Affinage

PROKR2

Prokineticin receptor 2 · UniProt Q8NFJ6

Length
384 aa
Mass
44.0 kDa
Annotated
2026-06-10
62 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PROKR2 is a G protein-coupled receptor for prokineticin 2 (PROK2) that is essential for the migration and positioning of GnRH neurons and olfactory bulb interneurons, linking it directly to reproductive and olfactory development (PMID:16537498, PMID:18052978, PMID:31132148). Knockout mice lack hypothalamic GnRH neurons, show olfactory bulb hypoplasia, and lose roughly three-quarters of OB GABAergic interneurons because postmitotic immature neuroblasts fail to migrate from the SVZ-RMS toward PROK2 (PMID:16537498, PMID:18052978, PMID:31132148); this migratory function is driven principally by Gαq signaling rather than the MAPK/ERK arm (PMID:36694982). Beyond development, PROKR2 transduces SCN circadian output to behavior without being required for the cellular oscillator itself (PMID:17202262) and contributes to nociceptive sensitization through functional coupling to TRPV1 and TRPA1 channels (PMID:31883821). Mechanistically, wild-type PROKR2 activates Gq, Gs, and Gi/o and recruits β-arrestins, and disease-associated missense mutations partition into distinct functional defects—impaired plasma-membrane trafficking, loss of ligand binding, or selective uncoupling from individual Gα proteins—frequently producing biased signaling rather than complete loss of function (PMID:18826963, PMID:24830383, PMID:30576231). Intracellular determinants of these behaviors have been mapped: a positively charged residue in IL2 (R164) is required for coupling to Gαq, Gαi, and Gα16 (PMID:21454486), and distinct motifs of IL3 separately govern surface trafficking versus G-protein coupling (PMID:23969157). Receptor surface delivery additionally depends on N-linked glycosylation at N27 and is negatively regulated by MRAP2, while the trafficking-defective P290S mutant cycles between ER and Golgi and undergoes enhanced ER-associated degradation (PMID:34483834, PMID:35173048). PROKR2 internalizes via a GRK2- and clathrin-dependent, β-arrestin-independent route, and its stability and trafficking are modulated by the binding partner snapin and by TRPV1 (PMID:24509228, PMID:26687946, PMID:40139621). Some disease alleles act dominantly, including a truncated receptor that paradoxically enhances wild-type receptor activity and additional dominant-negative variants revealed only under co-expression with wild-type receptor (PMID:28338294, PMID:29161432).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2006 High

    Established the developmental requirement for PROKR2 by showing its loss eliminates hypothalamic GnRH neurons and disrupts olfactory bulb formation, defining the receptor's physiological role.

    Evidence Targeted knockout mice with IHC, hormone assays, and mRNA quantification

    PMID:16537498

    Open questions at the time
    • Did not resolve which downstream G-protein pathway mediates the developmental defect
    • Did not distinguish cell-autonomous migration from survival effects
  2. 2007 High

    Separated PROKR2's role in circadian behavioral output from the timekeeping oscillator, showing it conveys SCN signals to behavior without being required for the clock.

    Evidence Null mice with locomotor/temperature monitoring and ex vivo SCN bioluminescence imaging

    PMID:17202262

    Open questions at the time
    • Did not identify the target neurons receiving the PROKR2-dependent output signal
    • Mechanism of output coupling unresolved
  3. 2008 High

    Defined PROKR2 as a chemoattractant receptor for neuronal progenitor migration into the olfactory bulb, showing Prokr2-deficient cells fail to migrate toward PROK2.

    Evidence Null mouse histology with BrdU/TUNEL and in vitro neurosphere migration assays

    PMID:18052978

    Open questions at the time
    • Did not define the intracellular signaling effector for migration
    • Did not separate proliferation from migration contributions to OB volume
  4. 2008 High

    First systematic functional triage of KS-associated mutations, showing missense variants impair the receptor through three distinct mechanisms—trafficking, ligand binding, or coupling—without dominant-negative effects.

