{"gene":"PROKR1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2002,"finding":"PROKR1 (ZAQ/GPR73) is a cognate receptor for EG-VEGF/prokineticin 1 and prokineticin 2; both ligands induce a transient increase in intracellular calcium ([Ca2+]i) with nanomolar potency in CHO cells expressing PROKR1, bind with high affinity, and display different receptor selectivity between PROKR1 and PROKR2.","method":"Radioligand binding assay and intracellular calcium mobilization assay in heterologous CHO cell expression system","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct ligand-receptor deorphanization with binding assays and functional calcium mobilization, replicated across two receptors with multiple orthogonal methods","pmids":["12054613"],"is_preprint":false},{"year":2008,"finding":"PROK1-PROKR1 interaction in endometrial epithelial cells induces inositol phosphate mobilization and sequential phosphorylation of c-Src, EGFR, and ERK1/2; downstream target genes include COX-2, LIF, IL-6, IL-8, and IL-11; COX-2 expression and prostaglandin synthesis are elevated via a Gq-PLC-β-cSrc-EGFR-MEK pathway.","method":"Stably transfected Ishikawa PROKR1 cell line; inositol phosphate assay; phosphorylation assays; signaling inhibitors; gene microarray; qPCR; Western blot","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IP assay, phosphorylation cascade, inhibitor pharmacology, microarray, qPCR/Western) in a defined cell model with functional validation","pmids":["18339712"],"is_preprint":false},{"year":2009,"finding":"PROK1 induces LIF expression in endometrial epithelial cells via PROKR1 through a Gq-Ca2+-cSrc-MEK-mediated pathway; hCG-mediated LIF induction is dependent on prior PROK1 induction (demonstrated by miRNA knockdown of PROK1).","method":"Endometrial epithelial cell treatment; signaling pathway inhibitors; miRNA knockdown of PROK1; in vivo baboon model; immunohistochemistry co-localization","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by loss-of-function miRNA knockdown, pharmacological inhibitors, and in vivo model with multiple orthogonal readouts","pmids":["19255255"],"is_preprint":false},{"year":2009,"finding":"PROK1-PROKR1 signaling induces IL-11 expression via a Gq/11-ERK-Ca2+-calcineurin-NFAT-dependent pathway; RCAN1-4 acts as a negative regulator of this calcineurin-mediated signaling to IL-11.","method":"PROKR1 Ishikawa stable cell line; calcineurin/NFAT pathway inhibitors; adenoviral RCAN1-4 overexpression; lentiviral miRNA PROK1 knockdown in decidua; ELISA","journal":"Molecular human reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal interventions (pharmacological inhibition, OE, KD) with functional readout in both cell line and primary tissue","pmids":["19801577"],"is_preprint":false},{"year":2010,"finding":"PROKR1 mediates EG-VEGF's angiogenic effects (proliferation, migration, survival, sprout formation, pseudovascular organization) in placental microvascular endothelial cells, whereas PROKR2 mediates EG-VEGF-induced cellular permeability.","method":"siRNA knockdown and neutralizing antibody strategies to differentiate PROKR1 vs PROKR2 in primary HPEC and HUVEC; proliferation, migration, survival, spheroid sprouting, permeability assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor-specific siRNA and antibody knockdown with multiple angiogenic functional assays, demonstrating differential receptor roles","pmids":["20587779"],"is_preprint":false},{"year":2010,"finding":"PROK1 regulates CTGF expression via the Gq-PLC-cSrc-EGFR-MAPK/ERK kinase pathway in PROKR1-expressing endometrial epithelial cells; miRNA knockdown of PROK1 in decidua reduces CTGF expression.","method":"PROKR1-Ishikawa stable cell line; signaling inhibitor panel; qPCR; Western blot; miRNA knockdown in decidua; immunohistochemistry","journal":"Human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with loss-of-function confirmation, single lab","pmids":["21098624"],"is_preprint":false},{"year":2010,"finding":"Cotinine exposure increases fallopian tube PROKR1 expression via nicotinic acetylcholine receptor α-7 (nAChRα-7); co-treatment with an nAChRα-7 antagonist abrogates cotinine-induced PROKR1 upregulation.","method":"FT explant culture and OE-E6/E7 cell line treatment with cotinine ± nAChRα-7 antagonist; qRT-PCR; Western blot; immunohistochemistry","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological antagonist rescue experiment with multiple readouts, single lab","pmids":["20864676"],"is_preprint":false},{"year":2007,"finding":"PKR1 (PROKR1) signaling in cardiomyocytes and cardiac endothelial cells promotes survival and vessel-like formation; prokineticin-2 activates Akt to protect cardiomyocytes against oxidative stress via PKR1, as siRNA knockdown of PKR1 reverses these effects; intramyocardial PKR1 gene transfer after coronary ligation reduces mortality and preserves left ventricular function by promoting neovascularization independently of VEGF.","method":"siRNA knockdown of PKR1; PKR1 overexpression in cardiac cells; Akt phosphorylation assay; in vivo intramyocardial gene transfer; coronary ligation mouse model; echocardiography; histology","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA loss-of-function, gain-of-function OE, in vivo gene transfer, multiple orthogonal readouts (cell survival, vessel formation, Akt activation, cardiac function)","pmids":["17442730"],"is_preprint":false},{"year":2011,"finding":"PROK1 induces DKK1 expression via PROKR1 through a Gq-calcium-calcineurin-NFAT-mediated pathway; PROK1-PROKR1 signaling negatively regulates endometrial epithelial cell proliferation via DKK1 (demonstrated by siRNA against DKK1 reducing PROK1-induced decrease in proliferation); decidualization of primary stromal cells requires PROK1 and DKK1.","method":"PROKR1-Ishikawa stable cell line; calcineurin-NFAT pathway inhibitors; siRNA against DKK1; miRNA knockdown of PROK1 in decidua; decidualization assay with progesterone and cAMP","journal":"Molecular human reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by siRNA rescue, pharmacological pathway inhibition, and primary tissue loss-of-function, multiple orthogonal methods","pmids":["21546446"],"is_preprint":false},{"year":2012,"finding":"EG-VEGF-induced trophoblast proliferation involves PROKR1 but not PROKR2, mediated through the homeobox gene HLX; EG-VEGF increases placental villi vascularization and survival.","method":"Trophoblast proliferation assay ([3H]-thymidine incorporation, Ki67); siRNA/antibody receptor subtype discrimination; HLX pathway analysis; placental explant cultures","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor subtype siRNA discrimination with functional proliferation readouts, single lab","pmids":["22941044"],"is_preprint":false},{"year":2013,"finding":"PROKR1 variant I379V decreases intracellular calcium influx but increases cell invasiveness compared to wild-type PROKR1; cell proliferation, cell-cell adhesion, and tube organization are not significantly affected