Affinage

PROK2

Prokineticin-2 · UniProt Q9HC23

Length
129 aa
Mass
14.3 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PROK2 (prokineticin 2/Bv8) is a small secreted signaling protein with a conserved N-terminal AVITGA hexapeptide and five disulfide bonds that acts through the GPCRs PROKR1 and PROKR2 to coordinate nociception, myeloid/hematopoietic mobilization, angiogenesis, and CNS circuit development (PMID:12466223, PMID:16113687, PMID:20677202). Structure-activity work establishes that receptor activation depends critically on the N-terminus: deletion of the first residues abolishes activity and yields a partial antagonist, while the core disulfide-stabilized fold (homologous to mamba intestinal toxin 1) is dispensable for binding, indicating a cooperative N-terminal interaction with the receptor (PMID:16113687, PMID:20677202). In the somatosensory system PROK2 drives nociceptive sensitization by binding PKR1/PKR2 on small-diameter DRG neurons, raising intracellular Ca2+ and sensitizing TRPV1 through PKCε translocation, and by acting peripherally on polymodal C-fibers and centrally in the spinal cord and descending PAG/RVM circuitry to release CGRP, substance P, and GABA (PMID:12466223, PMID:16687502, PMID:18005070, PMID:22641053, PMID:26914965); this pathway contributes to inflammatory and neuropathic pain involving neuron–glia interaction (PMID:19667192, PMID:24902717). As a myeloid effector, PROK2 is induced in CD11b+Gr1+ cells by G-CSF via direct STAT3 binding to its promoter, mobilizes neutrophils and monocytes, and promotes tumor angiogenesis; PROK2 in turn signals through JAK2 to activate STAT3 in myeloid cells, and it stimulates endothelial cell proliferation, survival, and migration to drive tissue-selective angiogenesis (PMID:15548611, PMID:18064003, PMID:18268320, PMID:22528488, PMID:23548897, PMID:12604792). PROK2 also supports neuronal survival via MAPK and PI3K/Akt pathways (PMID:11359521), is required via PROKR2 for migration of olfactory bulb GABAergic interneurons (PMID:31132148), mediates anorexigenic signaling through amygdala PKR2 neurons (PMID:36539034), and its circadian expression in the SCN is maintained downstream of TTX-sensitive neural activity rather than in the core oscillator (PMID:18279366).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1999 Medium

    Established that the Bv8/prokineticin peptide is a bioactive signaling molecule capable of smooth-muscle contraction and central nociceptive modulation, defining its core pharmacology before receptors were known.

    Evidence In vivo icv injection and guinea-pig ileum contraction bioassay

    PMID:10422759

    Open questions at the time
    • No receptor identified
    • Mammalian ortholog function not yet addressed
  2. 1999 Medium

    Identified the mammalian PROK2 gene and its restricted testicular expression with alternative splice forms, providing the molecular entity behind the amphibian bioactivity.

    Evidence cDNA cloning, in situ hybridization, Northern blot in mouse testis

    PMID:10580115

    Open questions at the time
    • Functional role of splice variants unresolved
    • No receptor or signaling pathway defined
  3. 2001 Medium

    Showed PROK2 promotes neuronal survival, extending its role beyond contraction/pain to trophic signaling via MAPK and PI3K/Akt.

    Evidence Primary neuron survival assays with PD98059/LY294002 inhibition and phospho-Western blots

    PMID:11359521

    Open questions at the time
    • Receptor identity not established in this system
    • In vivo relevance not tested
  4. 2002 High

    Defined high-affinity binding to PKR1/PKR2 and Ca2+ mobilization in DRG neurons as the mechanism linking PROK2 to systemic nociceptive sensitization.

    Evidence Radioligand binding, calcium imaging, in vivo behavioral pharmacology

    PMID:12466223

    Open questions at the time
    • Downstream ion-channel target not yet identified
    • Relative PKR1 vs PKR2 contribution unresolved
  5. 2003 High

    Demonstrated direct angiogenic activity of PROK2 on endothelial cells and in vivo, establishing a vascular function distinct from neuronal signaling.

    Evidence Endothelial proliferation/survival/migration assays, adenoviral delivery, receptor immunolocalization

    PMID:12604792

    Open questions at the time
    • Tissue selectivity mechanism not defined
    • Receptor subtype on endothelium not dissected
  6. 2004 High

    Established PROK2 as a hematopoietic/myeloid factor that drives granulocyte and monocyte differentiation and mobilization, broadening its role to immune cell biology.

    Evidence CFU assays, in vivo adenoviral delivery, leukocyte counts, pertussis-toxin-sensitive migration

    PMID:15548611

    Open questions at the time
    • Transcriptional regulator of PROK2 in myeloid cells unknown
    • Receptor subtype not yet resolved
  7. 2005 High

    Mapped the N-terminal AVITGA hexapeptide as essential for receptor activation, with des-Ala-Val-Bv8 acting as a partial antagonist, providing the first structure-activity framework.

    Evidence N-terminal deletion mutants tested by binding, Ca2+, MAPK in CHO-PKR cells and in vivo hyperalgesia

    PMID:16113687

    Open questions at the time
    • Structural basis of N-terminal engagement not yet solved
    • Receptor-subtype selectivity of mutants limited
  8. 2006 High

    Defined the molecular nociceptor mechanism: PROK2 sensitizes TRPV1 via PKCε translocation, explaining its hyperalgesic action at the channel level.

