Affinage

PROK2

Prokineticin-2 · UniProt Q9HC23

Length
129 aa
Mass
14.3 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PROK2 (prokineticin 2/Bv8) is a secreted cysteine-rich peptide that signals through two G protein-coupled receptors (PKR1/PROKR1 and PKR2/PROKR2) to regulate pain sensitization, angiogenesis, immune cell mobilization, neuronal migration, circadian feeding behavior, and reproductive axis function. In nociceptive pathways, PROK2 sensitizes peripheral C-fibers and TRPV1 via PKCε translocation, induces CGRP release from spinal cord, and activates GABAergic pronociceptive circuits in the periaqueductal grey; granulocyte-derived PROK2 is a primary mediator of inflammatory pain, as demonstrated by abolished hyperalgesia in PKR1/PKR2 knockout mice (PMID:19667192, PMID:16687502, PMID:26914965). In the tumor microenvironment, G-CSF drives PROK2 expression in CD11b+Gr1+ myeloid cells via STAT3 binding to the Bv8 promoter, and PROK2 in turn promotes myeloid mobilization from bone marrow and tumor angiogenesis through a BV8–STAT3–JAK2 feed-forward loop (PMID:18064003, PMID:22528488, PMID:23548897). Loss-of-function mutations in PROK2 or PROKR2 cause Kallmann syndrome, characterized by olfactory bulb agenesis and hypogonadotropic hypogonadism due to defective GnRH neuron and olfactory bulb interneuron migration (PMID:23596439, PMID:31132148).

Mechanistic history

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

    Identification of PROK2 (Bv8) as a bioactive secreted peptide established it as a nociceptive and smooth-muscle-active factor expressed in mammalian brain, intestine, and testis.

    Evidence ICV injection with behavioral pain assays in rats; cDNA cloning and in situ hybridization in mouse testes

    PMID:10422759 PMID:10580115

    Open questions at the time
    • Mammalian receptor identity unknown at this stage
    • Mechanism of hyperalgesia unresolved
    • Physiological relevance of testicular expression unclear
  2. 2001 Medium

    Demonstration that PROK2 protects neurons from apoptosis via MAPK and PI3K/Akt pathways revealed a neurotrophic function beyond nociception.

    Evidence In vitro apoptosis rescue of cerebellar granule cells with pathway inhibitors (PD98059, LY294002) and phospho-protein Western blots

    PMID:11359521

    Open questions at the time
    • In vivo neuroprotective relevance not tested
    • Receptor subtype mediating survival unclear
  3. 2002 High

    Identification of PKR1 and PKR2 as PROK2 receptors on nociceptors, with direct calcium mobilization in DRG neurons, provided the molecular basis for PROK2-mediated pain sensitization.

    Evidence Radioligand binding (125I-Bv8) in DRG and spinal cord, calcium imaging in DRG neurons, and behavioral nociception assays

    PMID:12466223

    Open questions at the time
    • Downstream intracellular signaling in nociceptors not dissected
    • Relative contributions of PKR1 vs PKR2 in pain not resolved
  4. 2003 High

    Establishing PROK2 as a tissue-selective angiogenic factor that promotes endothelial proliferation, survival, and migration — induced by hypoxia — placed it alongside VEGF as a vascular growth factor with restricted expression.

    Evidence Adenoviral delivery to mouse testis, endothelial cell proliferation/migration/survival assays, receptor immunohistochemistry

    PMID:12604792

    Open questions at the time
    • Whether PROK2 angiogenesis is relevant in pathological settings (tumors) not yet shown
    • Signaling cascade linking receptors to endothelial responses unknown
  5. 2004 High

    Discovery that PROK2 acts on hematopoietic cells — promoting monocyte migration via pertussis toxin-sensitive G proteins and increasing leukocyte counts — expanded its role to immune cell regulation, while hypothalamic expression with circadian variation linked it to feeding/drinking behavior.

    Evidence Adenoviral in vivo delivery with CBC counts and colony-forming assays; ICV/microinjection feeding assays; in situ hybridization in SCN

    PMID:15066905 PMID:15548611

    Open questions at the time
    • Whether circadian PROK2 rhythm directly drives behavioral outputs vs. acting as an output signal unclear
    • Brain circuit identity for appetite regulation not resolved
  6. 2005 High

    Structure–function analysis showing the N-terminal AVITGA motif is essential for receptor activation, and that its deletion creates a receptor antagonist, provided the first pharmacological tools and structural insight into PROK2–receptor interaction.