by this variant.","method":"Ectopic expression of PROKR1-I379V in HEK293 and JAR cells; intracellular calcium assay; cell invasion assay; cell proliferation and adhesion assays","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct functional characterization of PROKR1 variant by calcium assay and invasion assay, single lab, multiple functional readouts","pmids":["23687280"],"is_preprint":false},{"year":2015,"finding":"PROK1 treatment of germ cells stably expressing PROKR1 results in ERK phosphorylation and elevated COX2 expression; PROK1-PROKR1 signaling activates the ERK pathway in germ cells.","method":"TCam-2 germ cell line stably transfected with PROKR1; PROK1 treatment; ERK phosphorylation assay; COX2 expression qRT-PCR/Western blot","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable PROKR1 cell model with functional signaling readouts, single lab","pmids":["26192875"],"is_preprint":false},{"year":2016,"finding":"PROKR1 localizes to primary cilia in trophoblast cells; depletion of IFT88 (required for ciliogenesis) inhibits primary cilia growth and attenuates EG-VEGF-induced ERK1/2 activation, MMP2/MMP9 upregulation, and trophoblast invasion, demonstrating that primary cilia-localized PROKR1 is required for EG-VEGF signaling.","method":"Immunofluorescence localization of PROKR1 to primary cilia; IFT88 siRNA knockdown; ERK1/2 phosphorylation; MMP2/MMP9 expression; invasion assay in HTR-8/SVneo cells","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct subcellular localization experiment tied to loss-of-function phenotype (ciliogenesis KD), with multiple downstream functional readouts","pmids":["27736039"],"is_preprint":false},{"year":2018,"finding":"TBX20 regulates angiogenesis through the PROK2-PROKR1 pathway; in zebrafish, loss of prokr1a limits angiogenesis, and overexpression of prokr1a rescues impaired angiogenesis in tbx20-deficient animals.","method":"Zebrafish morpholino knockdown of tbx20 and prok2; CRISPR/Cas9 genetic disruption of tbx20; prokr1a overexpression rescue; in vivo Matrigel plug angiogenesis model; angiogenesis gene array","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis by loss-of-function and rescue gain-of-function in multiple in vivo models (zebrafish + murine), identifying PROKR1 position in TBX20-PROK2 pathway","pmids":["29545372"],"is_preprint":false},{"year":2018,"finding":"PROKR1 activation by prokineticin-2 in skeletal muscle myotubes activates Gq-mediated PI3K/AKT and MAPK/ERK signaling pathways; PROKR1 promotes GLUT4 translocation to the plasma membrane and enhances insulin-stimulated AKT phosphorylation and glucose uptake in palmitate-induced insulin-resistant myotubes.","method":"PROKR1-overexpressed HEK293T cells; calcium mobilization assay; RNA-seq of 578 differentially expressed genes; PI3K/AKT/MAPK pathway inhibitors; AKT phosphorylation assay; GLUT4 translocation imaging; glucose uptake assay in C2C12 and satellite cell-derived myotubes","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transcriptomics, pathway inhibitors, GLUT4 translocation, glucose uptake) in both cell line and primary cell models","pmids":["33184929"],"is_preprint":false},{"year":2019,"finding":"PKR1 (PROKR1) activation by the non-peptide agonist IS20 alleviates doxorubicin-induced toxicity in cardiomyocytes, endothelial cells, and epicardium-derived progenitor cells by activating Akt or MAPK pathways; genetic or pharmacological inactivation of PKR1 abolishes these protective effects of IS20.","method":"Cultured cardiomyocytes, ECs, EDPCs; Akt/MAPK phosphorylation assays; PKR1 genetic inactivation; pharmacological PKR1 antagonism; chronic DOX cardiotoxicity mouse model; cardiac function assessment","journal":"JACC CardioOncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor-specific loss-of-function (genetic + pharmacological) combined with in vivo mouse model and multiple cellular mechanistic readouts","pmids":["34396166"],"is_preprint":false},{"year":2020,"finding":"PROK1-PROKR1 signaling in porcine endometrial endothelial cells promotes angiogenesis via PI3K/AKT/mTOR, MAPK, cAMP, and NF-κB pathways; PROK1 via PROKR1 stimulates capillary-like structure formation and induces VEGFA and PGF2α secretion.","method":"Primary porcine endometrial endothelial cells; PROKR1 blocking antibody; pathway inhibitors (PI3K, MAPK, cAMP, NF-κB); proliferation assay; tube formation assay; VEGFA/PGF2α ELISA","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with receptor blocking antibody, multiple functional angiogenesis assays, single lab","pmids":["32355954"],"is_preprint":false},{"year":2021,"finding":"PROK1 acting via PROKR1 increases trophoblast cell proliferation (via PI3K/AKT/mTOR and MAPK and cAMP pathways) and adhesion (via MAPK and/or PI3K/AKT pathways); PROK1-PROKR1 signaling induces phosphorylation of MAPK and PTK2 in porcine trophoblasts.","method":"Porcine trophoblast cell treatment with PROK1 ± PROKR1 antagonist; PI3K/AKT/mTOR, MAPK, cAMP pathway inhibitors; proliferation and adhesion assays; phosphorylation assays; Ingenuity Pathway Analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific antagonist with pathway inhibitors, multiple functional readouts, single lab","pmids":["34215801"],"is_preprint":false},{"year":2021,"finding":"PROK1 acting via PROKR1 stimulates progesterone synthesis genes and progesterone secretion, reduces apoptosis and increases viability of luteal cells, and stimulates angiogenesis (capillary-like structure formation, angiogenin gene expression, VEGFA secretion) in porcine corpus luteum.","method":"Luteal tissue explants and luteal endothelial cells; PROKR1-specific antagonist PC7; steroidogenesis gene expression; progesterone ELISA; apoptosis and viability assays; tube formation assay; VEGFA ELISA","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific antagonist used with multiple functional assays in primary tissue, single lab","pmids":["36991037"],"is_preprint":false},{"year":2022,"finding":"The PROK2 splice variant PROK2C binds to the amino-terminal regions of PROKR1 (demonstrated by GST pull-down); PROK2C activates PROKR1 to induce ERK phosphorylation in CHO cells expressing PROKR1; tryptophan at position 212 of PROKR2 is required for PROK2C binding.","method":"GST pull-down; amber codon suppression photoactivatable crosslinking; CHO cell expression of PROKR1; STAT3 and ERK phosphorylation assays; in vivo nociceptive experiments","journal":"Life (Basel)","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct binding assay (GST pull-down, crosslinking) with functional signaling validation, single lab","pmids":["35207535"],"is_preprint":false},{"year":2024,"finding":"PROKR1 signaling activates the PROKR1-CREB-NR4A2 axis via Gs-mediated cAMP-CREB phosphorylation to upregulate NR4A2, promoting oxidative muscle fiber specification, mitochondrial biogenesis, and metabolic function; Prokr1-deficient mice show reduced oxidative fiber composition, impaired glucose/insulin tolerance, and reduced energy expenditure, all