    Evidence Patch-clamp, PKCε translocation imaging, PKC antagonists, behavioral assay

    PMID:16687502

    Open questions at the time
    • Receptor coupling to PKCε not fully mapped
    • Contribution of PKR1 vs PKR2 in nociceptors unresolved
  9. 2006 High

    Identified PKR1 (not pertussis-toxin-sensitive, U73122-blocked) as the receptor mediating macrophage chemotaxis and proinflammatory polarization, dissecting receptor-specific immune effects.

    Evidence Macrophage chemotaxis, cytokine ELISA, PT/U73122 inhibition, PKR1 knockout mice

    PMID:16299550

    Open questions at the time
    • Gq coupling inferred pharmacologically, not directly measured
    • Downstream transcriptional program undefined
  10. 2007 High

    Connected PROK2 to tumor biology by showing G-CSF-driven Bv8 in CD11b+Gr1+ cells mediates myeloid mobilization and tumor angiogenesis, defining a therapeutically targetable axis.

    Evidence Adenoviral delivery, anti-Bv8 neutralizing antibody, FACS, tumor growth/vascular density in multiple models

    PMID:18064003

    Open questions at the time
    • Direct STAT3-promoter mechanism not yet shown
    • Receptor on endothelium vs myeloid cells not separated
  11. 2007 Medium

    Localized a descending pain mechanism to GABAergic signaling in the PAG and RVM On/Off-cell modulation, expanding PROK2's pronociceptive action to supraspinal circuits.

    Evidence Intra-PAG injection, microdialysis, RVM electrophysiology, tail-flick test

    PMID:18005070

    Open questions at the time
    • Receptor subtype in PAG not defined
    • Cellular source of GABA effect unresolved
  12. 2008 Medium

    Showed PKR1-dependent modulation of lymphocyte cytokines toward a Th1 profile, establishing receptor-specific adaptive immune effects.

    Evidence Splenocyte cytokine ELISA, in vivo immunization, PROKR1 knockout mice

    PMID:18957080

    Open questions at the time
    • Direct vs indirect action on T cells not separated
    • Signaling pathway in lymphocytes undefined
  13. 2008 High

    Demonstrated in an endogenous transgenic tumor model that anti-Bv8 reduces angiogenic switching and links PROK2 to neutrophil-dependent angiogenesis.

    Evidence Anti-Bv8 antibody in RIP-Tag mice, vascular histology, FACS

    PMID:18268320

    Open questions at the time
    • Molecular link between neutrophils and vessel formation not detailed
    • Receptor mediating endothelial response not identified
  14. 2008 Medium

    Placed PK2 circadian expression downstream of TTX-sensitive SCN neural activity rather than in the core clock, clarifying its position as an output signal.

    Evidence SCN slice culture, TTX treatment, in situ hybridization of 13 genes

    PMID:18279366

    Open questions at the time
    • Mechanism coupling activity to PK2 transcription unknown
    • Receptor mediating circadian output not defined
  15. 2009 High

    Established endogenous granulocyte-derived PROK2 as a driver of inflammatory hypernociception and identified PKR1 as a regulator of PK2 levels during inflammation using dual-receptor knockouts.

    Evidence Granulocyte protein purification, PKR1/PKR2 knockouts, CFA model, antagonist dose-response

    PMID:19667192

    Open questions at the time
    • Feedback mechanism controlling PK2 upregulation unresolved
    • Relative spinal vs peripheral contribution not fully separated
  16. 2010 High

    Solved the NMR structure and showed the core fold is dispensable for binding while N-terminal truncation abolishes activity, refining the structural model of receptor engagement.

    Evidence Chemical synthesis, NMR structure, functional assay of truncation mutant

    PMID:20677202

    Open questions at the time
    • Receptor-bound structure not determined
    • Atomic contacts of N-terminus with receptor unknown
  17. 2010 Medium

    Identified Trp24 as a residue important for receptor interaction, adding a second determinant beyond the N-terminus.

    Evidence W24A mutagenesis, Pichia recombinant expression, binding assay

    PMID:20412858

    Open questions at the time
    • Single-method functional readout
    • Receptor-subtype selectivity of W24A not addressed here
  18. 2012 High

    Demonstrated phospho-STAT3 binds the Bv8 promoter as a functional enhancer downstream of G-CSF, establishing the direct transcriptional control of PROK2 in myeloid cells.

    Evidence siRNA, WP1066, ChIP, luciferase reporter, in vivo validation

    PMID:22528488

    Open questions at the time
    • Additional cofactors at the promoter not mapped
    • Cell-type specificity of regulation not fully defined
  19. 2012 Medium

    Dissected biphasic hyperalgesia into an early CGRP-release phase and a late protein-synthesis-dependent phase with CGRP/substance P upregulation, mechanistically separating acute and delayed sensitization.

    Evidence Ex vivo CGRP release, protein synthesis inhibitors, CGRP/SP immunohistochemistry

    PMID:22641053

    Open questions at the time
    • Genes induced in the late phase not identified
    • Receptor subtype driving each phase unresolved
  20. 2012 Medium

    Generated a PKR2-preferring W24A analog that antagonizes hyperalgesia and engages central opioid (β-endorphin) pathways, demonstrating receptor-biased pharmacology with analgesic potential.