    Evidence Receptor binding, calcium transients in PKR1/PKR2-expressing CHO cells, MAPK assays, in vivo hyperalgesia with truncated peptides

    PMID:16113687

    Open questions at the time
    • Atomic-level structure of PROK2–receptor complex unknown
    • Mechanism of antagonism (competitive vs. allosteric) unresolved
  7. 2006 High

    Mechanistic dissection of PROK2 nociception revealed PKCε translocation as the pathway sensitizing TRPV1, while PROK2 was shown to drive macrophage chemotaxis via PKR1-Gq signaling — not Gi — shifting understanding of receptor coupling in immune cells.

    Evidence PKCε translocation assay + PKC antagonists in DRG neurons; macrophage chemotaxis with U73122 and pertussis toxin; PKR1 knockout mice

    PMID:16299550 PMID:16687502

    Open questions at the time
    • Whether PKCε pathway operates in all nociceptor subtypes unclear
    • Gq-specific signaling intermediates in macrophages not mapped
  8. 2007 High

    The demonstration that G-CSF drives PROK2 expression in tumor-infiltrating CD11b+Gr1+ myeloid cells and that anti-Bv8 antibodies suppress myeloid mobilization and tumor angiogenesis established PROK2 as a key mediator linking innate immunity to tumor vasculature.

    Evidence Anti-Bv8 antibody treatment in tumor-bearing mice, flow cytometry of myeloid cells, vascular density analysis; confirmed in RIP-Tag transgenic model

    PMID:18064003 PMID:18268320

    Open questions at the time
    • Direct versus indirect effects on endothelial cells in tumors not fully dissected
    • Whether anti-Bv8 is effective in established (late-stage) tumors remains uncertain
  9. 2009 High

    Genetic knockout of PKR1 and PKR2 proved that granulocyte-derived PROK2 is the primary initiator of inflammatory pain; a PKR1-dependent feedback loop regulating PROK2 levels was uncovered, and a small-molecule PKR antagonist achieved analgesia.

    Evidence CFA inflammation model in PKR1/PKR2 KO mice, PROK2 purification from granulocytes, non-peptide antagonist treatment

    PMID:19667192

    Open questions at the time
    • Molecular identity of non-peptide antagonist target specificity not fully characterized
    • Contribution of neuronal vs. immune cell PROK2 not resolved
  10. 2010 High

    Determination of the 3D NMR structure of Bv8 revealed a colipase/mamba-toxin fold and showed that N-terminal residues critical for receptor activation are flexible and do not alter the core structure, suggesting an allosteric binding mechanism.

    Evidence Chemical synthesis, NMR spectroscopy, functional validation in neuroblastoma cells and DRG neurons

    PMID:20677202

    Open questions at the time
    • No receptor-bound co-structure available
    • How N-terminal flexibility translates to receptor activation mechanistically unknown
  11. 2012 High

    G-CSF-induced PROK2 expression was shown to require STAT3 binding directly to the Bv8 promoter, completing the transcriptional mechanism linking tumor-derived G-CSF to myeloid PROK2 upregulation; concurrently, receptor-selective Bv8 analogs demonstrated differential PKR1/PKR2 contributions to pain modulation.

    Evidence ChIP for pSTAT3 at Bv8 promoter, luciferase reporter, siRNA knockdown; W24A Bv8 binding/calcium assays and in vivo hyperalgesia with β-endorphin measurement

    PMID:22122547 PMID:22528488

    Open questions at the time
    • Whether STAT3 is sufficient or requires co-factors for Bv8 transcription unknown
    • Central opioid activation via PKR2 pathway not fully mapped
  12. 2013 High

    Discovery of a BV8–JAK2–STAT3 feed-forward loop in myeloid leukemia cells, where PROK2 both activates and is transcriptionally induced by STAT3, provided a mechanistic basis for autocrine amplification in tumor-associated myeloid cells; simultaneously, loss-of-function mutations in PROK2/PROKR2 were definitively linked to Kallmann syndrome through defective GnRH neuron migration.

