligand, indicating PTH1R acts as a mechanosensor. PTH1R siRNA knockdown, PTH1R overexpression in HEK-293 cells, pharmacological inhibitors, calcium imaging, apoptosis assays in MLO-Y4 osteocytes Journal of bone and mineral research High 25529820
2010 PTHrP increases MKP-1 (MAPK phosphatase-1) expression in differentiated osteoblasts via PTH1R activation through PKA and PKC pathways; MKP-1 then dephosphorylates pERK1/2 and down-regulates cyclin D1, inducing growth arrest in mature osteoblasts and mediating anabolic actions of PTH1R. MKP-1 overexpression, immunodepletion, in vitro pERK1/2 dephosphorylation assay with cell extracts, PKA/PKC inhibitors, in vivo PTH treatment with bone formation markers Cellular signalling High 19892016
2016 PTH1R mutations identified in PFE patients (e.g., Gly452Glu) are functionally inactive in G-protein/cAMP signaling; PTH1R/Gly452Glu acts as a dominant negative on wild-type PTH1R signaling and is retained intracellularly rather than expressed at the cell surface, abolishing coupling to TRESK K+ channels. cAMP ELISA, Western blot (VASP phosphorylation), confocal microscopy, electrophysiological recordings in Xenopus oocytes, co-transfection with WT and mutant PTH1R PloS one High 27898723
2023 Eiken syndrome PTH1R mutation R485X (truncation of C-terminal tail) increases basal cAMP signaling and decreases β-arrestin2 recruitment upon ligand stimulation; mutations E35K and Y134S weaken PTHrP binding, impairing β-arrestin2 recruitment and desensitization of cAMP response to PTHrP but not PTH, supporting a critical role for β-arrestin in PTH1R-regulated bone formation. Cell-based cAMP signaling assays, β-arrestin2 recruitment assays, ligand binding assays for multiple Eiken PTH1R mutants Communications biology High 37268817
2021 PTH1R is expressed in Leydig cells of the testis and epididymal epithelial cells; activation of PTH1R by abaloparatide alleviates inflammation-induced epididymitis/orchitis mainly through the Gq and β-arrestin-1 signaling pathways, as demonstrated by attenuated anti-inflammatory effects in Gnaq+/- and Arrb1-/- mouse models. Gnaq heterozygous and Arrb1 knockout mouse models, pharmacological activation with abaloparatide, inflammatory challenge models Proceedings of the National Academy of Sciences of the United States of America High 34740971
2020 Functional analysis of PFE-associated PTH1R variants P119L and P132L revealed severe reduction in N-linked glycosylation and markedly decreased affinity for PTH1-34, leading to severely impaired cAMP accumulation upon stimulation; these variants also failed to induce RANKL expression in osteoblastic cells derived from PFE patient iPSCs. Lentiviral expression in HeLa cells, N-linked glycosylation analysis, ligand binding assays, cAMP accumulation assays, iPSC disease modeling with osteoblastic differentiation Journal of dental research High 31986066
2016 N-cadherin reduces LRP6-PTH1R interaction and endocytosis in response to PTH, blunting PTH-induced suppression of sclerostin/SOST through impaired MEF2 downregulation; deletion of N-cadherin in osteocytes (Cdh2ΔDmp1 mice) accentuates iPTH-induced SOST suppression and bone anabolic effects. N-cadherin overexpression, immunoblot/qPCR for SOST/MEF2, co-IP for LRP6-PTHR1, Dmp1-Cre conditional Cdh2 KO mice with iPTH treatment Annals of the New York Academy of Sciences Medium 27723935
2010 PTH1R receptors are localized at the basolateral plasma membrane of proximal and distal tubule epithelial cells in human kidney and at the plasma membrane of osteocytes and osteoblasts (but not osteoclasts) in bone, as established by a validated anti-PTH1R antibody showing translocation of receptor immunostaining after agonist exposure. Anti-peptide antibody characterization (western blot, cell surface staining of transfected cells, agonist-induced translocation, preadsorption controls), immunohistochemistry of 320 human tumors and normal tissues European journal of endocrinology Medium 20156969