    Evidence Receptor binding, inflammatory/post-surgical pain models, β-endorphin radioimmunoassay

    PMID:22122547

    Open questions at the time
    • Mechanism of central opioid recruitment via PKR2 not detailed
    • Selectivity margin in vivo not fully quantified
  21. 2013 High

    Showed PROK2 signals through JAK2 to activate STAT3 in myeloid cells, creating a feed-forward autocrine loop that sustains angiogenic/proliferative gene expression and tumor growth.

    Evidence JAK2 inhibition/knockdown, BV8 shRNA, STAT3 Western blot, xenograft growth

    PMID:23548897

    Open questions at the time
    • Receptor subtype linking PROK2 to JAK2 not specified
    • Direct receptor-JAK2 coupling not biochemically resolved
  22. 2014 Medium

    Implicated PROK2/PKR2 signaling in neuropathic pain through neuron-glia interaction, with antagonism reducing microgliosis and restoring cytokine balance.

    Evidence CCI model, PKR antagonist (PC1) by multiple routes, immunohistochemistry, cytokine measurement

    PMID:24902717

    Open questions at the time
    • Cellular source vs target of PROK2 in glia not separated
    • Causal step from glial activation to hyperalgesia not proven
  23. 2016 Medium

    Provided direct evidence that PROK2 sensitizes peripheral polymodal C-fibers to heat and enhances cutaneous CGRP release, pinpointing the peripheral mechanism of the first hyperalgesic phase.

    Evidence Single-fiber skin-nerve electrophysiology, CGRP release from skin, immunohistochemistry

    PMID:26914965

    Open questions at the time
    • Channel target in C-fibers not directly identified here
    • Receptor subtype on cutaneous afferents not specified
  24. 2019 High

    Defined an essential developmental role for PROK2/PROKR2 in tangential and radial olfactory bulb interneuron migration, with cell-type-specific expression mapping ligand and receptor.

    Evidence Prok2-EGFP and Prokr2-LacZ reporter/knockout mice, immunohistochemistry, cell counting

    PMID:31132148

    Open questions at the time
    • Signaling mechanism guiding migration not detailed
    • Whether PROK2 acts as a chemoattractant gradient untested here
  25. 2020 Medium

    Identified an AKT/GSK3β-dependent cytoprotective role for PROK2 in cardiomyocytes under metabolic stress, extending its survival signaling to cardiac tissue.

    Evidence AKT inhibitor, AKT-knockout cardiomyocytes, p-AKT/p-GSK3β Western blot, ROS/apoptosis assays, PKRA7 antagonist

    PMID:32508669

    Open questions at the time
    • Relative PKR1 vs PKR2 contribution not separated
    • In vivo cardiac relevance not established
  26. 2022 High

    Localized PROK2's anorexigenic effect to amygdala PKR2 neurons modulated by MRAP2, defining a discrete neural circuit for feeding control.

    Evidence Viral PKR2 silencing, DREADD chemogenetics, food intake, MRAP2 manipulation

    PMID:36539034

    Open questions at the time
    • Downstream feeding circuitry not mapped
    • Mechanism of MRAP2 modulation of PKR2 unresolved
  27. 2022 Medium

    Identified miR-23a/b as direct post-transcriptional repressors of PROK2 mediating protection of spermatocytes from hypoxic apoptosis, adding a regulatory layer in reproductive tissue.

    Evidence miRNA mimics, luciferase 3'UTR reporter, PROK2 Western blot, apoptosis flow cytometry, miR-seq

    PMID:38301353

    Open questions at the time
    • Physiological context of repression beyond varicocele model unclear
    • Receptor-level consequences of PROK2 reduction not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single ligand achieves tissue-selective outcomes — pain, angiogenesis, myeloid mobilization, neuronal migration, feeding — through only two receptors remains unresolved, particularly the structural and signaling basis of PKR1 vs PKR2 selectivity and G-protein coupling.
  • No receptor-bound structure of PROK2
  • Mechanism partitioning Gq vs JAK2/STAT3 outputs across cell types undefined
  • Determinants of tissue-selective angiogenesis unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 1
Partners
JAK2MRAP2PROKR1PROKR2STAT3

