{"gene":"PROK1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2009,"finding":"PROK1 signals through PROKR1 (a G protein-coupled receptor) to induce IL-11 expression in endometrial cells via a Gq/11, ERK, Ca2+, and calcineurin-NFAT-dependent pathway; RCAN1-4 acts as a negative regulator of this calcineurin-mediated signaling.","method":"siRNA knockdown, pharmacological inhibitors of Gq, PLC, ERK, calcineurin; adenoviral overexpression of RCAN1-4; lentiviral miRNA to knock down endogenous PROK1; PROKR1-stably transfected Ishikawa cells","journal":"Molecular human reproduction","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (receptor knockdown, pathway inhibitors, gain/loss of function) in a single study with defined signaling cascade","pmids":["19801577"],"is_preprint":false},{"year":2009,"finding":"EG-VEGF (PROK1) inhibits extravillous trophoblast migration, invasion, and tube-like organization via its receptors PROKR1 and PROKR2 in human placenta; siRNA knockdown of PROKR2 reversed these inhibitory effects, and EG-VEGF decreases MMP-2 and MMP-9 production.","method":"Human villous explants, HTR-8/SVneo trophoblast cell line, siRNA against PROKR2, invasion and migration assays, MMP measurement","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — receptor-specific siRNA knockdown with defined functional phenotype (invasion, MMP production) in both primary tissue and cell line","pmids":["19602057"],"is_preprint":false},{"year":2010,"finding":"EG-VEGF (PROK1) stimulates proliferation, migration, and survival of placental microvascular endothelial cells (HPEC) and increases permeability; angiogenic effects are mediated by PROKR1, while cellular permeability effects are mediated by PROKR2.","method":"siRNA knockdown of PROKR1 vs PROKR2, neutralizing antibodies, proliferation/migration/survival/permeability assays in HPEC and HUVEC","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — receptor-specific knockdown with orthogonal antibody strategy differentiating PROKR1 vs PROKR2 contributions to distinct cellular functions","pmids":["20587779"],"is_preprint":false},{"year":2011,"finding":"hCG upregulates EG-VEGF (PROK1), PROKR1, and PROKR2 mRNA and protein expression in trophoblasts via cAMP and cAMP response elements in the EG-VEGF promoter; effects are both transcriptional and post-transcriptional and mediated through the LH/CG receptor.","method":"Placental explants and primary trophoblast cultures, dose/time-response experiments, cAMP pathway analysis, promoter-CRE element mapping","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods but single lab; transcriptional and post-transcriptional mechanisms defined","pmids":["22138749"],"is_preprint":false},{"year":2007,"finding":"PROK1 (Prok-1) cooperates with GDNF/RET signaling to promote proliferation and differentiation of enteric neural crest cells; GDNF upregulates prokineticin receptor 1 (PK-R1) expression, and Prok-1 can induce proliferation and differentiation markers even in c-Ret-deficient neural crest cells, sharing downstream targets with GDNF.","method":"Microarray analysis, isolated enteric NCCs, gene knockdown experiments, c-Ret-deficient mice, functional assays for proliferation and differentiation markers","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with c-Ret knockouts and gene knockdown, but single lab","pmids":["18006159"],"is_preprint":false},{"year":2010,"finding":"PROK1 regulates CTGF expression in early pregnancy decidua via the Gq, PLC, cSrc, EGFR, MAPK/ERK kinase pathway through PROKR1; CTGF in turn promotes trophoblast adhesion to collagen IV and tube-like structure formation.","method":"qPCR, siRNA/miRNA knockdown of PROK1, pharmacological inhibitors of Gq/PLC/cSrc/EGFR/ERK pathways, HTR-8/SVneo cell adhesion and network formation assays","journal":"Human reproduction (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pathway inhibitors with defined signaling cascade, and endogenous PROK1 knockdown