    Evidence Site-directed mutagenesis of ten mutations with calcium, surface-expression, and co-expression assays in HEK-293 cells

    PMID:18826963

    Open questions at the time
    • Tested only Gq/calcium signaling, missing pathway-selective defects
    • Did not assess heterozygous co-expression beyond dominant-negative screening for this readout
  5. 2008 Medium

    Revealed a peripheral, paracrine action of PROKR2 in the heart, where cardiomyocyte overexpression causes hypertrophy and vascular leakage via ZO-1 mislocalization.

    Evidence Transgenic mice with echocardiography, ZO-1 immunofluorescence, and endothelial conditioned-media experiments

    PMID:18806277

    Open questions at the time
    • Overexpression model may not reflect endogenous receptor levels
    • Paracrine mediator linking PKR2 signaling to ZO-1 not identified
  6. 2011 High

    Pinpointed an IL2 residue (R164) as a charge-dependent determinant of G-protein coupling, resolving how a disease mutation abolishes signaling without trafficking or ligand-binding defects.

    Evidence Charge-substitution mutagenesis with direct Gα binding and endocytosis assays

    PMID:21454486

    Open questions at the time
    • Structural basis of the IL2-Gα interaction not determined
    • Did not address β-arrestin coupling at this residue
  7. 2013 Medium

    Mapped IL3 as a bifunctional segment in which separate motifs independently govern trafficking versus G-protein coupling.

    Evidence Deletion and substitution mutagenesis with surface-expression and signaling assays

    PMID:23969157

    Open questions at the time
    • Single lab; structural mechanism of the RKR/RRK switch unresolved
    • Did not connect IL3 motifs to specific Gα subtypes
  8. 2013 Medium

    Demonstrated that single disease alleles can differentially impair Gq versus Gs cascades, refining mutation interpretation beyond binary loss-of-function.

    Evidence Parallel IP/Ca2+ and cAMP assays across multiple variants in HEK-293 cells

    PMID:24276467

    Open questions at the time
    • Single lab; did not test β-arrestin recruitment
    • Functional consequences in neurons not assessed
  9. 2014 High

    Established PROKR2 as a multi-G-protein receptor exhibiting mutation-induced biased agonism, with distinct alleles selectively losing Gq, β-arrestin, or Gi/o coupling.

    Evidence Parallel Gq/Gs/Gi/o and β-arrestin recruitment assays with systematic mutagenesis

    PMID:24830383

    Open questions at the time
    • Physiological readout of each biased profile not established in vivo
    • Structural basis of biased coupling unresolved
  10. 2014 High

    Defined the internalization route and an ERK-activation mechanism, showing endocytosis is GRK2/clathrin-dependent but β-arrestin-independent while ERK requires Gβγ and PLC-β/MEK.

    Evidence Dominant-negative constructs, siRNA, inhibitors, and ERK/endocytosis assays in transfected cells

    PMID:24509228

    Open questions at the time
    • Single lab; in vivo relevance of these routes not tested
    • Adaptor linking GRK2 to clathrin not identified
  11. 2014 Medium

    Provided proof-of-concept for pharmacological rescue of trafficking-defective mutants, with mutant-specific responsiveness to a small-molecule pharmacochaperone versus a chemical chaperone.

    Evidence Rescue with antagonist A457 and glycerol, surface-expression and signaling readouts

    PMID:24753254

    Open questions at the time
    • Single lab; rescue not demonstrated in vivo
    • Mechanism of mutant-selective rescue not resolved
  12. 2015 Medium

    Identified snapin as a C-terminal binding partner that regulates receptor stability rather than signaling, expanding the trafficking-control machinery.

    Evidence Yeast two-hybrid, GST pull-down, Co-IP, and motif-mapping mutagenesis

    PMID:26687946

    Open questions at the time
    • Single lab; physiological role of snapin in PROKR2 function not tested in vivo
    • How snapin slows ligand-induced degradation mechanistically unclear
  13. 2017 Medium

    Uncovered a paradoxical gain-of-function mechanism in which a signaling-dead truncated receptor enhances wild-type receptor activity, challenging simple loss-of-function interpretation.

    Evidence Co-transfection of frameshift mutant with wild-type PROKR2 and Ca2+ signaling assays

    PMID:28338294

    Open questions at the time
    • Single lab; molecular basis of WT enhancement not defined
    • In vivo phenotype of the gain-of-function allele not established
  14. 2018 Medium

    Showed that co-expression assays modeling heterozygosity reveal dominant-negative and dominant alleles missed by mutant-alone testing, improving variant pathogenicity classification.