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Bv8 (the amphibian homolog of PROK2) stimulates contraction of the guinea-pig ileum at nanomolar concentrations and induces hyperalgesia when injected intracerebroventricularly in rats, as assessed by tail-flick and paw pressure threshold tests. In vivo pharmacological injection; guinea-pig ileum contraction assay European journal of pharmacology Medium 10422759
1999 The mammalian homologs of Bv8 (PROK2) are predominantly expressed in mid-late pachytene spermatocytes of the mouse testis, with two alternative mRNA splice forms identified, one encoding a basic-amino-acid-rich domain. cDNA cloning, in situ hybridization, Northern blot FEBS letters Medium 10580115
2001 PROK2 (mBv8) promotes survival of cerebellar granule cells and cortical neurons against apoptotic and excitotoxic death by activating both the MAPK (p44/p42) and PI-3-kinase/Akt pathways, as demonstrated by Western blot phosphorylation analysis and pharmacological inhibition with PD98059 and LY294002. Primary neuron culture survival assay; Western blot for phospho-MAPK and phospho-Akt; pharmacological pathway inhibition The European journal of neuroscience Medium 11359521
2002 PROK2/Bv8 binds PK-R1 and PK-R2 receptors in rat dorsal root ganglia (DRG) and dorsal spinal cord with high affinity (IC50 ~4–7 nM), raises [Ca2+]i in small-diameter DRG neurons, and produces intense systemic nociceptive sensitization to mechanical and thermal stimuli via peripheral and spinal mechanisms. Radioligand binding assay ([125I]-Bv8); intracellular calcium imaging; in vivo behavioral pharmacology (tail-flick, paw pressure) British journal of pharmacology High 12466223
2003 PROK2/Bv8 induces proliferation, survival, and migration of adrenal cortical capillary endothelial cells, and adenoviral delivery to mouse testis produces a potent angiogenic response; Bv8/EG-VEGF receptors are localized to vascular endothelial cells within the testis. Endothelial cell proliferation/survival/migration assays; adenoviral gene delivery in vivo; receptor immunolocalization Proceedings of the National Academy of Sciences of the United States of America High 12604792
2004 PROK2/Bv8 promotes survival and differentiation of granulocytic and monocytic lineages from hematopoietic stem cells, stimulates monocyte migration in a pertussis-toxin-sensitive manner, and systemic exposure increases total leukocyte, neutrophil, and monocyte counts in vivo; its G-protein-coupled receptors are expressed on hematopoietic stem cells. Colony-forming unit assay (CFU-G, CFU-M); in vivo adenoviral Bv8 delivery; leukocyte counts; migration assay with pertussis toxin inhibition Proceedings of the National Academy of Sciences of the United States of America High 15548611
2006 PROK2/Bv8 sensitizes TRPV1 in dorsal root ganglion nociceptors through activation of PKCε, causing translocation of PKCε to the neuronal membrane and enhancing TRPV1-mediated inward current; PKC antagonists reduce both TRPV1 current enhancement and behavioral hyperalgesia. Patch-clamp electrophysiology; PKCε translocation imaging; behavioral hyperalgesia assay; single-cell RT-PCR for PKR mRNA; GDNF-induced receptor expression The Journal of neuroscience High 16687502
2006 PROK2/Bv8 induces potent chemotaxis of macrophages and a proinflammatory phenotype (increased IL-1, IL-12; decreased IL-10); these effects are not pertussis-toxin sensitive but are blocked by the phospholipase inhibitor U73122 (suggesting Gq coupling) and are absent in PKR-1 knockout mice, demonstrating PKR-1 as the mediating receptor. Macrophage chemotaxis assay; cytokine ELISA; pertussis toxin and U73122 pharmacological inhibition; PKR-1 knockout mice British journal of pharmacology High 16299550
2007 Bv8 (PROK2) is upregulated in CD11b+Gr1+ myeloid cells upon tumor implantation; G-CSF is identified as a major positive regulator of Bv8 expression; adenoviral Bv8 delivery to tumors promotes angiogenesis; anti-Bv8 antibodies reduce CD11b+Gr1+ cell mobilization and inhibit tumor angiogenesis and growth. Adenoviral gene delivery in vivo; anti-Bv8 neutralizing antibody treatment; FACS for CD11b+Gr1+ cells; tumor growth and vascular density measurements Nature High 18064003
2007 Intra-PAG injection of Bv8 increases GABA (but not glutamate) extracellular levels in the periaqueductal grey as measured by microdialysis, activates RVM On-cells and suppresses Off-cells, and decreases tail-flick latency, establishing a pronociceptive role via GABAergic signaling in the descending pain pathway. In vivo microdialysis; RVM electrophysiology (On/Off cell recording); tail-flick behavioral test The European journal of neuroscience Medium 18005070
2008 Bv8 (PROK2) decreases IL-4 and IL-10 production by mouse splenocytes while increasing IL-1β, shifting T cells toward a Th1 profile; this effect is absent in PROKR1 knockout mice, demonstrating PKR-1 as the sole mediating receptor for lymphocyte cytokine modulation. Cytokine ELISA in splenocyte culture; in vivo immunization; PROKR1 knockout mice BMC immunology Medium 18957080
2008 Anti-Bv8 treatment in RIP-Tag transgenic mice significantly reduces angiogenic switching in early pancreatic neoplasia and inhibits CD11b+Gr1+ cell mobilization and homing, with stage-dependent efficacy paralleling neutrophil ablation, implicating PROK2 as a mediator of neutrophil-dependent angiogenesis. In vivo anti-Bv8 antibody treatment in transgenic tumor model; histological vascular surface area measurement; FACS for CD11b+Gr1+ cells Proceedings of the National Academy of Sciences of the United States of America High 18268320
2009 Granulocyte-derived PROK2 (GrPK2) purified from peritoneal granulocytes binds prokineticin receptors with high affinity and induces hypernociception; PKR1 and PKR2 knockout mice show significantly less inflammation-induced hyperalgesia, and PKR1 knockout reduces inflammation-induced PK2 upregulation, establishing PKR1 as a regulator of PK2 levels during inflammation. Protein purification from peritoneal granulocytes; PKR1/PKR2 knockout mice; CFA paw inflammation model; PKR antagonist dose-response behavioral assay Proceedings of the National Academy of Sciences of the United States of America High 19667192
2012 G-CSF induces Bv8/PROK2 expression in CD11b+Gr1+ myeloid cells via STAT3 activation; STAT3 inhibition or siRNA knockdown reduces G-CSF-induced Bv8 expression; chromatin immunoprecipitation demonstrates phospho-STAT3 binding to the Bv8 promoter; luciferase assay confirms this binding site as a functional transcriptional enhancer. siRNA knockdown; pharmacological STAT3 inhibition (WP1066); chromatin immunoprecipitation (ChIP); luciferase reporter assay; in vivo validation The Journal of biological chemistry High 22528488