confirms pathway in primary tissue","pmids":["21098624"],"is_preprint":false},{"year":2016,"finding":"EG-VEGF (PROK1) promotes trophoblast invasion through PROKR1 localized to primary cilia; EG-VEGF activates ERK1/2 signaling and upregulates MMP2 and MMP9; depletion of the ciliogenesis factor IFT88 inhibits primary cilium growth and abrogates EG-VEGF-induced ERK1/2 activation, MMP upregulation, and invasion.","method":"siRNA knockdown of IFT88, ERK1/2 inhibition, PROKR1 immunolocalization to primary cilia in HTR-8/SVneo cells and first-trimester placental tissue, invasion assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — receptor localized to primary cilia by direct imaging, functional consequence confirmed by ciliogenesis knockdown with pathway readouts","pmids":["27736039"],"is_preprint":false},{"year":2015,"finding":"PPARγ transcriptionally activates EG-VEGF (PROK1) expression; rosiglitazone (PPARγ agonist) increases EG-VEGF secretion and receptor expression in trophoblasts; PPARγ-null mouse placentas have significantly decreased EG-VEGF levels; EG-VEGF mediates PPARγ effects on trophoblast vascularization (via PROKR1/PROKR2) and inhibition of invasion (via PROKR2).","method":"PPARγ agonist treatment in human trophoblast cells and placental explants, PROKR1/PROKR2 antagonists, PPARγ-deficient mouse placentas (in vivo), receptor-specific antagonism","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro pharmacology combined with PPARγ knockout mouse validation and receptor-specific antagonist strategy","pmids":["26081281"],"is_preprint":false},{"year":2017,"finding":"EG-VEGF (PROK1) promotes choriocarcinoma (JEG3) cell proliferation, migration, and invasion through PROKR1 and PROKR2; antagonism of these receptors reduces tumor development and metastasis in a placental SCID mouse model.","method":"2D and 3D cell culture invasion/migration assays, JEG3-luciferase placental xenograft mouse model, EG-VEGF receptor antagonists, antibody-array analysis","journal":"Clinical cancer research : an official journal of the American Association for Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo validation with receptor antagonists in a novel animal model","pmids":["28899975"],"is_preprint":false},{"year":2005,"finding":"EG-VEGF/PK-1 promotes luteal endothelial cell (LEC) proliferation via MAPK activation and c-jun/fos mRNA expression, and inhibits apoptosis; PK-R2 expression is upregulated under stress conditions (serum withdrawal, TNFα, hypoxia) while PK-R1 remains unchanged, suggesting anti-apoptotic effects are mediated via PK-R2; EG-VEGF/PK-1 also upregulates VEGF mRNA in luteal steroidogenic cells that express only PK-R1.","method":"[3H]-thymidine incorporation, MAPK activation assays, apoptosis assays, RT-PCR for receptor expression under stress conditions in bovine/human corpus luteum cells","journal":"Annals of anatomy = Anatomischer Anzeiger","confidence":"Low","confidence_rationale":"Tier 3 — single lab review with experimental data, indirect receptor-subtype assignment based on differential expression rather than direct knockdown","pmids":["16320832"],"is_preprint":false}],"current_model":"PROK1 (Prokineticin-1/EG-VEGF) is a secreted cysteine-rich protein that signals through two G protein-coupled receptors, PROKR1 and PROKR2, to regulate angiogenesis (proliferation, migration, survival of endothelial cells primarily via PROKR1), vascular permeability (via PROKR2), and trophoblast invasion and placentation (inhibiting invasion via PROKR2, promoting vascularization via PROKR1); its downstream signaling involves Gq/11, PLC, ERK/MAPK, cSrc, EGFR, and calcineurin-NFAT pathways, and it is transcriptionally regulated by hCG (through cAMP/CRE) and PPARγ, with PROKR1 localizing to primary cilia to mediate EG-VEGF-induced ERK activation and MMP-driven trophoblast invasion."