    Evidence Co-transfection of 59 variants across three signaling pathways

    PMID:29161432

    Open questions at the time
    • Single lab; in vitro classification not validated against clinical penetrance
    • Structural basis of dominant-negative interference not resolved
  15. 2018 High

    Demonstrated biochemically that selective disruption of IL3-Gαq binding underlies biased signaling, with R270H losing Gαq but retaining Gαs/ERK.

    Evidence GST pull-down with Gαq and Gαs plus pathway-specific signaling assays

    PMID:30576231

    Open questions at the time
    • Structural model of the IL3-Gαq interface not determined
    • In vivo consequence of selective Gαq loss not tested
  16. 2019 High

    Established the cell-type identity and migratory requirement of PROKR2 in OB interneurons, localizing expression to postmitotic neuroblasts and quantifying interneuron loss upon disruption.

    Evidence Prokr2-LacZ knockin and Prok2-EGFP transgenic mice with lineage analysis, ISH, and cell counting

    PMID:31132148

    Open questions at the time
    • Did not define the intracellular signaling pathway for tangential vs radial migration
    • Source and gradient of PROK2 guiding migration not mapped
  17. 2021 Medium

    Identified glycosylation as a trafficking and pathway-selectivity determinant, with N27 required for surface delivery and N7 selectively tuning Gαs signaling, and MRAP2 as a negative trafficking regulator.

    Evidence Glycosylation-site mutagenesis with surface-expression and Gαs/Gαq signaling assays

    PMID:34483834

    Open questions at the time
    • Single lab; MRAP2 regulation not validated in neurons in vivo
    • Mechanism by which N7 glycan biases Gαs unresolved
  18. 2021 Medium

    Defined PROKR2 as the receptor mediating EG-VEGF-induced trophoblast invasion via ERK1/2 and MMP-2/9 upregulation, extending its role to placentation.

    Evidence Antibody blockade of PROKR2 vs PROKR1 in HTR-8/SVneo cells with signaling and invasion assays

    PMID:34955534

    Open questions at the time
    • Single lab; in vivo placental requirement not tested
    • Did not establish G-protein link to the ERK/MMP cascade in this context
  19. 2022 High

    Resolved the post-ER quality-control fate of a trafficking-defective mutant, showing P290S cycles between ER and Golgi, undergoes enhanced ERAD, and assembles a distinct interactome.

    Evidence Mass-spec interactomics, ERAD and ER-to-Golgi trafficking assays, and ER stress measurements

    PMID:35173048

    Open questions at the time
    • Specific chaperones controlling the ER-Golgi cycle not pinpointed functionally
    • Whether other trafficking mutants share this fate not established
  20. 2022 Medium

    Identified Gαq as the primary effector for PROKR2-driven cell migration, mechanistically linking the migration phenotype to a specific signaling arm relevant to IHH.

    Evidence Pathway-specific pharmacological inhibition with migration assays in PROKR2-expressing cells

    PMID:36694982

    Open questions at the time
    • Single lab; not validated in primary GnRH neurons
    • Downstream cytoskeletal effectors of Gαq not identified
  21. 2025 Medium

    Established a physical and functional TRPV1-PROKR2 interaction, strengthened by snapin, that modulates receptor activation, localization, β-arrestin recruitment, and pain behavior, integrating PROKR2 into nociceptive channel signaling.

    Evidence Co-IP/interaction mapping, snapin co-expression, signaling/localization assays, and in vivo allodynia assay

    PMID:40139621

    Open questions at the time
    • Single lab; structural basis of the TRPV1-PROKR2 interface not determined
    • Whether the interaction occurs in defined sensory neuron subtypes in vivo not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PROKR2's diverse signaling outputs (Gq, Gs, Gi/o, β-arrestin) are selected and spatially organized in vivo to produce its distinct developmental, circadian, and nociceptive functions remains unresolved.
  • No high-resolution structure of PROKR2 or its Gα/effector complexes
  • Tissue-specific determinants of biased signaling not mapped
  • Endogenous regulation by MRAP2, snapin, and TRPV1 not validated in native cells in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-9909396 Circadian clock 1
Partners
GNAQGRK2MRAP2PROK2SNAPINTRPV1