rescued by AAV-mediated Prokr1 re-expression.","method":"ChIP-PCR; luciferase promoter assays; pharmacological inhibitors; Prokr1 knockout mice; AAV-mediated Prokr1 rescue; metabolic phenotyping; exercise performance testing; histological fiber-type analysis; human myotube experiments","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, luciferase, KO mice, AAV rescue, metabolic phenotyping) establishing the full PROKR1-CREB-NR4A2 mechanistic axis","pmids":["38232288"],"is_preprint":false},{"year":2025,"finding":"Celecoxib selectively activates Gs signaling via PROKR1 (EC50 ~4 μM), competitively inhibits PK2 binding to PROKR1, and increases NR4A2 protein levels, pCREB, and oxidative muscle fiber markers (Myh7, mitochondrial content, FAO activity) in myotubes; these effects are PROKR1-dependent.","method":"Molecular docking; competitive binding assay; cAMP accumulation assay; Gs signaling assay; PROKR1-overexpressing cell studies; murine and human myotube experiments; in vivo offspring phenotyping with HFD","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — binding competition, Gs signaling, and functional muscle assays confirm PROKR1 as celecoxib target, single lab","pmids":["39887895"],"is_preprint":false},{"year":2018,"finding":"PROKR1 activation by PROK2 (Prokr1-expressing 4T1 cells) promotes breast cancer cell proliferation in the lung metastasis context; deletion of Prokr1 in 4T1 cells abrogates 5-FU-enhanced lung metastasis, identifying PROKR1 as the receptor on tumor cells mediating PROK2 signals from infiltrating neutrophils.","method":"CRISPR/Cas9 Prokr1 deletion in 4T1 tumor cells; mouse lung metastasis model; tumor cell proliferation and metastasis quantification","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion with in vivo functional readout, single lab","pmids":["29643149"],"is_preprint":false}],"current_model":"PROKR1 is a Gq/Gs-coupled G protein-coupled receptor for prokineticin 1 (EG-VEGF) and prokineticin 2 that, upon ligand binding, activates multiple intracellular cascades including Gq-PLC-Ca2+-calcineurin-NFAT, cSrc-EGFR-MAPK/ERK, PI3K/AKT, and Gs-cAMP-CREB pathways to drive angiogenesis, cardiomyocyte survival, endometrial gene regulation (COX-2, LIF, IL-11, DKK1, CTGF), trophoblast proliferation and invasion, skeletal muscle oxidative fiber specification via the PROKR1-CREB-NR4A2 axis, and insulin sensitivity through GLUT4 translocation; it localizes to primary cilia where it relays EG-VEGF signals to ERK-MMP-dependent cell invasion, and its activity is regulated by upstream transcription factors (TBX20 via PROK2) and by receptor variants that alter calcium signaling and cell invasiveness."},"narrative":{"mechanistic_narrative":"PROKR1 (ZAQ/GPR73) is a G protein-coupled receptor for the prokineticin ligands EG-VEGF/prokineticin 1 and prokineticin 2, deorphanized through high-affinity binding and nanomolar-potency intracellular calcium mobilization in heterologous cells [PMID:12054613]. Ligand engagement drives a Gq-PLC-Ca2+ branch that proceeds through c-Src, EGFR, and ERK1/2, as well as a calcineurin-NFAT arm, to control a panel of endometrial target genes including COX-2, LIF, IL-11, CTGF and DKK1, thereby coordinating prostaglandin synthesis, decidualization, and epithelial proliferation [PMID:18339712, PMID:19801577, PMID:21546446]; in parallel PROKR1 couples to PI3K/AKT and Gs-cAMP-CREB cascades [PMID:33184929, PMID:38232288]. Through these outputs PROKR1 promotes angiogenesis and cell survival: it mediates EG-VEGF-driven endothelial proliferation, migration, survival and sprouting (distinct from PROKR2-mediated permeability) [PMID:20587779], protects cardiomyocytes and cardiac cells from oxidative and chemotherapeutic stress via Akt/MAPK [PMID:17442730, PMID:34396166], and supports trophoblast proliferation and invasion [PMID:22941044, PMID:27736039]. In trophoblasts the receptor localizes to primary cilia, where it relays EG-VEGF to ERK-MMP2/9-dependent invasion [PMID:27736039]. A Gs-cAMP-CREB-NR4A2 axis specifies oxidative skeletal-muscle fibers and governs mitochondrial biogenesis and systemic glucose handling, with Prokr1-deficient mice showing impaired glucose tolerance and energy expenditure rescued by re-expression [PMID:38232288], consistent with a role in GLUT4 translocation and insulin sensitivity in myotubes [PMID:33184929]. PROKR1 sits downstream of TBX20-PROK2 control of angiogenesis [PMID:29545372], and a coding variant (I379V) that reduces calcium signaling while increasing invasiveness illustrates how receptor sequence tunes its outputs [PMID:23687280].","teleology":[{"year":2002,"claim":"Established the identity of PROKR1 as a functional receptor by showing both prokineticin ligands bind and trigger calcium signaling, converting an orphan GPCR into a defined signaling entity.","evidence":"Radioligand binding and intracellular calcium mobilization in CHO cells expressing PROKR1","pmids":["12054613"],"confidence":"High","gaps":["G protein coupling specificity not resolved at deorphanization","no endogenous physiological context defined"]},{"year":2007,"claim":"Defined a cytoprotective and pro-angiogenic role by showing PROKR1 activation drives Akt-dependent cardiomyocyte survival and vessel formation, extending the receptor beyond reproductive tissue into cardiac biology.","evidence":"siRNA knockdown, overexpression, Akt phosphorylation, and in vivo intramyocardial gene transfer in a coronary ligation mouse model","pmids":["17442730"],"confidence":"High","gaps":["did not dissect Gq vs other couplings in cardiomyocytes","VEGF-independence of neovascularization mechanism not fully mapped"]},{"year":2008,"claim":"Mapped the proximal endometrial signaling cascade, showing PROKR1 links Gq-PLC to a c-Src-EGFR-ERK relay that drives inflammatory and implantation-related gene expression.","evidence":"Stable PROKR1 Ishikawa cell line with IP assays, phosphorylation cascade analysis, inhibitor pharmacology, microarray and qPCR","pmids":["18339712"],"confidence":"High","gaps":["EGFR transactivation mechanism not structurally defined","in vivo relevance of full gene panel not established"]},{"year":2009,"claim":"Resolved branch-specific outputs by showing distinct target genes route through either MEK (LIF) or calcineurin-NFAT (IL-11), revealing PROKR1 engages parallel intracellular arms.","evidence":"PROKR1 Ishikawa cells, pathway inhibitors, miRNA PROK1 knockdown, RCAN1-4 overexpression, baboon in vivo model","pmids":["19255255","19801577"],"confidence":"High","gaps":["how a single receptor partitions signal between MEK and calcineurin arms unknown","regulatory role of RCAN1-4 in intact tissue not quantified"]},{"year":2010,"claim":"Separated receptor subtype functions, showing PROKR1 (not PROKR2) carries EG-VEGF angiogenic actions while extending the CTGF target set and identifying upstream control of PROKR1 expression by nAChRα-7.","evidence":"Receptor-specific siRNA and neutralizing antibodies in primary endothelial cells; pathway