    Evidence JAK2 inhibition + BV8 shRNA in leukemia xenografts; Prok2/Prokr2 KO mouse phenotyping with olfactory bulb and GnRH analyses; patient mutation functional characterization

    PMID:23548897 PMID:23596439

    Open questions at the time
    • Whether the feed-forward loop operates in non-myeloid tumors unclear
    • Molecular mechanism of GnRH neuron guidance by PROK2 gradient not resolved
  13. 2019 High

    Quantitative analysis in Prok2 and Prokr2 mutant mice revealed that ~75% of GABAergic olfactory bulb interneurons require PROK2/PROKR2 for tangential and radial migration from the SVZ-RMS, establishing PROK2 as a dominant guidance cue for postnatal interneuron migration.

    Evidence Prok2-EGFP and Prokr2-LacZ knockin reporters, genetic KO phenotyping with immunofluorescence and cell counting

    PMID:31132148

    Open questions at the time
    • Downstream cytoskeletal effectors in migrating neuroblasts unknown
    • Whether PROK2 acts as chemoattractant versus motogen in this context unresolved
  14. 2020 Medium

    PROK2 was shown to activate AKT/GSK3β signaling for cardiomyocyte protection and to promote cervical cancer cell invasion via MMP15 upregulation, extending its functional repertoire to cardiac and oncological contexts.

    Evidence AKT KO cardiomyocytes + PKRA7 antagonist in diabetic mice; PROK2 siRNA/overexpression in HeLa cells with transwell invasion assays

    PMID:32508669 PMID:32887509

    Open questions at the time
    • Transcriptional mechanism linking PROK2 to MMP15 not identified
    • Whether cardiomyocyte effects are receptor subtype-specific not resolved
    • Single-lab findings for each
  15. 2022 High

    Circuit-level dissection showed that PROK2's anorexigenic action is mediated specifically by PKR2 neurons in the amygdala — not hypothalamus — with MRAP2 acting as a modulator of receptor signaling, resolving the anatomical locus of PROK2 appetite suppression.

    Evidence Targeted PKR2 silencing and DREADD chemogenetic manipulation of amygdala neurons; MRAP2 overexpression/knockdown with behavioral food intake assays

    PMID:36539034

    Open questions at the time
    • Downstream amygdala circuits mediating anorexia not mapped
    • Whether MRAP2 modulation is specific to amygdala PKR2 neurons unclear
  16. 2024 Medium

    Central PROK2 infusion was shown to activate the hypothalamic-pituitary-gonadal axis by increasing GnRH mRNA and elevating FSH, LH, and testosterone, providing direct evidence that PROK2 is an upstream regulator of reproductive hormone release.

    Evidence ICV osmotic mini-pump infusion with RT-PCR for GnRH and ELISA for gonadotropins/testosterone

    PMID:38740671

    Open questions at the time
    • Whether the effect is mediated by direct action on GnRH neurons vs. intermediate neurons unknown
    • Receptor subtype mediating HPG activation not identified
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of PROK2 bound to PKR1 or PKR2, the molecular basis for receptor subtype selectivity in different tissues, and the intracellular signaling cascades linking PROK2 to cytoskeletal rearrangements during neuronal migration.
  • No co-crystal or cryo-EM structure of PROK2–receptor complex
  • Receptor subtype-specific signaling pathways in neuronal migration undefined
  • In vivo redundancy between PKR1 and PKR2 in most physiological contexts not systematically addressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5
Localization
GO:0005576 extracellular region 5
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 3
Partners
CSF3JAK2MMP15MRAP2PROKR1PROKR2STAT3TRPV1