2012 Bv8 induces biphasic hyperalgesia: the early phase involves direct CGRP release from spinal cord tissue, while the late phase requires de novo protein synthesis and is associated with upregulation of CGRP and substance P immunoreactivity in dorsal horn and DRG; protein synthesis inhibitors block only the late phase. Ex vivo spinal cord CGRP release assay; in vivo protein synthesis inhibitor pretreatment; CGRP/substance P immunohistochemistry Neuroscience letters Medium 22641053
2013 BV8/PROK2 activates STAT3 in myeloid cells via JAK2; JAK2 genetic and pharmacological inhibition abrogates BV8-induced STAT3 activation; BV8 shRNA knockdown in human myeloid leukemia cells reduces STAT3 activity and downstream angiogenic/proliferative gene expression, decreasing tumor cell viability and in vivo tumor growth. JAK2 genetic knockdown and pharmacological inhibition; BV8 shRNA; STAT3 phosphorylation Western blot; in vivo xenograft tumor growth The Journal of biological chemistry High 23548897
2005 Deletion of the N-terminal alanine of Bv8 (des-Ala-Bv8) reduces receptor affinity and potency fivefold at both PKR1 and PKR2 and reduces hyperalgesic potency ~20-fold; deletion of the first two residues (des-Ala-Val-Bv8) abolishes all biological activity in vitro and in vivo but enables partial antagonism of Bv8-induced hyperalgesia, demonstrating that the N-terminal hexapeptide AVITGA is essential for receptor activation. Radioligand binding; intracellular Ca2+ mobilization; MAPK phosphorylation in CHO cells expressing PKR1/PKR2; in vivo hyperalgesia assay British journal of pharmacology High 16113687
2010 Chemical synthesis and NMR structure determination of Bv8 (77 residues, five disulfide bonds) revealed it is structurally homologous to mamba intestinal toxin 1; a truncated mutant lacking five N-terminal residues shows no perturbation to the core structure yet loses receptor binding activity, indicating receptor interaction is highly cooperative and likely involves the N-terminal region without global structural rearrangement. Chemical synthesis (Boc SPPS + native chemical ligation); NMR structure determination; in vitro functional assay in neuroblastoma cells and DRG neurons Chembiochem High 20677202
2010 Tryptophan at position 24 of Bv8/PROK2 is important for PKR interaction; W24A substitution reduces receptor binding affinity and biological activity, as demonstrated by recombinant protein production in Pichia pastoris and receptor binding assays. Site-directed mutagenesis (W24A); recombinant protein expression in Pichia pastoris; PKR binding assay Protein expression and purification Medium 20412858
2012 A W24A Bv8 analog (A-24) preferentially binds PKR2 over PKR1 with lower potency; at inactive doses it antagonizes Bv8-induced hyperalgesia; systemically it increases β-endorphin levels in mouse brain and shows anti-hyperalgesic activity in inflammatory and post-surgical pain models by blocking peripheral PKR1 and activating central opioid pathways via PKR2. Receptor binding assay; in vivo hyperalgesia models (inflammatory, post-surgical); β-endorphin radioimmunoassay British journal of pharmacology Medium 22122547
2014 PROK2 and PKR2 are upregulated in nociceptors, Schwann cells, and activated astrocytes of the spinal cord after chronic constriction injury; systemic PKR antagonist treatment reduces neuropathic hyperalgesia and allodynia, blunts microgliosis and astrocyte activation, and restores cytokine balance, establishing PROK2/PKR2 signaling as a contributor to neuropathic pain via neuron-glia interaction. CCI neuropathic pain model; intrathecal, perineural, and subcutaneous PKR antagonist (PC1) injection; immunohistochemistry for PROK2/PKR2/glia markers; cytokine measurement British journal of pharmacology Medium 24902717
2016 Peripheral cutaneous application of Bv8 at nanomolar concentrations directly sensitizes unmyelinated polymodal C-fibers to heat (increased heat-evoked discharge, lower threshold), and increases heat- and capsaicin-evoked CGRP release from hind-paw skin, confirming peripheral nociceptor sensitization as the mechanism for the first phase of Bv8-induced thermal hyperalgesia. Single cutaneous fiber electrophysiology; skin-nerve preparation; CGRP release assay from hind-paw skin flaps; immunohistochemistry European journal of pain Medium 26914965
2019 PROK2/PROKR2 signaling is required for tangential and radial migration of olfactory bulb interneurons through the SVZ-RMS-OB pathway; Prok2 and Prokr2 mutant mice show ~75% loss of GABAergic interneurons in the olfactory bulb; PROKR2 is expressed in postmitotic immature interneurons, while PROK2 is expressed in a subset of mature OB granule and tufted cells but not in SVZ progenitors. Prok2EGFP transgenic and Prokr2LacZ/+ knockin mice; immunohistochemistry; cell counting in mutant vs. wildtype OB The Journal of comparative neurology High 31132148
2022 The anorexigenic effect of PK2/PROK2 is mediated specifically by PKR2 neurons in the amygdala (not hypothalamus); targeted PKR2 silencing in the amygdala abolishes PK2-induced food intake reduction; chemogenetic activation of amygdala PKR2 neurons suppresses feeding; MRAP2 expression in PKR2 neurons modulates PK2 anorexigenic activity. Targeted PKR2 silencing (viral); chemogenetic (DREADD) manipulation of amygdala PKR2 neurons; food intake measurement; MRAP2 overexpression/knockdown The Journal of biological chemistry High 36539034
2008 TTX-sensitive local electrophysiological activity in the suprachiasmatic nucleus (SCN) is required for full expression of PK2 circadian mRNA rhythm; TTX application substantially dampened the PK2 mRNA rhythm while leaving core clock gene rhythms (Per1, Per2, Bmal1, Cry1) intact, placing PK2 downstream of clock-driven neural activity rather than directly in the core oscillator. SCN slice culture; TTX pharmacological treatment; in situ hybridization for 13 genes including PK2 at 4-h intervals The European journal of neuroscience Medium 18279366
2020 PK2/PROK2 signals through PKR1/PKR2 to activate the AKT/GSK3β pathway in cardiomyocytes; PK2 attenuates high glucose/palmitic acid-induced ROS, apoptosis, and autophagosome accumulation in H9c2 cells; an AKT inhibitor abolishes PK2 protective effects, and AKT-knockout cardiomyocytes are unresponsive to PK2, establishing AKT as the required effector. AKT1/2 kinase inhibitor; AKT-knockout mouse cardiomyocytes; Western blot for p-AKT/p-GSK3β; ROS detection (DCFH-DA); flow cytometry for apoptosis; PKRA7 antagonist Frontiers in physiology Medium 32508669
2022 miR-23a and miR-23b directly bind the 3′ UTR of PROK2 mRNA and downregulate PROK2 expression; overexpression of miR-23a/b mimics reduces hypoxia-induced GC-2 spermatocyte apoptosis in vitro, identifying PROK2 as a direct miR-23a/b target mediating lycopene's protective effect in varicocele. miRNA mimic transfection; luciferase reporter (implied by 'directly bind'); Western blot for PROK2; flow cytometry for apoptosis; miR-seq in vivo Reproduction, fertility, and development Medium 38301353