inhibitors; cotinine/nAChRα-7 antagonist experiments","pmids":["20587779","21098624","20864676"],"confidence":"High","gaps":["molecular basis of PROKR1 vs PROKR2 functional divergence unresolved","transcriptional control of PROKR1 beyond nAChRα-7 not characterized"]},{"year":2011,"claim":"Connected calcium-calcineurin-NFAT signaling to anti-proliferative control, showing PROK1-PROKR1 induces DKK1 to restrain epithelial proliferation and enable decidualization.","evidence":"PROKR1 Ishikawa cells, calcineurin-NFAT inhibitors, DKK1 siRNA rescue, decidualization assays in primary stromal cells","pmids":["21546446"],"confidence":"High","gaps":["link between DKK1 induction and Wnt pathway output not measured","context determining proliferative vs anti-proliferative outcome unclear"]},{"year":2012,"claim":"Extended subtype specificity to placental development, attributing EG-VEGF-induced trophoblast proliferation to PROKR1 acting via the homeobox factor HLX.","evidence":"Trophoblast proliferation assays, receptor-subtype siRNA/antibody discrimination, placental explants","pmids":["22941044"],"confidence":"Medium","gaps":["mechanism linking PROKR1 to HLX not defined","single-lab finding"]},{"year":2013,"claim":"Demonstrated that receptor sequence variation tunes signaling output, with the I379V variant uncoupling reduced calcium influx from enhanced invasiveness.","evidence":"Ectopic PROKR1-I379V expression in HEK293 and JAR cells with calcium, invasion, proliferation and adhesion assays","pmids":["23687280"],"confidence":"Medium","gaps":["structural basis of altered signaling not determined","physiological/clinical association of variant not established"]},{"year":2016,"claim":"Localized PROKR1 to the primary cilium and made ciliary signaling a requirement for EG-VEGF-driven invasion, defining a subcellular platform for receptor function.","evidence":"Immunofluorescence localization, IFT88 siRNA ciliogenesis disruption, ERK/MMP2/9 and invasion readouts in HTR-8/SVneo cells","pmids":["27736039"],"confidence":"High","gaps":["ciliary targeting mechanism of PROKR1 unknown","ciliary localization in non-trophoblast cell types not examined"]},{"year":2018,"claim":"Positioned PROKR1 within an upstream transcriptional program by showing TBX20 drives angiogenesis through PROK2-PROKR1, with prokr1 overexpression rescuing tbx20 loss.","evidence":"Zebrafish morpholino and CRISPR knockdown, prokr1a overexpression rescue, in vivo Matrigel plug angiogenesis","pmids":["29545372"],"confidence":"High","gaps":["direct vs indirect TBX20 regulation of PROK2 not delineated","mammalian conservation of the axis only partially addressed"]},{"year":2018,"claim":"Implicated PROKR1 on tumor cells as the receptor relaying neutrophil-derived PROK2 to promote metastatic proliferation.","evidence":"CRISPR/Cas9 Prokr1 deletion in 4T1 cells, mouse lung metastasis model","pmids":["29643149"],"confidence":"Medium","gaps":["downstream tumor signaling pathway not mapped","single tumor model"]},{"year":2020,"claim":"Broadened the angiogenic and reproductive signaling repertoire by linking PROKR1 to PI3K/AKT/mTOR, MAPK, cAMP and NF-κB pathways driving endothelial, trophoblast and luteal functions.","evidence":"Primary porcine endothelial, trophoblast and luteal cells with PROKR1 blocking antibody/antagonist, pathway inhibitors, tube formation, proliferation, steroidogenesis and ELISA readouts","pmids":["32355954","34215801","36991037"],"confidence":"Medium","gaps":["cross-species conservation to human tissue not confirmed","single-lab pharmacological dissection"]},{"year":2024,"claim":"Established a Gs-cAMP-CREB-NR4A2 axis as the mechanism by which PROKR1 specifies oxidative muscle fibers and controls systemic metabolism, with knockout and AAV rescue defining causality.","evidence":"ChIP-PCR, luciferase assays, Prokr1 knockout mice, AAV rescue, metabolic phenotyping and human myotubes; complemented by GLUT4 translocation and glucose uptake studies","pmids":["38232288","33184929"],"confidence":"High","gaps":["coordination between Gs-cAMP and Gq arms in muscle unresolved","tissue selectivity of metabolic effects not fully mapped"]},{"year":2025,"claim":"Identified small-molecule pharmacology of PROKR1, showing celecoxib selectively activates Gs signaling and competes with PK2 to drive the NR4A2/oxidative-fiber program.","evidence":"Molecular docking, competitive binding, cAMP/Gs assays, PROKR1-overexpressing cells, murine and human myotubes, in vivo offspring phenotyping","pmids":["39887895"],"confidence":"Medium","gaps":["selectivity over other prokineticin receptors not exhaustively profiled","single-lab finding"]},{"year":null,"claim":"How PROKR1 selects among its multiple G protein arms (Gq, Gs, PI3K/AKT) in a given cell type, and the structural basis for ligand and small-molecule selectivity, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no structural model of ligand-bound PROKR1 in the corpus","rules governing biased coupling across tissues undefined","in vivo human disease links not established in the timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,19]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,14,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,9,13]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[3,8,18]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14,20]}],"complexes":[],"partners":["PROK1","PROK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TCW9","full_name":"Prokineticin receptor 1","aliases":["G-protein coupled receptor 73","G-protein coupled receptor ZAQ","GPR73a"],"length_aa":393,"mass_kda":44.8,"function":"Receptor for prokineticin 1. Exclusively coupled to the G(q) subclass of heteromeric G proteins. Activation leads to mobilization of calcium, stimulation of phosphoinositide turnover and activation of p44/p42 mitogen-activated protein kinase. May play a role during early pregnancy","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TCW9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PROKR1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PROKR1","total_profiled":1310},"omim":[{"mim_id":"607123","title":"PROKINETICIN RECEPTOR 2; PROKR2","url":"https://www.omim.org/entry/607123"},{"mim_id":"607122","title":"PROKINETICIN RECEPTOR 1; PROKR1","url":"https://www.omim.org/entry/607122"},{"mim_id":"607002","title":"PROKINETICIN 2; PROK2","url":"https://www.omim.org/entry/607002"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adipose tissue","ntpm":1.5},{"tissue":"adrenal 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and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G-protein-coupled receptors.