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 PKR2 knockout mice exhibit hypoplasia of the olfactory bulb and severe atrophy of the reproductive system, with absence of GnRH neurons in the hypothalamus and reduced plasma testosterone and gonadotropin levels, establishing that PROKR2 signaling is essential for olfactory bulb development and GnRH neuron positioning/function. Targeted gene knockout (Pkr2-/- mice), immunohistochemistry, hormone assays, mRNA quantification Proceedings of the National Academy of Sciences of the United States of America High 16537498
2007 Prokr2 null mice lose precision in circadian locomotor activity onset and show redistribution of activity across circadian night and depressed nocturnal body temperature, but their SCN circadian oscillator remains intact; demonstrating PROKR2 is required for SCN-to-behavior circadian output but not for cellular timekeeping or light entrainment. Targeted null mutation, locomotor activity monitoring under LD and DD, bioluminescence real-time imaging of SCN slices Proceedings of the National Academy of Sciences of the United States of America High 17202262
2007 Prokr2 null mice show decreased OB volume, reduced BrdU+ proliferating cells, TUNEL+ cells in the glomerular layer, decreased TH+ neurons, accumulation of doublecortin+ neuroblasts in the RMS, and Prokr2-deficient neurosphere cells fail to migrate toward PROK2 in vitro; establishing PROKR2 as necessary for neuronal progenitor migration and differentiation into the olfactory bulb. Prokr2 null mouse analysis, BrdU labeling, TUNEL, immunohistochemistry, in vitro neurosphere migration assay The European journal of neuroscience High 18052978
2008 Ten KS-associated PROKR2 missense mutations impair receptor signaling via distinct mechanisms: three (L173R, W178S, P290S) impair cell surface targeting; one (Q210R) abolishes ligand binding; five (R85C, R85H, R164Q, R268C, V331M) impair G protein coupling; none exert dominant negative effects on co-expressed wild-type receptor. Site-directed mutagenesis of recombinant murine Prokr2, transfection in HEK-293 cells, intracellular calcium release assay, cell surface expression assays Human molecular genetics High 18826963
2011 The R164Q disease-causing mutation in the second intracellular loop (IL2) of PKR2 abolishes signaling without affecting cell surface expression or ligand binding; R164 is required for interaction of the IL2 loop with Gαq, Gαi, and Gα16 proteins, and a positive charge at position 164 is essential; R164Q also reduces ligand-induced endocytosis. Site-directed mutagenesis, transfection assays, G-protein binding studies, endocytosis assays, charge-substitution series The Journal of biological chemistry High 21454486
2014 Wild-type PROKR2 activates Gq, Gs, and Gi/o signaling pathways and recruits β-arrestins; KS-associated mutations cause pathway-selective signaling bias: R85C, R85H, R164Q, V331M lose Gq signaling but retain β-arrestin recruitment; R80C activates all three G proteins but cannot recruit β-arrestins; R268C can recruit β-arrestins and activate Gq/Gs but not Gi/o. Transfection in HEK-293 cells, pathway-specific signaling assays (Gq, Gs, Gi/o, β-arrestin recruitment), site-directed mutagenesis FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 24830383
2014 PKR2 endocytosis is GRK2-dependent and clathrin-dependent, but β-arrestin-independent; PKC activation can also induce PKR2 endocytosis but is not necessary for ligand-induced endocytosis; PK2-induced ERK1/2 activation requires Gβγ subunits and PLC-β/MEK but not receptor internalization or PKC. Dominant-negative constructs, siRNA knockdown, pharmacological inhibitors, ERK1/2 phosphorylation assays, endocytosis assays in transfected cells Cellular signalling High 24509228
2014 The small molecule PKR2 antagonist A457 rescues cell surface expression and function of the P290S trafficking-deficient mutant but not W178S or G234D mutants; glycerol (chemical chaperone) rescues surface expression and signaling of both P290S and W178S mutants. Pharmacological rescue with small molecule antagonist and chemical chaperone, cell surface expression assays, functional signaling assays in transfected cells The Journal of biological chemistry Medium 24753254