2023 PTH1R activation by a novel PTH analog (MY-1) promotes keratinocyte migration and epithelial-mesenchymal transition in wound healing through the PTHR1-PI3K/AKT signaling axis, as demonstrated by siRNA knockdown of PTHR1 abolishing PI3K/AKT activation in HaCaT cells. siRNA knockdown of PTHR1, PI3K/AKT pathway analysis by western blot, migration and EMT assays, in vivo wound models with GelMA hydrogel delivery Cell communication and signaling : CCS Medium 37612710
2010 Impaired phosphorylation/internalization of PTH1R (phosphorylation-deficient knock-in mice) results in sustained cyclin D1 downregulation in osteoblasts compared to wild-type, indicating that receptor phosphorylation and subsequent internalization regulate the duration of intracellular signaling responses including ERK1/2 and cyclin D1 in bone cells. Phosphorylation-deficient PTH1R knock-in mouse model, primary calvarial osteoblast culture, pERK1/2 and cyclin D1 assays The Journal of endocrinology Medium 20929987
2023 Loss of Zfp467 in osteogenic precursors leads to increased nuclear translocation of NFκB1, which binds the P2 promoter of Pth1r and increases its transcription, creating a positive feedback loop; PTH suppresses Zfp467 primarily via the cAMP/PKA pathway downstream of PTH1R. Conditional KO (Prrx1Cre;Zfp467), dual fluorescence reporter assays, confocal immunofluorescence, PKA inhibitor, Pth1r siRNA, cAMP production assays eLife Medium 37159501
2017 IL-17 upregulates N-cadherin which disrupts PTH1R/LRP-6 interaction, thereby inhibiting Wnt signaling and promoting bone loss; combination of PTH(1-34) with anti-IL17 reduces PTH1R expression and has synergistic bone-protective effects in ovariectomized mice, placing IL-17 upstream of the PTHR1/LRP-6/Wnt axis. Immunofluorescence analysis, anti-IL17 antibody treatment plus iPTH in OVX mice, bone mineral density measurement Bone Low 28935557
2018 Hyperstimulation of CaSR by biomimetic hydroxyapatite causes temporal downregulation of PTH1R in human BM-derived MSCs, inhibiting chondrogenic differentiation; rescuing PTH1R expression with PTH(1-34) partially restores chondrogenesis, demonstrating cross-talk between CaSR and PTH1R in controlling MSC ossification pathway choice. CaSR knockdown, PTH(1-34) rescue experiments, chondrogenic differentiation assays, in vivo ectopic implantation Proceedings of the National Academy of Sciences of the United States of America Medium 29915064
2015 Conditional deletion of PTH1R in limb mesenchyme (Prx1-Cre;PTH1R fl/fl) causes symphalangism (digit joint fusion) due to failure of epiphyseal growth plate formation and replacement of cartilage by bone, demonstrating a novel role for PTH1R signaling in digit formation and segmentation distinct from its known role in long bone growth plates. Prx1-Cre conditional PTH1R KO mice, histomorphometry, comparison with Ihh conditional KO and Jansen transgenic rescue Bone High 26620087
2017 Loss of RAMP2 in mice decreases PTH1R expression and causes a blunted response to systemic PTH administration, providing in vivo evidence that RAMP2 regulates PTH1R expression and function. Ramp2 KO mice, PTH administration, gene expression analysis PloS one Medium 28727763
2008 Three PTHR1 missense mutations identified in Ollier disease enchondromas (G121E, A122T, R255H) impair receptor function by reducing either PTH binding affinity or receptor expression at the cell surface, establishing loss-of-function as the mechanistic basis for PTHR1-associated enchondromatosis. Functional assays of receptor-ligand affinity and cell surface expression in patient-derived mutation-expressing cells Human molecular genetics Medium 18559376
1999 Zebrafish PTH1R ortholog (zPTH1R) binds PTH, PTHrP, and fuguPTHrP with high affinity (IC50 1.2-3.5 nM) and efficiently stimulates cAMP accumulation and inositol phosphate (IP) production when expressed in COS-7 cells, establishing dual G-protein coupling (Gs and Gq). COS-7 cell expression, radioligand competition binding, cAMP accumulation assay, inositol phosphate accumulation assay The Journal of biological chemistry High 10497171