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12054613","citation_count":183,"is_preprint":false},{"pmid":"19255255","id":"PMC_19255255","title":"Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukemia inhibitory factor.","date":"2009","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/19255255","citation_count":89,"is_preprint":false},{"pmid":"18339712","id":"PMC_18339712","title":"Prokineticin 1 signaling and gene regulation in early human pregnancy.","date":"2008","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18339712","citation_count":88,"is_preprint":false},{"pmid":"20587779","id":"PMC_20587779","title":"Molecular characterization of EG-VEGF-mediated angiogenesis: 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both ligands induce a transient increase in intracellular calcium ([Ca2+]i) with nanomolar potency in CHO cells expressing PROKR1, bind with high affinity, and display different receptor selectivity between PROKR1 and PROKR2.\",\n      \"method\": \"Radioligand binding assay and intracellular calcium mobilization assay in heterologous CHO cell expression system\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct ligand-receptor deorphanization with binding assays and functional calcium mobilization, replicated across two receptors with multiple orthogonal methods\",\n      \"pmids\": [\"12054613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PROK1-PROKR1 interaction in endometrial epithelial cells induces inositol phosphate mobilization and sequential phosphorylation of c-Src, EGFR, and ERK1/2; downstream target genes include COX-2, LIF, IL-6, IL-8, and IL-11; COX-2 expression and prostaglandin synthesis are elevated via a Gq-PLC-β-cSrc-EGFR-MEK pathway.\",\n      \"method\": \"Stably transfected Ishikawa PROKR1 cell line; inositol phosphate assay; phosphorylation assays; signaling inhibitors; gene microarray; qPCR; Western blot\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IP assay, phosphorylation cascade, inhibitor pharmacology, microarray, qPCR/Western) in a defined cell model with functional validation\",\n      \"pmids\": [\"18339712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PROK1 induces LIF expression in endometrial epithelial cells via PROKR1 through a Gq-Ca2+-cSrc-MEK-mediated pathway; hCG-mediated LIF induction is dependent on prior PROK1 induction (demonstrated by miRNA knockdown of PROK1).\",\n      \"method\": \"Endometrial epithelial cell treatment; signaling pathway inhibitors; miRNA knockdown of PROK1; in vivo baboon model; immunohistochemistry co-localization\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by loss-of-function miRNA knockdown, pharmacological inhibitors, and in vivo model with multiple orthogonal readouts\",\n      \"pmids\": [\"19255255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PROK1-PROKR1 signaling induces IL-11 expression via a Gq/11-ERK-Ca2+-calcineurin-NFAT-dependent pathway; RCAN1-4 acts as a negative regulator of this calcineurin-mediated signaling to IL-11.\",\n      \"method\": \"PROKR1 Ishikawa stable cell line; calcineurin/NFAT pathway inhibitors; adenoviral RCAN1-4 overexpression; lentiviral miRNA PROK1 knockdown in decidua; ELISA\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal interventions (pharmacological inhibition, OE, KD) with functional readout in both cell line and primary tissue\",\n      \"pmids\": [\"19801577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PROKR1 mediates EG-VEGF's angiogenic effects (proliferation, migration, survival, sprout formation, pseudovascular organization) in placental microvascular endothelial cells, whereas PROKR2 mediates EG-VEGF-induced cellular permeability.\",\n      \"method\": \"siRNA knockdown and neutralizing antibody strategies to differentiate PROKR1 vs PROKR2 in primary HPEC and HUVEC; proliferation, migration, survival, spheroid sprouting, permeability assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor-specific siRNA and antibody knockdown with multiple angiogenic functional assays, demonstrating differential receptor roles\",\n      \"pmids\": [\"20587779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PROK1 regulates CTGF expression via the Gq-PLC-cSrc-EGFR-MAPK/ERK kinase pathway in PROKR1-expressing endometrial epithelial cells; miRNA knockdown of PROK1 in decidua reduces CTGF expression.\",\n      \"method\": \"PROKR1-Ishikawa stable cell line; signaling inhibitor panel; qPCR; Western blot; miRNA knockdown in decidua; immunohistochemistry\",\n      \"journal\": \"Human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with loss-of-function confirmation, single lab\",\n      \"pmids\": [\"21098624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cotinine exposure increases fallopian tube PROKR1 expression via nicotinic acetylcholine receptor α-7 (nAChRα-7); co-treatment with an nAChRα-7 antagonist abrogates cotinine-induced PROKR1 upregulation.\",\n      \"method\": \"FT explant culture and OE-E6/E7 cell line treatment with cotinine ± nAChRα-7 antagonist; qRT-PCR; Western blot; immunohistochemistry\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological antagonist rescue experiment with multiple readouts, single lab\",\n      \"pmids\": [\"20864676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PKR1 (PROKR1) signaling in cardiomyocytes and cardiac endothelial cells promotes survival and vessel-like formation; prokineticin-2 activates Akt to protect cardiomyocytes against oxidative stress via PKR1, as siRNA knockdown of PKR1 reverses these effects; intramyocardial PKR1 gene transfer after coronary ligation reduces mortality and preserves left ventricular function by promoting neovascularization independently of VEGF.\",\n      \"method\": \"siRNA knockdown of PKR1; PKR1 overexpression in cardiac cells; Akt phosphorylation assay; in vivo intramyocardial gene transfer; coronary ligation mouse model; echocardiography; histology\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA loss-of-function, gain-of-function OE, in vivo gene transfer, multiple orthogonal readouts (cell survival, vessel formation, Akt activation, cardiac function)\",\n      \"pmids\": [\"17442730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PROK1 induces DKK1 expression via PROKR1 through a Gq-calcium-calcineurin-NFAT-mediated pathway; PROK1-PROKR1 signaling negatively regulates endometrial epithelial cell proliferation via DKK1 (demonstrated by siRNA against DKK1 reducing PROK1-induced decrease in proliferation); decidualization of primary stromal cells requires PROK1 and DKK1.\",\n      \"method\": \"PROKR1-Ishikawa stable cell line; calcineurin-NFAT pathway inhibitors; siRNA against DKK1; miRNA knockdown of PROK1 in decidua; decidualization assay with progesterone and cAMP\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by siRNA rescue, pharmacological pathway inhibition, and primary tissue loss-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"21546446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EG-VEGF-induced trophoblast proliferation involves PROKR1 but not PROKR2, mediated through the homeobox gene HLX; EG-VEGF increases placental villi vascularization and survival.