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Bv8 (PROK2 amphibian homolog) induces hyperalgesia when injected intracerebroventricularly in rats, acting on receptors present in mammalian brain and intestine, stimulating guinea-pig ileum contraction at nanomolar concentrations. In vivo injection (i.c.v.) with tail-flick test and paw pressure threshold; in vitro smooth muscle contraction assay European journal of pharmacology Medium 10422759
1999 Mammalian homologues of Bv8 (PROK2) are most highly expressed in mid-late pachytene spermatocytes of the mouse testis, with two mRNA forms due to alternative splicing. cDNA cloning, in situ hybridization, developmental expression profiling in mouse testes FEBS letters Medium 10580115
2001 Mammalian PROK2 (mBv8) is expressed in rodent CNS (cerebral cortex, limbic regions, cerebellar Purkinje cells, spinal cord) and supports neuronal survival by activating the MAPK and PI-3-kinase pathways, protecting cerebellar granule cells and cortical neurons from apoptotic death. In situ hybridization, immunocytochemistry, in vitro apoptosis assay with PD98059/LY294002 inhibitors, Western blot for phospho-p44/p42 MAPK and phospho-Akt The European journal of neuroscience Medium 11359521
2002 PROK2 (Bv8) acts on two G-protein coupled prokineticin receptors (PK-R1 and PK-R2) expressed in rat dorsal root ganglia and dorsal spinal cord, inducing Ca2+ elevation in small-diameter nociceptors and causing intense systemic nociceptive sensitization to thermal and mechanical stimuli. Radioligand binding assay (125I-Bv8), intracellular Ca2+ imaging in DRG neurons, behavioral nociception assays (i.v., s.c., i.t. injection) British journal of pharmacology High 12466223
2003 PROK2 (Bv8) induces proliferation, survival, and migration of adrenal cortical capillary endothelial cells; Bv8/EG-VEGF receptors are localized to vascular endothelial cells in the testis; Bv8 gene expression is induced by hypoxic stress. Adenoviral delivery to mouse testis, cell proliferation/survival/migration assays, receptor localization by immunohistochemistry Proceedings of the National Academy of Sciences of the United States of America High 12604792
2004 PROK2 (Bv8) and its receptors are expressed in hematopoietic stem cells and mature blood cells (monocytes, neutrophils, dendritic cells, lymphocytes); Bv8 stimulates migration of monocytes in a pertussis toxin-sensitive manner, promotes survival and differentiation of granulocytic and monocytic lineages, and increases leukocyte/neutrophil/monocyte counts in vivo. Systemic in vivo Bv8/EG-VEGF adenoviral delivery, colony-forming unit assays of hematopoietic stem cells, monocyte migration assay (pertussis toxin inhibition), complete blood counts Proceedings of the National Academy of Sciences of the United States of America High 15548611
2004 PROK2 (Bv8) injected into rat brain lateral ventricles suppresses feeding and stimulates drinking; PK-2 mRNA is expressed in the suprachiasmatic nucleus (SCN) with circadian variation (highest during light phase); PKR-2 is expressed in arcuate nucleus, SCN, and other hypothalamic regions. Bv8 microinjected into the arcuate nucleus selectively suppresses feeding, and into the subfornical organ stimulates drinking. ICV and microinjection of Bv8 in rats; in situ hybridization for mRNA localization; behavioral assays for feeding and drinking British journal of pharmacology Medium 15066905
2005 The N-terminal sequence of PROK2 (Bv8), specifically the AVITGA motif, is essential for receptor binding and biological activity; deletion of the first two amino acids (des-AlaVal-Bv8) abolishes biological activity in vitro and in vivo and produces receptor antagonism. Receptor binding assays, Ca2+ transient assays in CHO cells expressing PKR1/PKR2, MAPK phosphorylation assays, in vivo hyperalgesia assays British journal of pharmacology High 16113687
2006 PROK2 (Bv8) sensitizes TRPV1 (the heat/capsaicin receptor) in dorsal root ganglion nociceptors via a pathway involving PKCε translocation; Bv8 causes Ca2+ increases in capsaicin/bradykinin/mustard oil-responsive DRG neurons through prokineticin receptors. GDNF induces de novo expression of functional prokineticin receptors in non-peptidergic DRG neurons. Intracellular Ca2+ imaging, PKCε translocation assay, behavioral hyperalgesia assay with PKC antagonists, single-cell RT-PCR, GDNF treatment experiments The Journal of neuroscience High 16687502
2006 PROK2 (Bv8) is expressed by macrophages along with PKR1 and PKR2; Bv8 induces potent macrophage chemotaxis (at 10^-12 M) and stimulates LPS-induced IL-1 and IL-12 production while reducing IL-10. These effects are not pertussis-toxin sensitive but are blocked by the phospholipase inhibitor U73122, implicating Gq protein. PKR1 knockout mice studies show all macrophage effects are mediated by PKR1. Macrophage chemotaxis assay, cytokine ELISA, pharmacological inhibition (pertussis toxin, U73122), PKR1 knockout mice British journal of pharmacology High 16299550