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 536 18064003
2008 Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proceedings of the National Academy of Sciences of the United States of America 269 18268320
2004 Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proceedings of the National Academy of Sciences of the United States of America 181 15548611
2003 The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the testis: Localization of Bv8 receptors to endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 165 12604792
1999 Bv8, a small protein from frog skin and its homologue from snake venom induce hyperalgesia in rats. European journal of pharmacology 150 10422759
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
2006 Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of mouse macrophages. British journal of pharmacology 100 16299550
1992 Overexpression of Dd PK2 protein kinase causes rapid development and affects the intracellular cAMP pathway of Dictyostelium discoideum. Development (Cambridge, England) 100 1330484
2007 Bv8/Prokineticin proteins and their receptors. Life sciences 99 17881008
2016 Mit1 Transcription Factor Mediates Methanol Signaling and Regulates the Alcohol Oxidase 1 (AOX1) Promoter in Pichia pastoris. The Journal of biological chemistry 92 26828066
2004 Expression and regulation of the prokineticins (endocrine gland-derived vascular endothelial growth factor and Bv8) and their receptors in the human endometrium across the menstrual cycle. The Journal of clinical endocrinology and metabolism 89 15126578
2006 Sensitization of transient receptor potential vanilloid 1 by the prokineticin receptor agonist Bv8. The Journal of neuroscience : the official journal of the Society for Neuroscience 85 16687502
2012 Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling. The Journal of biological chemistry 81 22528488
1999 MIT(1), a black mamba toxin with a new and highly potent activity on intestinal contraction. FEBS letters 79 10567694
2009 The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain. Proceedings of the National Academy of Sciences of the United States of America 78 19667192
1999 The mammalian homologues of frog Bv8 are mainly expressed in spermatocytes. FEBS letters 77 10580115
2001 The mammalian homologue of the novel peptide Bv8 is expressed in the central nervous system and supports neuronal survival by activating the MAP kinase/PI-3-kinase pathways. The European journal of neuroscience 76 11359521
2002 Nociceptive sensitization by the secretory protein Bv8. British journal of pharmacology 75 12466223
2009 Characterization and regulation of bv8 in human blood cells. Clinical cancer research : an official journal of the American Association for Cancer Research 62 19336519
1991 Purification and properties of an ethylene-forming enzyme from Pseudomonas syringae pv. phaseolicola PK2. Journal of general microbiology 62 1770346
2004 EG-VEGF and Bv8: a novel family of tissue-restricted angiogenic factors. Biochimica et biophysica acta 60 14984768
2014 Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy. Neoplasia (New York, N.Y.) 58 24957319
2008 Triazine compounds as antagonists at Bv8-prokineticin receptors. Journal of medicinal chemistry 53 19006379
2004 Bv8, the amphibian homologue of the mammalian prokineticins, modulates ingestive behaviour in rats. British journal of pharmacology 53 15066905
2019 Metformin Ameliorates Testicular Damage in Male Mice with Streptozotocin-Induced Type 1 Diabetes through the PK2/PKR Pathway. Oxidative medicine and cellular longevity 52 31871550
2013 PROK2/PROKR2 Signaling and Kallmann Syndrome. Frontiers in endocrinology 51 23596439
2013 A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer. PloS one 49 23372791
2000 Mit1/Lb9 and Copg2, new members of mouse imprinted genes closely linked to Peg1/Mest(1). FEBS letters 48 10788617
2010 Kallmann syndrome caused by mutations in the PROK2 and PROKR2 genes: pathophysiology and genotype-phenotype correlations. Frontiers of hormone research 47 20389090
2003 EG-VEGF and Bv8. a novel family of tissue-selective mediators of angiogenesis, endothelial phenotype, and function. Trends in cardiovascular medicine 47 14522467
2016 Biochemical and Spectroscopic Characterization of the Non-Heme Fe(II)- and 2-Oxoglutarate-Dependent Ethylene-Forming Enzyme from Pseudomonas syringae pv. phaseolicola PK2. Biochemistry 46 27749027
2013 G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells. The Journal of biological chemistry 46 23548897
2014 Controlling the activation of the Bv8/prokineticin system reduces neuroinflammation and abolishes thermal and tactile hyperalgesia in neuropathic animals. British journal of pharmacology 45 24902717
2005 Biological activities of Bv8 analogues. British journal of pharmacology 43 16113687
2013 Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. The Journal of clinical endocrinology and metabolism 42 23386640