\",\n      \"method\": \"Trophoblast proliferation assay ([3H]-thymidine incorporation, Ki67); siRNA/antibody receptor subtype discrimination; HLX pathway analysis; placental explant cultures\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor subtype siRNA discrimination with functional proliferation readouts, single lab\",\n      \"pmids\": [\"22941044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PROKR1 variant I379V decreases intracellular calcium influx but increases cell invasiveness compared to wild-type PROKR1; cell proliferation, cell-cell adhesion, and tube organization are not significantly affected by this variant.\",\n      \"method\": \"Ectopic expression of PROKR1-I379V in HEK293 and JAR cells; intracellular calcium assay; cell invasion assay; cell proliferation and adhesion assays\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct functional characterization of PROKR1 variant by calcium assay and invasion assay, single lab, multiple functional readouts\",\n      \"pmids\": [\"23687280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PROK1 treatment of germ cells stably expressing PROKR1 results in ERK phosphorylation and elevated COX2 expression; PROK1-PROKR1 signaling activates the ERK pathway in germ cells.\",\n      \"method\": \"TCam-2 germ cell line stably transfected with PROKR1; PROK1 treatment; ERK phosphorylation assay; COX2 expression qRT-PCR/Western blot\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable PROKR1 cell model with functional signaling readouts, single lab\",\n      \"pmids\": [\"26192875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PROKR1 localizes to primary cilia in trophoblast cells; depletion of IFT88 (required for ciliogenesis) inhibits primary cilia growth and attenuates EG-VEGF-induced ERK1/2 activation, MMP2/MMP9 upregulation, and trophoblast invasion, demonstrating that primary cilia-localized PROKR1 is required for EG-VEGF signaling.\",\n      \"method\": \"Immunofluorescence localization of PROKR1 to primary cilia; IFT88 siRNA knockdown; ERK1/2 phosphorylation; MMP2/MMP9 expression; invasion assay in HTR-8/SVneo cells\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct subcellular localization experiment tied to loss-of-function phenotype (ciliogenesis KD), with multiple downstream functional readouts\",\n      \"pmids\": [\"27736039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TBX20 regulates angiogenesis through the PROK2-PROKR1 pathway; in zebrafish, loss of prokr1a limits angiogenesis, and overexpression of prokr1a rescues impaired angiogenesis in tbx20-deficient animals.\",\n      \"method\": \"Zebrafish morpholino knockdown of tbx20 and prok2; CRISPR/Cas9 genetic disruption of tbx20; prokr1a overexpression rescue; in vivo Matrigel plug angiogenesis model; angiogenesis gene array\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis by loss-of-function and rescue gain-of-function in multiple in vivo models (zebrafish + murine), identifying PROKR1 position in TBX20-PROK2 pathway\",\n      \"pmids\": [\"29545372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PROKR1 activation by prokineticin-2 in skeletal muscle myotubes activates Gq-mediated PI3K/AKT and MAPK/ERK signaling pathways; PROKR1 promotes GLUT4 translocation to the plasma membrane and enhances insulin-stimulated AKT phosphorylation and glucose uptake in palmitate-induced insulin-resistant myotubes.\",\n      \"method\": \"PROKR1-overexpressed HEK293T cells; calcium mobilization assay; RNA-seq of 578 differentially expressed genes; PI3K/AKT/MAPK pathway inhibitors; AKT phosphorylation assay; GLUT4 translocation imaging; glucose uptake assay in C2C12 and satellite cell-derived myotubes\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transcriptomics, pathway inhibitors, GLUT4 translocation, glucose uptake) in both cell line and primary cell models\",\n      \"pmids\": [\"33184929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PKR1 (PROKR1) activation by the non-peptide agonist IS20 alleviates doxorubicin-induced toxicity in cardiomyocytes, endothelial cells, and epicardium-derived progenitor cells by activating Akt or MAPK pathways; genetic or pharmacological inactivation of PKR1 abolishes these protective effects of IS20.\",\n      \"method\": \"Cultured cardiomyocytes, ECs, EDPCs; Akt/MAPK phosphorylation assays; PKR1 genetic inactivation; pharmacological PKR1 antagonism; chronic DOX cardiotoxicity mouse model; cardiac function assessment\",\n      \"journal\": \"JACC CardioOncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor-specific loss-of-function (genetic + pharmacological) combined with in vivo mouse model and multiple cellular mechanistic readouts\",\n      \"pmids\": [\"34396166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PROK1-PROKR1 signaling in porcine endometrial endothelial cells promotes angiogenesis via PI3K/AKT/mTOR, MAPK, cAMP, and NF-κB pathways; PROK1 via PROKR1 stimulates capillary-like structure formation and induces VEGFA and PGF2α secretion.\",\n      \"method\": \"Primary porcine endometrial endothelial cells; PROKR1 blocking antibody; pathway inhibitors (PI3K, MAPK, cAMP, NF-κB); proliferation assay; tube formation assay; VEGFA/PGF2α ELISA\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with receptor blocking antibody, multiple functional angiogenesis assays, single lab\",\n      \"pmids\": [\"32355954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PROK1 acting via PROKR1 increases trophoblast cell proliferation (via PI3K/AKT/mTOR and MAPK and cAMP pathways) and adhesion (via MAPK and/or PI3K/AKT pathways); PROK1-PROKR1 signaling induces phosphorylation of MAPK and PTK2 in porcine trophoblasts.\",\n      \"method\": \"Porcine trophoblast cell treatment with PROK1 ± PROKR1 antagonist; PI3K/AKT/mTOR, MAPK, cAMP pathway inhibitors; proliferation and adhesion assays; phosphorylation assays; Ingenuity Pathway Analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific antagonist with pathway inhibitors, multiple functional readouts, single lab\",\n      \"pmids\": [\"34215801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PROK1 acting via PROKR1 stimulates progesterone synthesis genes and progesterone secretion, reduces apoptosis and increases viability of luteal cells, and stimulates angiogenesis (capillary-like structure formation, angiogenin gene expression, VEGFA secretion) in porcine corpus luteum.\",\n      \"method\": \"Luteal tissue explants and luteal endothelial cells; PROKR1-specific antagonist PC7; steroidogenesis gene expression; progesterone ELISA; apoptosis and viability assays; tube formation assay; VEGFA ELISA\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific antagonist used with multiple functional assays in primary tissue, single lab\",\n      \"pmids\": [\"36991037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The PROK2 splice variant PROK2C binds to the amino-terminal regions of PROKR1 (demonstrated by GST pull-down); PROK2C activates PROKR1 to induce ERK phosphorylation in CHO cells expressing PROKR1; tryptophan at position 212 of PROKR2 is required for PROK2C binding.