2007 In tumors, G-CSF is a major positive regulator of PROK2 (Bv8) expression in CD11b+Gr1+ myeloid cells; Bv8 modulates mobilization of CD11b+Gr1+ cells from bone marrow during tumor development and promotes angiogenesis locally. Anti-Bv8 antibodies reduce myeloid cell mobilization and suppress tumor angiogenesis. Adenoviral Bv8 delivery to tumors, anti-Bv8 antibody treatment, flow cytometry of myeloid cells, tumor growth/vascular density assays in mice Nature High 18064003
2007 Intra-PAG PROK2 (Bv8) increases GABA (but not glutamate) extracellular levels in the periaqueductal grey, exerts pronociceptive action, and modulates RVM On-cell and Off-cell activities, consistent with pain facilitation through a GABAergic mechanism. Intra-PAG microinjection, microdialysis measurement of GABA/glutamate, extracellular single-unit recording of RVM neurons, behavioral thermoceptive reflex tests The European journal of neuroscience Medium 18005070
2008 PROK2 (Bv8) mediates neutrophil-dependent angiogenesis in RIP-Tag transgenic mice; early anti-Bv8 treatment inhibits the angiogenic switch and reduces CD11b+Gr1+ cell mobilization and homing to neoplastic lesions, demonstrating Bv8's role in the early stages of tumor angiogenesis. Anti-Bv8 antibody treatment in RIP-Tag transgenic mice, histological vascular analysis, flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 18268320
2008 PROK2 (Bv8) expression in human neutrophils and bone marrow cells is regulated by G-CSF and GM-CSF; in monocytes and lymphocytes by IL-10. Bv8 potently promotes neutrophil chemotaxis; only PKR2 is detectable in human neutrophils. Cytokine treatment of isolated human blood cells, RT-PCR, Bv8 partial purification from neutrophils with bioactivity assay, receptor expression analysis Clinical cancer research Medium 19336519
2009 Granulocyte-derived PROK2 (GrPK2) is the primary mediator of inflammatory pain initiation and peripheral sensitization; PK2 mRNA is up-regulated in granulocytes at sites of inflammation; mice lacking PKR1 or PKR2 develop significantly less inflammation-induced hyperalgesia; PKR1 regulates PK2 levels during inflammation (feedback loop); a non-peptide PKR antagonist abolishes prokineticin-induced hypernociception. CFA-induced paw inflammation model, PK2 protein purification from peritoneal granulocytes, receptor binding assays, PKR1/PKR2 knockout mice, PKR antagonist treatment, behavioral pain assays Proceedings of the National Academy of Sciences of the United States of America High 19667192
2010 The 3D structure of synthetic Bv8 (PROK2 homolog) was determined by NMR spectroscopy; the protein adopts a structure homologous to mamba intestinal toxin 1. The N-terminal five residues critical for receptor binding do not perturb the core structure when deleted, suggesting receptor binding involves cooperative/allosteric rearrangements. Chemical synthesis (Boc SPPS + native chemical ligation + in vitro folding), NMR structure determination, functional assays in neuroblastoma cells and rat DRG neurons Chembiochem High 20677202
2012 G-CSF-induced PROK2 (Bv8) expression in CD11b+Gr1+ myeloid cells requires STAT3 activation; phospho-STAT3 binds the Bv8 promoter (shown by ChIP); siRNA-mediated STAT3 knockdown reduces G-CSF-induced Bv8 expression; this regulation is conserved in human bone marrow cells. Pharmacological inhibitors of signaling pathways, siRNA knockdown, chromatin immunoprecipitation (ChIP), luciferase reporter assay, in vivo mouse studies The Journal of biological chemistry High 22528488
2012 PROK2 (Bv8) induces biphasic hyperalgesia through: (1) direct release of CGRP from spinal cord tissue; (2) a protein-synthesis dependent late phase involving upregulation of CGRP and substance P in lumbar dorsal horn and DRG. Protein synthesis inhibitors block the late but not early phase. Spinal cord slice CGRP release assay, protein synthesis inhibitor pretreatment, immunohistochemistry for CGRP/substance P, behavioral hyperalgesia assays Neuroscience letters Medium 22641053
2013 PROK2 (BV8) activates STAT3 in normal and malignant myeloid cells through JAK2; BV8-induced STAT3 activation regulates genes important for tumor cell proliferation/survival and angiogenesis; BV8 knockdown in human myeloid leukemia cells inhibits STAT3 activity and reduces tumor growth in vivo. A BV8-STAT3 feed-forward loop exists in myeloid cells. JAK2 genetic and pharmacological inhibition, BV8 shRNA knockdown, tumor xenograft assays, gene expression analysis The Journal of biological chemistry High 23548897