},"narrative":{"teleology":[{"year":2005,"claim":"Early work established that EG-VEGF/PK-1 is a mitogen and survival factor for endothelial cells acting through MAPK, and suggested receptor-subtype-specific roles based on differential expression under stress conditions.","evidence":"Proliferation, MAPK activation, and apoptosis assays in luteal endothelial and steroidogenic cells with RT-PCR-based receptor profiling","pmids":["16320832"],"confidence":"Low","gaps":["Receptor-subtype assignment was based on expression patterns rather than direct knockdown or antagonism","Bovine system findings not validated in human cells","VEGF upregulation downstream of PK-R1 not confirmed by loss-of-function"]},{"year":2007,"claim":"PROK1 was shown to function beyond the vasculature, cooperating with GDNF/RET signaling to drive enteric neural crest cell proliferation and differentiation, establishing it as a neurodevelopmental factor.","evidence":"Microarray, enteric NCC cultures, and c-Ret-deficient mouse epistasis analysis","pmids":["18006159"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Downstream signaling pathway in NCCs not fully dissected","In vivo enteric phenotype of Prok1 loss not characterized"]},{"year":2009,"claim":"Two studies resolved receptor-specific functions: PROKR1 was identified as the conduit for Gq/11–ERK–calcineurin–NFAT signaling to IL-11 in endometrium, while PROKR2 was shown to mediate inhibition of trophoblast invasion and MMP-2/9 suppression.","evidence":"siRNA knockdown of PROKR1/PROKR2, pathway inhibitors, and gain/loss-of-function in Ishikawa cells, HTR-8/SVneo cells, and villous explants","pmids":["19801577","19602057"],"confidence":"High","gaps":["NFAT-target gene repertoire beyond IL-11 not defined","Whether PROKR1 and PROKR2 signal independently or form heterodimers in trophoblasts is unknown"]},{"year":2010,"claim":"Receptor dichotomy was extended to placental endothelial cells: PROKR1 drives angiogenic responses (proliferation, migration, survival) while PROKR2 controls permeability, and a PROKR1-specific Gq–PLC–cSrc–EGFR–ERK cascade inducing CTGF was mapped in decidua.","evidence":"siRNA and neutralizing antibody approaches in HPEC/HUVEC; pharmacological inhibitor cascade dissection with functional trophoblast adhesion and tube-formation readouts","pmids":["20587779","21098624"],"confidence":"High","gaps":["EGFR transactivation mechanism (ligand shedding vs. intracellular) not resolved","In vivo confirmation of receptor-specific angiogenic vs. permeability functions lacking"]},{"year":2011,"claim":"hCG was identified as a major upstream regulator of PROK1 transcription via cAMP and CRE elements in the EG-VEGF promoter, linking gonadotropin signaling to prokineticin expression in early pregnancy.","evidence":"Placental explants and primary trophoblast cultures with dose–time responses, cAMP pathway analysis, and promoter element mapping","pmids":["22138749"],"confidence":"Medium","gaps":["CRE element identity not confirmed by mutagenesis","Post-transcriptional regulatory mechanism not molecularly defined"]},{"year":2015,"claim":"PPARγ was established as a second transcriptional activator of EG-VEGF, with PPARγ-null mouse placentas showing reduced EG-VEGF levels and PPARγ-mediated effects on trophoblast vascularization and invasion routed through PROKR1 and PROKR2 respectively.","evidence":"PPARγ agonist treatment in human trophoblasts, receptor-specific antagonists, and PPARγ-knockout mouse placental analysis","pmids":["26081281"],"confidence":"Medium","gaps":["Direct PPARγ binding to PROK1 promoter not demonstrated (e.g., ChIP)","Relative contributions of hCG vs. PPARγ to PROK1 expression in vivo not determined"]},{"year":2016,"claim":"PROKR1 was found to localize to primary cilia in trophoblasts, and ciliary integrity (via IFT88) was shown to be required for EG-VEGF-induced ERK1/2 activation and MMP-dependent invasion, revealing a novel subcellular compartment for prokineticin signaling.","evidence":"PROKR1 immunolocalization to cilia in HTR-8/SVneo and first-trimester placenta; IFT88 siRNA abrogated