\",\n      \"method\": \"GST pull-down; amber codon suppression photoactivatable crosslinking; CHO cell expression of PROKR1; STAT3 and ERK phosphorylation assays; in vivo nociceptive experiments\",\n      \"journal\": \"Life (Basel)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding assay (GST pull-down, crosslinking) with functional signaling validation, single lab\",\n      \"pmids\": [\"35207535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PROKR1 signaling activates the PROKR1-CREB-NR4A2 axis via Gs-mediated cAMP-CREB phosphorylation to upregulate NR4A2, promoting oxidative muscle fiber specification, mitochondrial biogenesis, and metabolic function; Prokr1-deficient mice show reduced oxidative fiber composition, impaired glucose/insulin tolerance, and reduced energy expenditure, all rescued by AAV-mediated Prokr1 re-expression.\",\n      \"method\": \"ChIP-PCR; luciferase promoter assays; pharmacological inhibitors; Prokr1 knockout mice; AAV-mediated Prokr1 rescue; metabolic phenotyping; exercise performance testing; histological fiber-type analysis; human myotube experiments\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, luciferase, KO mice, AAV rescue, metabolic phenotyping) establishing the full PROKR1-CREB-NR4A2 mechanistic axis\",\n      \"pmids\": [\"38232288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Celecoxib selectively activates Gs signaling via PROKR1 (EC50 ~4 μM), competitively inhibits PK2 binding to PROKR1, and increases NR4A2 protein levels, pCREB, and oxidative muscle fiber markers (Myh7, mitochondrial content, FAO activity) in myotubes; these effects are PROKR1-dependent.\",\n      \"method\": \"Molecular docking; competitive binding assay; cAMP accumulation assay; Gs signaling assay; PROKR1-overexpressing cell studies; murine and human myotube experiments; in vivo offspring phenotyping with HFD\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — binding competition, Gs signaling, and functional muscle assays confirm PROKR1 as celecoxib target, single lab\",\n      \"pmids\": [\"39887895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PROKR1 activation by PROK2 (Prokr1-expressing 4T1 cells) promotes breast cancer cell proliferation in the lung metastasis context; deletion of Prokr1 in 4T1 cells abrogates 5-FU-enhanced lung metastasis, identifying PROKR1 as the receptor on tumor cells mediating PROK2 signals from infiltrating neutrophils.\",\n      \"method\": \"CRISPR/Cas9 Prokr1 deletion in 4T1 tumor cells; mouse lung metastasis model; tumor cell proliferation and metastasis quantification\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion with in vivo functional readout, single lab\",\n      \"pmids\": [\"29643149\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PROKR1 is a Gq/Gs-coupled G protein-coupled receptor for prokineticin 1 (EG-VEGF) and prokineticin 2 that, upon ligand binding, activates multiple intracellular cascades including Gq-PLC-Ca2+-calcineurin-NFAT, cSrc-EGFR-MAPK/ERK, PI3K/AKT, and Gs-cAMP-CREB pathways to drive angiogenesis, cardiomyocyte survival, endometrial gene regulation (COX-2, LIF, IL-11, DKK1, CTGF), trophoblast proliferation and invasion, skeletal muscle oxidative fiber specification via the PROKR1-CREB-NR4A2 axis, and insulin sensitivity through GLUT4 translocation; it localizes to primary cilia where it relays EG-VEGF signals to ERK-MMP-dependent cell invasion, and its activity is regulated by upstream transcription factors (TBX20 via PROK2) and by receptor variants that alter calcium signaling and cell invasiveness.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PROKR1 (ZAQ/GPR73) is a G protein-coupled receptor for the prokineticin ligands EG-VEGF/prokineticin 1 and prokineticin 2, deorphanized through high-affinity binding and nanomolar-potency intracellular calcium mobilization in heterologous cells [#0]. Ligand engagement drives a Gq-PLC-Ca2+ branch that proceeds through c-Src, EGFR, and ERK1/2, as well as a calcineurin-NFAT arm, to control a panel of endometrial target genes including COX-2, LIF, IL-11, CTGF and DKK1, thereby coordinating prostaglandin synthesis, decidualization, and epithelial proliferation [#1, #3, #8]; in parallel PROKR1 couples to PI3K/AKT and Gs-cAMP-CREB cascades [#14, #20]. Through these outputs PROKR1 promotes angiogenesis and cell survival: it mediates EG-VEGF-driven endothelial proliferation, migration, survival and sprouting (distinct from PROKR2-mediated permeability) [#4], protects cardiomyocytes and cardiac cells from oxidative and chemotherapeutic stress via Akt/MAPK [#7, #15], and supports trophoblast proliferation and invasion [#9, #12]. In trophoblasts the receptor localizes to primary cilia, where it relays EG-VEGF to ERK-MMP2/9-dependent invasion [#12]. A Gs-cAMP-CREB-NR4A2 axis specifies oxidative skeletal-muscle fibers and governs mitochondrial biogenesis and systemic glucose handling, with Prokr1-deficient mice showing impaired glucose tolerance and energy expenditure rescued by re-expression [#20], consistent with a role in GLUT4 translocation and insulin sensitivity in myotubes [#14]. PROKR1 sits downstream of TBX20-PROK2 control of angiogenesis [#13], and a coding variant (I379V) that reduces calcium signaling while increasing invasiveness illustrates how receptor sequence tunes its outputs [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the identity of PROKR1 as a functional receptor by showing both prokineticin ligands bind and trigger calcium signaling, converting an orphan GPCR into a defined signaling entity.\",\n      \"evidence\": \"Radioligand binding and intracellular calcium mobilization in CHO cells expressing PROKR1\",\n      \"pmids\": [\"12054613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G protein coupling specificity not resolved at deorphanization\", \"no endogenous physiological context defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined a cytoprotective and pro-angiogenic role by showing PROKR1 activation drives Akt-dependent cardiomyocyte survival and vessel formation, extending the receptor beyond reproductive tissue into cardiac biology.\",\n      \"evidence\": \"siRNA knockdown, overexpression, Akt phosphorylation, and in vivo intramyocardial gene transfer in a coronary ligation mouse model\",\n      \"pmids\": [\"17442730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"did not dissect Gq vs other couplings in cardiomyocytes\", \"VEGF-independence of neovascularization mechanism not fully mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the proximal endometrial signaling cascade, showing PROKR1 links Gq-PLC to a c-Src-EGFR-ERK relay that drives inflammatory and implantation-related gene expression.\",\n      \"evidence\": \"Stable PROKR1 Ishikawa cell line with IP assays, phosphorylation cascade analysis, inhibitor pharmacology, microarray and qPCR\",\n      \"pmids\": [\"18339712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EGFR transactivation mechanism not structurally defined\", \"in vivo relevance of full gene panel not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved branch-specific outputs by showing distinct target genes route through either MEK (LIF) or calcineurin-NFAT (IL-11), revealing PROKR1 engages parallel intracellular arms.