2013 PROK2/PROKR2 signaling mutations cause Kallmann syndrome through loss-of-function effects including defective cell surface-targeting of the receptor, defective G protein coupling, or impaired receptor-ligand interaction. Homozygous Prok2 and Prokr2 knockout mice have olfactory bulb agenesis/hypoplasia and hypogonadotropic hypogonadism due to failed GnRH neuron migration. Functional characterization of mutations in transfected cells, Prok2/Prokr2 knockout mouse phenotyping Frontiers in endocrinology High 23596439
2014 PROK2 and its receptor PKR2 are up-regulated in nociceptors, Schwann cells, and activated astrocytes of the spinal cord following chronic sciatic nerve constriction injury; PKR antagonism (PC1) reduces microgliosis, astrocyte activation, restores cytokine balance, and abolishes thermal hyperalgesia and allodynia, demonstrating PROK2 involvement in neuropathic pain through neuron-glia interaction. Chronic constriction injury mouse model, intrathecal/perineural/s.c. injection of PKR antagonist, immunohistochemistry, cytokine measurement (IL-1β, IL-10), glia activation analysis British journal of pharmacology Medium 24902717
2019 PROK2/PROKR2 signaling is required for migration of most olfactory bulb interneurons; Prokr2 is expressed in postmitotic immature interneurons in the SVZ-RMS-OB; in Prok2 and Prokr2 mutant mice, ~75% of GABAergic interneurons in the OB are lost due to severe tangential and radial migration defects of neuroblasts. Prok2EGFP transgenic and Prokr2LacZ/+ knockin mice, genetic knockout phenotyping, immunofluorescence, cell counting The Journal of comparative neurology High 31132148
2022 The anorexigenic effect of PROK2 is mediated by PKR2 in the amygdala (not hypothalamus); targeted silencing of PKR2 and chemogenetic manipulation of amygdala PKR2 neurons blocks PK2-induced food intake inhibition; MRAP2 expression in PKR2 neurons modulates PK2 signaling activity in vivo. Targeted PKR2 silencing, DREADD-based chemogenetic manipulation of amygdala PKR2 neurons, MRAP2 overexpression/knockdown, behavioral food intake assays The Journal of biological chemistry High 36539034
2012 PROK2 (Bv8) W24A substitution preferentially binds PKR2 with 5-fold lower potency; des-AlaVal-Bv8 (N-terminal deletion) abolishes receptor activation but retains binding and antagonizes Bv8-induced hyperalgesia; Bv8 modified at W24 (A-24) shows anti-hyperalgesic activity by blocking nociceptor PKR1 receptors and activating central opioid systems via PKR2. Receptor binding competition assays, Ca2+ mobilization in CHO cells expressing PKR1/PKR2, in vivo hyperalgesia assays, β-endorphin measurement British journal of pharmacology Medium 22122547
2016 Cutaneous application of PROK2 (Bv8) at nanomolar concentrations sensitizes peripheral unmyelinated polymodal C-fibers to heat by increasing heat-induced discharge, reducing threshold temperature, and increasing heat-induced CGRP release; PROK2 co-localizes with CGRP in plantar skin and nerve. The sensitization is partly but not exclusively through TRPV1. Single-fiber electrophysiology recordings from cutaneous nerve, CGRP release assay from skin flaps and trigeminal ganglia, immunohistochemistry European journal of pain Medium 26914965
2020 PROK2 activates the AKT/GSK3β signaling pathway via PKR1 and PKR2 receptors to protect cardiomyocytes; the cardioprotective effects of metformin are mediated through the PK2/PKR-AKT/GSK3β pathway, as demonstrated by AKT inhibitor and PKRA7 (PK2 antagonist) blocking these effects in high-glucose-treated cardiomyocytes and diabetic mice. Western blotting for p-AKT/AKT and p-GSK3β, AKT-knockout mice cardiomyocytes, PKRA7 antagonist treatment, streptozotocin diabetic mouse model Frontiers in physiology Medium 32508669
2024 Intracerebroventricular PROK2 infusion increases GnRH mRNA expression in the hypothalamus and elevates serum FSH, LH, and testosterone levels, demonstrating that PROK2 activates the hypothalamic-pituitary-gonadal (HPG) axis. ICV osmotic mini-pump infusion of PROK2, RT-PCR for GnRH mRNA, ELISA for FSH/LH/testosterone, histological analysis of testicular tissue Molecular biology reports Medium 38740671
2020 PROK2 knockdown in HeLa cells significantly inhibits cell migration, invasion, and MMP15 protein expression; PROK2 overexpression reverses these effects and upregulates MMP15, demonstrating that PROK2 promotes cervical cancer invasion by regulating MMP15 expression. siRNA knockdown, PROK2 overexpression plasmid, migration/invasion assays (transwell), Western blot for MMP15 International journal of molecular sciences Medium 32887509
2022 miR-141-3p targets PBX1, and PBX1 transcriptionally regulates PROK2 expression; inhibition of miR-141-3p reduces NSC apoptosis in MCAO mice through the miR-141-3p/PBX1/PROK2 axis. Luciferase reporter assay (miR-141-3p targeting PBX1), RT-PCR and Western blot for PROK2 regulation by PBX1, ICV injection of agomir/antagomir in MCAO mice, TUNEL staining Cell cycle Medium 36548024