2015 Snapin is a novel binding partner of PKR2, interacting via the PKR2 C-terminus (YFK 343-345 and HWR 351-353 motifs) and two α-helix domains of Snapin; disruption of Snapin-PKR2 interaction does not affect PKR2 signaling but increases ligand-induced receptor degradation, indicating Snapin regulates PKR2 trafficking/stability. Yeast two-hybrid screening, GST pull-down, co-immunoprecipitation, mutagenesis mapping of interaction motifs Biochemical and biophysical research communications Medium 26687946
2013 The distal region of the third intracellular loop (IL3) of PROKR2 differentially controls receptor trafficking and G-protein coupling: deletion of RRK (270-272) abolishes cell surface expression, whereas deletion of RKR (264-266) preserves surface expression but causes loss of G-protein coupling; charged residue at V274 is required for normal surface expression. Site-directed mutagenesis, deletion analysis, cell surface expression assays, functional signaling assays in transfected cells Biochemical and biophysical research communications Medium 23969157
2018 IHH-associated PROKR2 mutations L218P and R270H disrupt Gαq-dependent signaling while maintaining normal Gαs and ERK1/2 signaling; GST pull-down demonstrated that R270H specifically disrupts the interaction of intracellular loop 3 of PROKR2 with Gαq but not Gαs protein, establishing that selective Gα-coupling disruption underlies biased signaling in some mutations. Site-directed mutagenesis, pathway-specific signaling assays, GST pull-down with Gαq and Gαs proteins FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 30576231
2013 Multiple PROKR2 missense variants differentially affect Gq (IP/Ca2+) and Gs (cAMP) signaling pathways: variants T260M, R268C, V331M show preserved cAMP response but impaired IP signaling; L173R and V274D lack cAMP response; V334M (gain of expression) elevates EC50 for both pathways; demonstrating single allelic variants can selectively or differentially impair distinct PROKR2 signaling cascades. Transfection in HEK-293 cells, IP/Ca2+ assay (Gq), cAMP accumulation assay (Gs), surface expression quantification The Journal of clinical endocrinology and metabolism Medium 24276467
2008 Transgenic overexpression of PKR2 in cardiomyocytes induces eccentric cardiac hypertrophy (increased hypertrophic gene expression, increased heart-to-body weight ratio, increased cardiomyocyte length) and vascular leakage through mislocalization of tight junction protein ZO-1, without inducing angiogenesis; conditioned media from PKR2-overexpressing cardioblasts recapitulates impaired ZO-1 localization in endothelial cells, indicating paracrine signaling. Transgenic mouse generation, morphological and echocardiographic analysis, immunofluorescence for ZO-1, vascular leakage assay, conditioned media experiment in H5V endothelial cells Cardiovascular research Medium 18806277
2019 PROK2/PROKR2 signaling is required for both tangential and radial migration of olfactory bulb interneurons; Prokr2 is expressed in postmitotic immature interneurons in the SVZ-RMS-OB; loss of Prok2 or Prokr2 causes loss of ~75% of GABAergic interneurons in the OB due to migration failure. Prokr2-LacZ knockin mice, Prok2-EGFP transgenic mice, cell lineage analysis, in situ hybridization, quantitative cell counting The Journal of comparative neurology High 31132148
2021 N-linked glycosylation at position N27 of PKR2 is required for plasma membrane localization and signaling; glycosylation at position N7 selectively reduces PKR2 signaling through Gαs without impairing Gαq/11 signaling; MRAP2 prevents PKR2 from trafficking to the plasma membrane. Site-directed mutagenesis of glycosylation sites, cell surface expression assays, pathway-specific signaling assays (Gαs/cAMP, Gαq/Ca2+) Frontiers in neuroscience Medium 34483834