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science (New York, N.Y.) 599 12595692
2009 A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Science translational medicine 160 20368153
2008 PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption. American journal of human genetics 99 19061984
2021 Physiological and Pharmacological Roles of PTH and PTHrP in Bone Using Their Shared Receptor, PTH1R. Endocrine reviews 84 33564837
1999 Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide. The Journal of biological chemistry 79 10497171
2008 Safety and immunogenicity of recombinant low-dosage HIV-1 A vaccine candidates vectored by plasmid pTHr DNA or modified vaccinia virus Ankara (MVA) in humans in East Africa. Vaccine 76 18440674
2010 Primary failure of eruption and PTH1R: the importance of a genetic diagnosis for orthodontic treatment planning. American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics 69 20152661
2008 PTHR1 mutations associated with Ollier disease result in receptor loss of function. Human molecular genetics 64 18559376
2004 Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Human molecular genetics 62 15525660
2016 Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism. Nature communications 56 27857062
2010 Immunohistochemical identification of the PTHR1 parathyroid hormone receptor in normal and neoplastic human tissues. European journal of endocrinology 52 20156969
2020 Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice. Signal transduction and targeted therapy 47 33361757
2004 Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C. Human mutation 47 15523647
2016 Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth. Molecular biology of the cell 46 26912788
1994 Cloning of a parathyroid hormone/parathyroid hormone-related peptide receptor (PTHR) cDNA from a rat osteosarcoma (UMR 106) cell line: chromosomal assignment of the gene in the human, mouse, and rat genomes. Genomics 46 8020952
2019 Inhibition of Ihh Reverses Temporomandibular Joint Osteoarthritis via a PTH1R Signaling Dependent Mechanism. International journal of molecular sciences 45 31382618
2011 Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 45 21404329
2011 The bone-protective effect of genistein in the animal model of bilateral ovariectomy: roles of phytoestrogens and PTH/PTHR1 against post-menopausal osteoporosis. International journal of molecular sciences 45 22312238
2015 Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism. Seminars in cell & developmental biology 43 26688334
2015 Role of the Parathyroid Hormone Type 1 Receptor (PTH1R) as a Mechanosensor in Osteocyte Survival. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 42 25529820
2010 Distinct roles for mitogen-activated protein kinase phosphatase-1 (MKP-1) and ERK-MAPK in PTH1R signaling during osteoblast proliferation and differentiation. Cellular signalling 42 19892016
2008 Lessons from IAVI-006, a phase I clinical trial to evaluate the safety and immunogenicity of the pTHr.HIVA DNA and MVA.HIVA vaccines in a prime-boost strategy to induce HIV-1 specific T-cell responses in healthy volunteers. Vaccine 42 18812202
2013 Novel mutations in PTH1R associated with primary failure of eruption and osteoarthritis. Journal of dental research 41 24300310
2013 Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption. Clinical oral investigations 40 23771181
2012 Thymoquinone blocks pSer/pThr recognition by Plk1 Polo-box domain as a phosphate mimic. ACS chemical biology 40 23135290
2014 Knockdown of PTHR1 in osteosarcoma cells decreases invasion and growth and increases tumor differentiation in vivo. Oncogene 39 25043296
2013 Identification of six novel PTH1R mutations in families with a history of primary failure of tooth eruption. PloS one 38 24058597
2020 Role of PTH1R Signaling in Prx1+ Mesenchymal Progenitors during Eruption. Journal of dental research 34 32585127