\",\n      \"evidence\": \"PROKR1 Ishikawa cells, pathway inhibitors, miRNA PROK1 knockdown, RCAN1-4 overexpression, baboon in vivo model\",\n      \"pmids\": [\"19255255\", \"19801577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how a single receptor partitions signal between MEK and calcineurin arms unknown\", \"regulatory role of RCAN1-4 in intact tissue not quantified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Separated receptor subtype functions, showing PROKR1 (not PROKR2) carries EG-VEGF angiogenic actions while extending the CTGF target set and identifying upstream control of PROKR1 expression by nAChRα-7.\",\n      \"evidence\": \"Receptor-specific siRNA and neutralizing antibodies in primary endothelial cells; pathway inhibitors; cotinine/nAChRα-7 antagonist experiments\",\n      \"pmids\": [\"20587779\", \"21098624\", \"20864676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular basis of PROKR1 vs PROKR2 functional divergence unresolved\", \"transcriptional control of PROKR1 beyond nAChRα-7 not characterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected calcium-calcineurin-NFAT signaling to anti-proliferative control, showing PROK1-PROKR1 induces DKK1 to restrain epithelial proliferation and enable decidualization.\",\n      \"evidence\": \"PROKR1 Ishikawa cells, calcineurin-NFAT inhibitors, DKK1 siRNA rescue, decidualization assays in primary stromal cells\",\n      \"pmids\": [\"21546446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"link between DKK1 induction and Wnt pathway output not measured\", \"context determining proliferative vs anti-proliferative outcome unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended subtype specificity to placental development, attributing EG-VEGF-induced trophoblast proliferation to PROKR1 acting via the homeobox factor HLX.\",\n      \"evidence\": \"Trophoblast proliferation assays, receptor-subtype siRNA/antibody discrimination, placental explants\",\n      \"pmids\": [\"22941044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism linking PROKR1 to HLX not defined\", \"single-lab finding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that receptor sequence variation tunes signaling output, with the I379V variant uncoupling reduced calcium influx from enhanced invasiveness.\",\n      \"evidence\": \"Ectopic PROKR1-I379V expression in HEK293 and JAR cells with calcium, invasion, proliferation and adhesion assays\",\n      \"pmids\": [\"23687280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis of altered signaling not determined\", \"physiological/clinical association of variant not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Localized PROKR1 to the primary cilium and made ciliary signaling a requirement for EG-VEGF-driven invasion, defining a subcellular platform for receptor function.\",\n      \"evidence\": \"Immunofluorescence localization, IFT88 siRNA ciliogenesis disruption, ERK/MMP2/9 and invasion readouts in HTR-8/SVneo cells\",\n      \"pmids\": [\"27736039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ciliary targeting mechanism of PROKR1 unknown\", \"ciliary localization in non-trophoblast cell types not examined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned PROKR1 within an upstream transcriptional program by showing TBX20 drives angiogenesis through PROK2-PROKR1, with prokr1 overexpression rescuing tbx20 loss.\",\n      \"evidence\": \"Zebrafish morpholino and CRISPR knockdown, prokr1a overexpression rescue, in vivo Matrigel plug angiogenesis\",\n      \"pmids\": [\"29545372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct vs indirect TBX20 regulation of PROK2 not delineated\", \"mammalian conservation of the axis only partially addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated PROKR1 on tumor cells as the receptor relaying neutrophil-derived PROK2 to promote metastatic proliferation.\",\n      \"evidence\": \"CRISPR/Cas9 Prokr1 deletion in 4T1 cells, mouse lung metastasis model\",\n      \"pmids\": [\"29643149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"downstream tumor signaling pathway not mapped\", \"single tumor model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened the angiogenic and reproductive signaling repertoire by linking PROKR1 to PI3K/AKT/mTOR, MAPK, cAMP and NF-κB pathways driving endothelial, trophoblast and luteal functions.\",\n      \"evidence\": \"Primary porcine endothelial, trophoblast and luteal cells with PROKR1 blocking antibody/antagonist, pathway inhibitors, tube formation, proliferation, steroidogenesis and ELISA readouts\",\n      \"pmids\": [\"32355954\", \"34215801\", \"36991037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"cross-species conservation to human tissue not confirmed\", \"single-lab pharmacological dissection\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a Gs-cAMP-CREB-NR4A2 axis as the mechanism by which PROKR1 specifies oxidative muscle fibers and controls systemic metabolism, with knockout and AAV rescue defining causality.\",\n      \"evidence\": \"ChIP-PCR, luciferase assays, Prokr1 knockout mice, AAV rescue, metabolic phenotyping and human myotubes; complemented by GLUT4 translocation and glucose uptake studies\",\n      \"pmids\": [\"38232288\", \"33184929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"coordination between Gs-cAMP and Gq arms in muscle unresolved\", \"tissue selectivity of metabolic effects not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified small-molecule pharmacology of PROKR1, showing celecoxib selectively activates Gs signaling and competes with PK2 to drive the NR4A2/oxidative-fiber program.\",\n      \"evidence\": \"Molecular docking, competitive binding, cAMP/Gs assays, PROKR1-overexpressing cells, murine and human myotubes, in vivo offspring phenotyping\",\n      \"pmids\": [\"39887895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"selectivity over other prokineticin receptors not exhaustively profiled\", \"single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PROKR1 selects among its multiple G protein arms (Gq, Gs, PI3K/AKT) in a given cell type, and the structural basis for ligand and small-molecule selectivity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no structural model of ligand-bound PROKR1 in the corpus\", \"rules governing biased coupling across tissues undefined\", \"in vivo human disease links not established in the timeline\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 19]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 14, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 9, 13]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [3, 8, 18]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PROK1\",\n      \"PROK2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}