2022 Trafficking-defective P290S PROKR2 mutant cycles between the ER and Golgi rather than reaching the cell surface; both WT and P290S mutant undergo ER-associated degradation, but the mutant is degraded to greater extent; the post-ER cycling of the mutant to the Golgi reduces ER stress; distinct interactomes were identified for WT versus P290S PROKR2. Interactome analysis (MS), ER-associated degradation assays, ER-to-Golgi trafficking assays, ER stress measurements, pharmacological perturbations Proceedings of the National Academy of Sciences of the United States of America High 35173048
2017 A heterozygous frameshift PROKR2 mutation generating a truncated receptor lacking two transmembrane domains and the C-terminal tail has no intrinsic signaling activity in vitro, but cells co-expressing this mutant with wild-type PROKR2 show markedly exaggerated ligand-induced Ca2+ responses, establishing a paradoxical gain-of-function mechanism via enhancement of wild-type receptor activity. Frameshift mutation identification, in vitro signaling assays (Ca2+ response) in cells transfected with mutant alone or co-transfected with wild-type PROKR2 Journal of cellular and molecular medicine Medium 28338294
2018 In vitro co-transfection of mutant with wild-type PROKR2 (modeling heterozygosity) identified 15/34 IGD-associated variants as loss-of-function including 3 novel dominant negatives, while only 4/25 control variants were LoF; variants LoF in ≥2 signaling assays under co-transfection conditions were more likely disease-associated, revealing dominant-negative and dominant mechanisms not detected by mutant-alone assays. Co-transfection assays modeling heterozygosity, three parallel signaling pathway assays, comparison of 59 variants Human molecular genetics Medium 29161432
2010 C. trachomatis infection increases PROKR2 mRNA in fallopian tube epithelial cells via TLR2 ligation and NFκB activation; transfection with dominant-negative TLR2 or IκBα abrogated the C. trachomatis-induced PROKR2 upregulation, placing PROKR2 downstream of TLR2/NFκB in this inflammatory signaling cascade. C. trachomatis infection of fallopian tube explants and OE-E6/E7 cell line, dominant-negative TLR2 and IκBα transfection, mRNA quantification The American journal of pathology Medium 21224062
2021 EG-VEGF activates ERK1/2 signaling and upregulates MMP-2 and MMP-9 in HTR-8/SVneo trophoblast cells, promoting cell migration and invasion; anti-PROKR2 antibody (but not anti-PROKR1) suppresses ERK1/2 activation and inhibits EG-VEGF-stimulated migration and invasion, establishing PROKR2 as the receptor mediating EG-VEGF-induced trophoblast invasion via ERK1/2/MMP pathway. Antibody blocking of PROKR2 and PROKR1 in HTR-8/SVneo cells, ERK1/2 phosphorylation assay, MMP-2/9 qRT-PCR and western blot, wound-healing and invasion assays Acta medica Okayama Medium 34955534
2019 Pkr2-null mice show reduced nociceptive sensitization to heat (46-48°C), capsaicin, and protons (TRPV1 agonists), and reduced response to cold and mustard oil (TRPA1 agonists); DRG culture analysis shows the percentage of Bv8-responsive neurons also responsive to mustard oil is much higher in PKR1-/- than PKR2-/- mice, establishing functional interactions between PKR2 and both TRPV1 and TRPA1 in nociception. Pkr2-/- mouse behavioral nociception assays, DRG primary neuron culture, capsaicin/proton/mustard oil/cold stimulation, comparison with PKR1-/- mice Neuroscience Medium 31883821
2025 TRPV1 physically interacts with PKR2; in the presence of snapin, the strength of the TRPV1-PKR2 interaction is increased; TRPV1 modulates PKR2 activation, subcellular localization, and β-arrestin-2 recruitment, and regulates PK2-induced mechanical allodynia in vivo. Co-immunoprecipitation/interaction mapping, snapin co-expression experiments, PKR2 localization and signaling assays, in vivo allodynia assay Cellular signalling Medium 40139621
2022 Blockage of Gαq signaling, but not the MAPK/ERK pathway, inhibits PROK2-induced migration of PROKR2-expressing cells, establishing that Gαq is the primary downstream effector of PROKR2 mediating GnRH neuron migration-related signaling relevant to IHH pathogenesis. Pathway-specific pharmacological inhibition combined with cell migration assay in PROKR2-expressing cells Human molecular genetics Medium 36694982