2020 Long noncoding RNA LINC01278 favors the progression of osteosarcoma via modulating miR-133a-3p/PTHR1 signaling. Journal of cellular physiology 29 31994731
2014 Differential diagnosis of primary failure of eruption (PFE) with and without evidence of pathogenic mutations in the PTHR1 gene. Journal of orofacial orthopedics = Fortschritte der Kieferorthopadie : Organ/official journal Deutsche Gesellschaft fur Kieferorthopadie 28 24825834
2006 Type 1 parathyroid hormone receptor (PTH1R) nuclear trafficking: association of PTH1R with importin alpha1 and beta. Endocrinology 28 16574786
2002 Expression of parathyroid hormone-related peptide (PthrP) and its receptor (PTH1R) during the histogenesis of cartilage and bone in the chicken mandibular process. Journal of anatomy 28 12220122
2022 PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway. Frontiers in endocrinology 27 35126319
2022 PTH1R translocation to primary cilia in mechanically-stimulated ostecytes prevents osteoclast formation via regulation of CXCL5 and IL-6 secretion. Journal of cellular physiology 26 35933642
2019 Modulation of PTH1R signaling by an ECD binding antibody results in inhibition of β-arrestin 2 coupling. Scientific reports 26 31594997
2018 Parathyroid Hormone-Related Protein Negatively Regulates Tumor Cell Dormancy Genes in a PTHR1/Cyclic AMP-Independent Manner. Frontiers in endocrinology 26 29867773
2018 Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R. Proceedings of the National Academy of Sciences of the United States of America 25 29915064
2009 Ischemic injury activates PTHrP and PTH1R expression in human ventricular cardiomyocytes. Basic research in cardiology 25 19190955
2006 A functional polymorphism in the PTHR1 promoter region is associated with adult height and BMD measured at the femoral neck in a large cohort of young caucasian women. Human genetics 25 16508749
2022 Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation. Nature communications 24 36271004
2021 Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways. Proceedings of the National Academy of Sciences of the United States of America 24 34740971
2016 Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia. The Journal of clinical endocrinology and metabolism 24 27410178
2010 Decrease in the expression of the type 1 PTH/PTHrP receptor (PTH1R) on chondrocytes in animals with osteoarthritis. Journal of orthopaedic surgery and research 24 20420676
2011 Ubiquitination-deubiquitination balance dictates ligand-stimulated PTHR sorting. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 23 21898592
2012 Non-proteinogenic amino acids in the pThr-2 position of a pentamer peptide that confer high binding affinity for the polo box domain (PBD) of polo-like kinase 1 (Plk1). Bioorganic & medicinal chemistry letters 22 23159568
2007 Type 1 parathyroid hormone receptor (PTH1R) nuclear trafficking: regulation of PTH1R nuclear-cytoplasmic shuttling by importin-alpha/beta and chromosomal region maintenance 1/exportin 1. Endocrinology 22 17317770
2007 Genetic variation in the PTH pathway and bone phenotypes in elderly women: evaluation of PTH, PTHLH, PTHR1 and PTHR2 genes. Bone 22 18280230
2023 MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism. eLife 21 36892459
2022 Functional modulation of PTH1R activation and signaling by RAMP2. Proceedings of the National Academy of Sciences of the United States of America 21 35914163
2016 Identification of key phosphorylation sites in PTH1R that determine arrestin3 binding and fine-tune receptor signaling. The Biochemical journal 21 27623777
2021 Validating clinical characteristic of primary failure of eruption (PFE) associated with PTH1R variants. Progress in orthodontics 20 34897565
2017 Combination of PTH (1-34) with anti-IL17 prevents bone loss by inhibiting IL-17/N-cadherin mediated disruption of PTHR1/LRP-6 interaction. Bone 20 28935557