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 535 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 268 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 149 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
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
2016 Mit1 Transcription Factor Mediates Methanol Signaling and Regulates the Alcohol Oxidase 1 (AOX1) Promoter in Pichia pastoris. The Journal of biological chemistry 88 26828066
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 80 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.) 57 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 51 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
2019 Mitochondrial Iron Transporters (MIT1 and MIT2) Are Essential for Iron Homeostasis and Embryogenesis in Arabidopsis thaliana. Frontiers in plant science 31 31850005
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 The PROK2/PROKR2 signaling pathway is required for the migration of most olfactory bulb interneurons. The Journal of comparative neurology 27 31132148
2019 Transcriptional gene silencing requires dedicated interaction between HP1 protein Chp2 and chromatin remodeler Mit1. Genes & development 26 30808655
2015 Prokineticin 2 (PROK2) is an important factor for angiogenesis in colorectal cancer. Oncotarget 26 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 22 22497736
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
2019 Efficient influenza A virus production in high cell density using the novel porcine suspension cell line PBG.PK2.1. Vaccine 21 31005427
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
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
2019 Involvement of the Chemokine Prokineticin-2 (PROK2) in Alzheimer's Disease: From Animal Models to the Human Pathology. Cells 17 31766244
2024 Targeting JAK2/STAT3, NLRP3/Caspase-1, and PK2/PKR2 Pathways with Arbutin Ameliorates Lead Acetate-Induced Testicular Injury in Rats. Pharmaceuticals (Basel, Switzerland) 16 39065759
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
2024 Overexpression of the transcriptional activators Mxr1 and Mit1 enhances lactic acid production on methanol in Komagataellaphaffii. Metabolic engineering 13 39067842
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 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
2019 Bv8-Like Toxin from the Frog Venom of Amolops jingdongensis Promotes Wound Healing via the Interleukin-1 Signaling Pathway. Toxins 11 31905801
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
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 10 34055003
2022 Enhancing xylanase expression of Komagataella phaffii induced by formate through Mit1 co-expression. Bioprocess and biosystems engineering 9 35881246
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
2023 PK2/PKRs pathway is involved in the protective effect of artemisinin against trimethyltin chloride-induced hippocampal injury. Toxicology 8 36696940
2022 Alzheimer's disease-associated inflammatory pathways might contribute to osteoporosis through the interaction between PROK2 and CSF3. Frontiers in neurology 8 36203970
2022 Prokineticin 2/PROK2 and Male Infertility. Biomedicines 8 36289651
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
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
2024 Intracerebroventricular PROK2 infusion could increase the secretion of male reproductive hormones by stimulating the HPG axis. Molecular biology reports 3 38740671
2013 GRANULOCYTE INFILTRATION AND EXPRESSION OF THE PRO-ANGIOGENIC BV8 PROTEIN IN EXPERIMENTAL EL4 AND LEWIS LUNG CARCINOMA TUMORS. Cureus 3 25493215