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proceedings of the National Academy of Sciences of the United States of America 224 16537498
2007 Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proceedings of the National Academy of Sciences of the United States of America 123 17202262
2008 The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 118 18987492
2008 PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Human molecular genetics 100 18826963
2012 PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption. The Journal of clinical endocrinology and metabolism 64 22466334
2007 Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation. The European journal of neuroscience 59 18052978
2010 Chlamydia trachomatis infection increases fallopian tube PROKR2 via TLR2 and NFκB activation resulting in a microenvironment predisposed to ectopic pregnancy. The American journal of pathology 53 21224062
2013 PROK2/PROKR2 Signaling and Kallmann Syndrome. Frontiers in endocrinology 51 23596439
2010 Kallmann syndrome caused by mutations in the PROK2 and PROKR2 genes: pathophysiology and genotype-phenotype correlations. Frontiers of hormone research 47 20389090
2013 Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. The Journal of clinical endocrinology and metabolism 42 23386640
2007 Placental expression of EG-VEGF and its receptors PKR1 (prokineticin receptor-1) and PKR2 throughout mouse gestation. Placenta 42 17531315
2009 Possible association of prokineticin 2 receptor gene (PROKR2) with mood disorders in the Japanese population. Neuromolecular medicine 41 19544013
2014 Biased signaling through G-protein-coupled PROKR2 receptors harboring missense mutations. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 24830383
2017 Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome. The Journal of clinical endocrinology and metabolism 38 28453858
2015 FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies. Endocrine connections 35 25759380
2008 Transgenic myocardial overexpression of prokineticin receptor-2 (GPR73b) induces hypertrophy and capillary vessel leakage. Cardiovascular research 35 18806277
2012 An ancient founder mutation in PROKR2 impairs human reproduction. Human molecular genetics 29 22773735
2013 Germline prokineticin receptor 2 (PROKR2) variants associated with central hypogonadism cause differental modulation of distinct intracellular pathways. The Journal of clinical endocrinology and metabolism 28 24276467
2019 The PROK2/PROKR2 signaling pathway is required for the migration of most olfactory bulb interneurons. The Journal of comparative neurology 27 31132148
2018 PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Gα-protein leads to biased signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 30576231
2017 Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty. Journal of cellular and molecular medicine 24 28338294
2011 Expression of PROKR1 and PROKR2 in human enteric neural precursor cells and identification of sequence variants suggest a role in HSCR. PloS one 23 21858136
2018 Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency. Human molecular genetics 21 29161432
2013 Greater prevalence of PROKR2 mutations in Kallmann syndrome patients from the Maghreb than in European patients. European journal of endocrinology 21 24031091
2012 PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency. European journal of endocrinology 20 23082007
2017 Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model. Brain structure & function 19 28616754
2014 Mechanisms that underlie the internalization and extracellular signal regulated kinase 1/2 activation by PKR2 receptor. Cellular signalling 19 24509228
2012 PROKR2 mutations in autosomal recessive Kallmann syndrome. Fertility and sterility 19 23200691
2011 Disease-causing mutation in PKR2 receptor reveals a critical role of positive charges in the second intracellular loop for G-protein coupling and receptor trafficking. The Journal of biological chemistry 19 21454486
2024 Targeting JAK2/STAT3, NLRP3/Caspase-1, and PK2/PKR2 Pathways with Arbutin Ameliorates Lead Acetate-Induced Testicular Injury in Rats. Pharmaceuticals (Basel, Switzerland) 18 39065759
2019 Abnormal Pain Sensation in Mice Lacking the Prokineticin Receptor PKR2: Interaction of PKR2 with Transient Receptor Potential TRPV1 and TRPA1. Neuroscience 16 31883821
2014 Functional rescue of Kallmann syndrome-associated prokineticin receptor 2 (PKR2) mutants deficient in trafficking. The Journal of biological chemistry 16 24753254
2010 PROKR2 is associated with methamphetamine dependence in the Japanese population. Progress in neuro-psychopharmacology & biological psychiatry 15 20576534