2020 Metformin Ameliorates Diabetic Cardiomyopathy by Activating the PK2/PKR Pathway. Frontiers in physiology 41 32508669
2005 Prokineticins (endocrine gland-derived vascular endothelial growth factor and BV8) in the bovine ovary: expression and role as mitogens and survival factors for corpus luteum-derived endothelial cells. Endocrinology 41 15932929
1992 Molecular cloning in Escherichia coli, expression, and nucleotide sequence of the gene for the ethylene-forming enzyme of Pseudomonas syringae pv. phaseolicola PK2. Biochemical and biophysical research communications 41 1445325
2018 Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia. PLoS pathogens 37 29621339
2008 Organic solvent tolerance of an alkaline protease from salt-tolerant alkaliphilic Streptomyces clavuligerus strain Mit-1. Journal of industrial microbiology & biotechnology 37 18941814
2008 The prokineticin receptor agonist Bv8 decreases IL-10 and IL-4 production in mice splenocytes by activating prokineticin receptor-1. BMC immunology 37 18957080
2009 Bv8/Prokineticins and their Receptors A New Pronociceptive System. International review of neurobiology 35 19607967
2002 Clonal expansion of CD8+ BV8 T lymphocytes in bone marrow characterizes thymoma-associated B lymphopenia. Blood 34 12515721
2001 Comparison of the proteomes of three yeast wild type strains: CEN.PK2, FY1679 and W303. Comparative and functional genomics 34 18628919
2011 Bv8/PK2 and prokineticin receptors: a druggable pronociceptive system. Current opinion in pharmacology 29 22136937
2006 Modulators of pain: Bv8 and prokineticins. Current neuropharmacology 28 18615143
2019 Transcriptional gene silencing requires dedicated interaction between HP1 protein Chp2 and chromatin remodeler Mit1. Genes & development 27 30808655
2019 The PROK2/PROKR2 signaling pathway is required for the migration of most olfactory bulb interneurons. The Journal of comparative neurology 27 31132148
2015 Prokineticin 2 (PROK2) is an important factor for angiogenesis in colorectal cancer. Oncotarget 27 26317645
2007 Two-step purification of a highly thermostable alkaline protease from salt-tolerant alkaliphilic Streptomyces clavuligerus strain Mit-1. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 25 17499566
2000 Murine Bv8 gene maps near a synteny breakpoint of mouse chromosome 6 and human 3p21. Gene 24 11054548
2014 The Mi-2 homolog Mit1 actively positions nucleosomes within heterochromatin to suppress transcription. Molecular and cellular biology 23 24662054
2012 The expression of one ankyrin pk2 allele of the WO prophage is correlated with the Wolbachia feminizing effect in isopods. BMC microbiology 23 22497736
2019 Efficient influenza A virus production in high cell density using the novel porcine suspension cell line PBG.PK2.1. Vaccine 22 31005427
2008 A TTX-sensitive local circuit is involved in the expression of PK2 and BDNF circadian rhythms in the mouse suprachiasmatic nucleus. The European journal of neuroscience 22 18279366
2011 Bv8-prokineticins and their receptors: modulators of pain. Current pharmaceutical biotechnology 21 21466441
2008 Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma. World journal of gastroenterology 21 18300343
2012 PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency. European journal of endocrinology 20 23082007
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
2020 Prokineticin 2 (PK2) Rescues Cardiomyocytes from High Glucose/High Palmitic Acid-Induced Damage by Regulating the AKT/GSK3β Pathway In Vitro. Oxidative medicine and cellular longevity 18 32509142
2010 Chemical synthesis and structure of the prokineticin Bv8. Chembiochem : a European journal of chemical biology 18 20677202
2024 Overexpression of the transcriptional activators Mxr1 and Mit1 enhances lactic acid production on methanol in Komagataellaphaffii. Metabolic engineering 17 39067842
2019 Involvement of the Chemokine Prokineticin-2 (PROK2) in Alzheimer's Disease: From Animal Models to the Human Pathology. Cells 17 31766244
2015 Baculovirus protein PK2 subverts eIF2α kinase function by mimicry of its kinase domain C-lobe. Proceedings of the National Academy of Sciences of the United States of America 16 26216977
2020 Methane Ameliorates Lipopolysaccharide-Induced Acute Orchitis by Anti-inflammatory, Antioxidative, and Antiapoptotic Effects via Regulation of the PK2/PKR1 Pathway. Oxidative medicine and cellular longevity 15 32922653
2022 Improving AOX1 promoter efficiency by overexpression of Mit1 transcription factor. Molecular biology reports 14 36002652
2010 Expression of Bv8 in Pichia pastoris to identify structural features for receptor binding. Protein expression and purification 14 20412858
2019 Bv8-Like Toxin from the Frog Venom of Amolops jingdongensis Promotes Wound Healing via the Interleukin-1 Signaling Pathway. Toxins 13 31905801
2015 Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of Cancer-Induced Bone Pain. Basic & clinical pharmacology & toxicology 13 25641661