2016 A novel homozygous PTH1R variant identified through whole-exome sequencing further expands the clinical spectrum of primary failure of tooth eruption in a consanguineous Saudi family. Archives of oral biology 20 27019138
2015 Bovine parathyroid hormone enhances osteoclast bone resorption by modulating V-ATPase through PTH1R. International journal of molecular medicine 20 26647715
2021 PTH-rP and PTH-R1 Expression in Placentas from Pregnancies Complicated by Gestational Diabetes: New Insights into the Pathophysiology of Hyperglycemia in Pregnancy. Diagnostics (Basel, Switzerland) 19 34441291
2020 CHD7 Regulates Osteogenic Differentiation of Human Dental Follicle Cells via PTH1R Signaling. Stem cells international 18 33014071
2012 KRT8, FAF1 and PTH1R gene polymorphisms are associated with leg weakness traits in pigs. Molecular biology reports 18 23196707
2007 PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton. Calcified tissue international 18 17885720
2020 USP7 regulates the proliferation and differentiation of ATDC5 cells through the Sox9-PTHrP-PTH1R axis. Bone 17 33127578
2013 Prenatal presentation and postnatal evolution of a patient with Jansen metaphyseal dysplasia with a novel missense mutation in PTH1R. American journal of medical genetics. Part A 17 23950054
2016 PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling. PloS one 16 27898723
2010 Parathyroid hormone-related peptide (PTHrP), parathyroid hormone/parathyroid hormone-related peptide receptor 1 (PTHR1), and MSX1 protein are expressed in central and peripheral giant cell granulomas of the jaws. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 16 20060342
2021 Enzalutamide-induced and PTH1R-mediated TGFBR2 degradation in osteoblasts confers resistance in prostate cancer bone metastases. Cancer letters 15 34752846
2010 Role of PTH1R internalization in osteoblasts and bone mass using a phosphorylation-deficient knock-in mouse model. The Journal of endocrinology 15 20929987
2018 RANKL/OPG system regulation by endogenous PTH and PTH1R/ATF4 axis in bone: Implications for bone accrual and strength in growing rats with mild uremia. Cytokine 14 29529595
2004 The (GT)n polymorphism and haplotype of the COL1A2 gene, but not the (AAAG)n polymorphism of the PTHR1 gene, are associated with bone mineral density in Chinese. Human genetics 14 15599596
2003 PTHrP, PTHr, and FGFR3 are involved in the process of endochondral ossification in human osteophytes. Histochemistry and cell biology 14 12692671
2020 Functional Analysis of PTH1R Variants Found in Primary Failure of Eruption. Journal of dental research 13 31986066
2019 PTHR1 May Be Involved in Progression of Osteosarcoma by Regulating miR-124-3p-AR-Tgfb1i1, miR-27a-3p-PPARG-Abca1, and miR-103/590-3p-AXIN2 Axes. DNA and cell biology 13 31536386
2018 Synthesis of α,α-Difluorinated Phosphonate pSer/pThr Mimetics via Rhodium-Catalyzed Asymmetric Hydrogenation of β-Difluorophosphonomethyl α-(Acylamino)acrylates. Organic letters 13 29782177
2018 PTH1R-CaSR Cross Talk: New Treatment Options for Breast Cancer Osteolytic Bone Metastases. International journal of endocrinology 12 30151009
2017 A cumulative effect involving malfunction of the PTH1R and ATP4A genes explains a familial gastric neuroendocrine tumor with hypothyroidism and arthritis. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 12 28474257
2016 Pseudohypoparathyroidism type I-b with neurological involvement is associated with a homozygous PTH1R mutation. Genes, brain, and behavior 12 27415614
2016 N-cadherin restrains PTH repressive effects on sclerostin/SOST by regulating LRP6-PTH1R interaction. Annals of the New York Academy of Sciences 12 27723935
2015 Ihh and PTH1R signaling in limb mesenchyme is required for proper segmentation and subsequent formation and growth of digit bones. Bone 12 26620087
2023 Human Parathyroid Hormone Analog (3-34/29-34) promotes wound re-epithelialization through inducing keratinocyte migration and epithelial-mesenchymal transition via PTHR1-PI3K/AKT activation. Cell communication and signaling : CCS 11 37612710