2013 Prokineticin receptor variants (PKR1-I379V and PKR2-V331M) are protective genotypes in human early pregnancy. Reproduction (Cambridge, England) 14 23687280
2015 Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation. Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 13 25678757
2021 Control of hippocampal prothrombin kringle-2 (pKr-2) expression reduces neurotoxic symptoms in five familial Alzheimer's disease mice. British journal of pharmacology 11 34524687
2021 Role of N-Linked Glycosylation in PKR2 Trafficking and Signaling. Frontiers in neuroscience 10 34483834
2013 Functional analysis of the distal region of the third intracellular loop of PROKR2. Biochemical and biophysical research communications 10 23969157
2021 Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism. Frontiers in genetics 9 34539727
2018 Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its receptor PROKR2 are associated to human colorectal cancer progression and peritoneal carcinomatosis. Cancer biomarkers : section A of Disease markers 9 29226856
2013 Multiplex ligation dependent probe amplification analysis of KAL1, GNRH1, GNRHR, PROK2 and PROKR2 in male patients with idiopathic hypogonadotropic hypogonadism. Endokrynologia Polska 9 24002956
2021 Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty. Italian journal of pediatrics 8 33413516
2017 A heterozygous microdeletion of 20p12.2-3 encompassing PROKR2 and BMP2 in a patient with congenital hypopituitarism and growth hormone deficiency. American journal of medical genetics. Part A 7 28586151
2017 Kallmann syndrome with a Tyr113His PROKR2 mutation. Medicine 7 28858133
2015 Snapin interacts with G-protein coupled receptor PKR2. Biochemical and biophysical research communications 7 26687946
2023 Phenotypic and genotypic landscape of PROKR2 in neuroendocrine disorders. Frontiers in endocrinology 6 36843573
2021 Pressure Overload-Mediated Sustained PKR2 (Prokineticin-2 Receptor) Signaling in Cardiomyocytes Contributes to Cardiac Hypertrophy and Endotheliopathies. Hypertension (Dallas, Tex. : 1979) 6 33677981
2021 Comparison of Clinical Characteristics and Spermatogenesis in CHH Patients Caused by PROKR2 and FGFR1 Mutations. Reproductive sciences (Thousand Oaks, Calif.) 6 33983622
2009 Cloning and developmental expression analysis of prokineticin 2 and its receptor PKR2 in the Syrian hamster surpachiasmatic nucleus. Brain research 6 19327346
2023 pKr-2 induces neurodegeneration via upregulation of microglial TLR4 in the hippocampus of AD brain. Brain, behavior, & immunity - health 5 36798617
2016 Association between polymorphisms of prokineticin receptor (PKR1 rs4627609 and PKR2 rs6053283) and recurrent pregnancy loss. Journal of Zhejiang University. Science. B 5 26984842
2023 A functional spectrum of PROKR2 mutations identified in isolated hypogonadotropic hypogonadism. Human molecular genetics 4 36694982
2023 PROKR2 Mutations in Patients with Short Stature Who Have Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiency. Journal of clinical research in pediatric endocrinology 4 37338295
2022 Trafficking-defective mutant PROKR2 cycles between endoplasmic reticulum and Golgi to attenuate endoplasmic reticulum stress. Proceedings of the National Academy of Sciences of the United States of America 4 35173048
2024 Additional mutation in PROKR2 and phenotypic differences in a Kallmann syndrome/normosmic congenital hypogonadotropic hypogonadism family carrying FGFR1 missense mutation. BMJ case reports 3 38272512
2022 Biallelic PROKR2 variants and congenital hypogonadotropic hypogonadism: a case report and a literature review. Endocrine journal 3 35236788
2021 EG-VEGF Induces Invasion of a Human Trophoblast Cell Line via PROKR2. Acta medica Okayama 3 34955534
2017 PKR2 and β-catenin genes regulates pancreatic cancer chemosensitivity. European review for medical and pharmacological sciences 3 28121357
2025 Physical TRPV1-PKR2 interaction modulates PKR2 localization, activation and β-arrestin-2 recruitment. Cellular signalling 1 40139621
2022 [Analysis of PROKR2 gene mutation in patients with hypogonadotropic hypogonadism]. Zhonghua nei ke za zhi 1 35922219
2025 Expanding the phenotypic spectrum of PROK2/PROKR2: a recall-by-genotype study. Human genetics 0 40498399
2024 46 XX Ovotesticular Disorder of Sex Development with Gonadotropin-Releasing Hormone Receptor, Autosomal Recessive Heterozygous Missense Mutation and Autosomal Dominant Heterozygous Missense Mutation of the PROKR2 Gene: A Case Report. Global medical genetics 0 38988852

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