2007 The prokineticin receptor agonist Bv8 increases GABA release in the periaqueductal grey and modifies RVM cell activities and thermoceptive reflexes in the rat. The European journal of neuroscience 13 18005070
2022 Matrine alleviates spatial learning and memory impairment in diabetic mice by inhibiting endoplasmic reticulum stress and through modulation of PK2/PKRs pathway. Neurochemistry international 12 35074478
2022 S-1 eliminates MDSCs and enhances the efficacy of PD-1 blockade via regulation of tumor-derived Bv8 and S100A8 in thoracic tumor. Cancer science 12 36285504
2015 PK2/PKR1 Signaling Regulates Bladder Function and Sensation in Rats with Cyclophosphamide-Induced Cystitis. Mediators of inflammation 12 26798205
2012 Pharmacological activity of a Bv8 analogue modified in position 24. British journal of pharmacology 12 22122547
2012 Mechanisms of Bv8-induced biphasic hyperalgesia: increased excitatory transmitter release and expression. Neuroscience letters 12 22641053
2021 Lycopene Attenuates Hypoxia-Induced Testicular Injury by Inhibiting PROK2 Expression and Activating PI3K/AKT/mTOR Pathway in a Varicocele Adult Rat. Evidence-based complementary and alternative medicine : eCAM 11 34055003
2021 Trehalose Ameliorates Diabetic Cardiomyopathy: Role of the PK2/PKR Pathway. Oxidative medicine and cellular longevity 11 34970418
2020 Silencing PROK2 Inhibits Invasion of Human Cervical Cancer Cells by Targeting MMP15 Expression. International journal of molecular sciences 11 32887509
2022 Inhibition of miR-141-3p attenuates apoptosis of neural stem cells via targeting PBX1 to regulate PROK2 transcription in MCAO mice. Cell cycle (Georgetown, Tex.) 10 36548024
2023 PK2/PKRs pathway is involved in the protective effect of artemisinin against trimethyltin chloride-induced hippocampal injury. Toxicology 9 36696940
2022 Enhancing xylanase expression of Komagataella phaffii induced by formate through Mit1 co-expression. Bioprocess and biosystems engineering 9 35881246
2022 Prokineticin 2/PROK2 and Male Infertility. Biomedicines 9 36289651
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
2022 Alzheimer's disease-associated inflammatory pathways might contribute to osteoporosis through the interaction between PROK2 and CSF3. Frontiers in neurology 8 36203970
2015 EG-VEGF, BV8, and their receptor expression in human bronchi and their modification in cystic fibrosis: Impact of CFTR mutation (delF508). American journal of physiology. Lung cellular and molecular physiology 8 26047640
2009 The Bv8 gene from Bombina orientalis: molecular cloning, genomic organization and functional characterization of the promoter. Peptides 8 19747954
2022 [PK2/PKR1 signaling pathway participates in geniposide protection against diabetic nephropathy in mice]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 6 35347960
2022 Bv8 Blockade Sensitizes Anti-PD1 Therapy Resistant Tumors. Frontiers in immunology 6 35874722
2018 Relationship between PK2 and number of Kupffer cells during the progression of liver fibrosis in patients with HBV. Turkish journal of medical sciences 6 29479955
1997 Evolution and selection of primate T cell antigen receptor BV8 gene subfamily. Molecular phylogenetics and evolution 6 9242595
2024 Lycopene inhibits apoptosis of mouse spermatocytes in varicocele via miR-23a/b-induced downregulation of PROK2. Reproduction, fertility, and development 5 38301353
2022 Activation of amygdala prokineticin receptor 2 neurons drives the anorexigenic activity of the neuropeptide PK2. The Journal of biological chemistry 5 36539034
2016 The prokineticin Bv8 sensitizes cutaneous terminals of female mice to heat. European journal of pain (London, England) 5 26914965
2024 Intracerebroventricular PROK2 infusion could increase the secretion of male reproductive hormones by stimulating the HPG axis. Molecular biology reports 4 38740671
2023 Bv8 mediates myeloid cell migration and enhances malignancy of colorectal cancer. Frontiers in immunology 4 37090721
2023 Comparative metabolomic and transcriptomic analysis of Saccharomyces cerevisiae W303a and CEN.PK2-1C. World journal of microbiology & biotechnology 4 37661201
2020 The novel function of miR-3195 for mutant PROK2 (c.223-4C>A) degradation. Cell biology international 4 33140874
2016 Method development to quantify Bv8 expression in circulating CD11b+ cells in patients with neovascular age-related macular degeneration (nvAMD) exhibiting Anti-VEGF refractoriness. Experimental eye research 4 27256991
2025 Gallic acid mitigates lipopolysaccharide-induced testicular inflammation via regulation of the NF-κB and PK2/PKR1 pathway. Journal of molecular histology 3 39825958
2013 GRANULOCYTE INFILTRATION AND EXPRESSION OF THE PRO-ANGIOGENIC BV8 PROTEIN IN EXPERIMENTAL EL4 AND LEWIS LUNG CARCINOMA TUMORS. Cureus 3 25493215

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