2019 A novel nonsense PTH1R variant shows incomplete penetrance of primary failure of eruption: a case report. BMC oral health 11 31730001
2017 Loss of receptor activity-modifying protein 2 in mice causes placental dysfunction and alters PTH1R regulation. PloS one 11 28727763
2005 The VDR, COL1A1, PTH, and PTHR1 gene polymorphisms are not associated with bone size and height in Chinese nuclear families. Journal of bone and mineral metabolism 11 16261459
2022 Actions of Parathyroid Hormone Ligand Analogues in Humanized PTH1R Knockin Mice. Endocrinology 10 35460406
2022 Convallatoxin suppresses osteosarcoma cell proliferation, migration, invasion, and enhances osteogenic differentiation by downregulating parathyroid hormone receptor 1 (PTHR1) expression and inactivating Wnt/β-catenin pathway. Bioengineered 10 35635031
2022 Dynamic Balance between PTH1R-Dependent Signal Cascades Determines Its Pro- or Anti-Osteogenic Effects on MSC. Cells 10 36359914
2019 Parathyroid hormone-like hormone plays a dual role in neuroblastoma depending on PTH1R expression. Molecular oncology 10 31293052
2017 Transcriptomic analyses reveal the underlying pro-malignant functions of PTHR1 for osteosarcoma via activation of Wnt and angiogenesis pathways. Journal of orthopaedic surgery and research 10 29121993
2011 Type 1 receptor parathyroid hormone (PTH1R) influences breast cancer cell proliferation and apoptosis induced by high levels of glucose. Medical oncology (Northwood, London, England) 10 21312071
2024 Etiological Mechanisms and Genetic/Biological Modulation Related to PTH1R in Primary Failure of Tooth Eruption. Calcified tissue international 9 38833001
2023 Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome. Communications biology 9 37268817
2023 Substantially Delayed Maturation of Growth Plate Chondrocytes in "Humanized" PTH1R Mice with the H223R Mutation of Jansen's Disease. JBMR plus 9 37808400
2022 Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling. Nature communications 9 36114179
2019 Primary failure of eruption of teeth in two siblings with a novel mutation in the PTH1R gene. European archives of paediatric dentistry : official journal of the European Academy of Paediatric Dentistry 9 30904994
2017 Twenty-year follow-up of a familial case of PTH1R-associated primary failure of tooth eruption. American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics 9 28257744
2009 Association of parathyroid hormone-like hormone (PTHLH) and its receptor (PTHR1) with the number of functional and inverted teats in pigs. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 9 19646152
2003 Expression patterns of parathyroid hormone-related peptide (PTHrP) and parathyroid hormone receptor type 1 (PTHR1) during human development are suggestive of roles specific for each gene that are not mediated through the PTHrP/PTHR1 paracrine signaling pathway. Gene expression patterns : GEP 9 12609604
2024 Parathyroid hormone-PTH1R signaling in cardiovascular disease and homeostasis. Trends in endocrinology and metabolism: TEM 8 38429163
2023 PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner. eLife 8 37159501
2004 PTH-1R responses to PTHrP and regulation by vitamin D in keratinocytes and adjacent fibroblasts. The Journal of steroid biochemistry and molecular biology 8 15225805
2022 Critical Extracellular Ca2+ Dependence of the Binding between PTH1R and a G-Protein Peptide Revealed by MD Simulations. ACS chemical neuroscience 7 35543321
2021 PTHR1 in osteosarcoma: Specific molecular mechanisms and comprehensive functional perspective. Journal of cellular and molecular medicine 7 33675132
2020 A 51 bp indel polymorphism within the PTH1R gene is significantly associated with chicken growth and carcass traits. Animal genetics 7 32400914
2009 PTH and PTH antagonist induce different conformational changes in the PTHR1 receptor. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 7 19063682