ciliary growth, ERK activation, MMP upregulation, and invasion","pmids":["27736039"],"confidence":"Medium","gaps":["Mechanism of ciliary enrichment of PROKR1 not defined","Whether ciliary PROKR1 signaling differs qualitatively from non-ciliary signaling is unclear","In vivo ciliary requirement not tested"]},{"year":2017,"claim":"The PROK1–PROKR1/R2 axis was shown to drive choriocarcinoma cell proliferation, migration, and invasion, and receptor antagonism reduced tumor growth and metastasis in vivo, establishing PROK1 as a potential therapeutic target in gestational trophoblastic neoplasia.","evidence":"JEG3 2D/3D assays and luciferase-labeled placental xenograft SCID mouse model with receptor antagonists","pmids":["28899975"],"confidence":"Medium","gaps":["Antagonist specificity and off-target effects not fully characterized","Human clinical relevance beyond xenograft model not established"]},{"year":null,"claim":"Key unresolved questions include the structural basis of PROKR1 vs. PROKR2 signaling selectivity, the identity of the full downstream transcriptional program of PROK1 in different tissues, and the in vivo requirement for PROK1 in human placental development and enteric nervous system formation.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PROK1–receptor complexes exists","Prok1-knockout phenotype in mouse placenta and ENS not reported in the literature","Comprehensive transcriptomic profiling of PROK1 target genes across tissues is lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2,5,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,3,8]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,3,7]}],"complexes":[],"partners":["PROKR1","PROKR2","CTGF","EGFR","IFT88","RCAN1"],"other_free_text":[]},"mechanistic_narrative":"PROK1 (Prokineticin-1/EG-VEGF) is a secreted cysteine-rich ligand that signals through two G protein-coupled receptors, PROKR1 and PROKR2, to regulate angiogenesis, vascular permeability, trophoblast invasion, and enteric neural crest cell development. PROKR1 mediates proliferation, migration, and survival of endothelial cells and activates downstream Gq/11–PLC–ERK, cSrc–EGFR–MAPK, and calcineurin–NFAT cascades to induce target genes including IL-11, CTGF, and MMPs, while PROKR2 mediates vascular permeability and inhibition of trophoblast invasion with associated downregulation of MMP-2/MMP-9 [PMID:20587779, PMID:19801577, PMID:21098624, PMID:19602057]. PROKR1 localizes to primary cilia in trophoblasts, where ciliogenesis is required for EG-VEGF-induced ERK1/2 activation and MMP-dependent invasion [PMID:27736039]. PROK1 expression is transcriptionally regulated by hCG via cAMP/CRE elements and by PPARγ, as demonstrated by PPARγ-null mouse placentas showing decreased EG-VEGF levels [PMID:22138749, PMID:26081281]."},"prefetch_data":{"uniprot":{"accession":"P58294","full_name":"Prokineticin-1","aliases":["Endocrine-gland-derived vascular endothelial growth factor","EG-VEGF","Mambakine"],"length_aa":105,"mass_kda":11.7,"function":"Potently contracts gastrointestinal (GI) smooth muscle. Induces proliferation, migration and fenestration (the formation of membrane discontinuities) in capillary endothelial cells derived from endocrine glands. Has little or no effect on a variety of other endothelial and non-endothelial cell types. Induces proliferation and differentiation, but not migration, of enteric neural crest cells. Directly influences neuroblastoma progression by promoting the proliferation and migration of neuroblastoma cells. Positively regulates PTGS2 expression and prostaglandin synthesis. May play a role in placentation. May play a role in normal and pathological testis angiogenesis","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P58294/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PROK1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PROK1","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"},{"mim_id":"606233","title":"PROKINETICIN 1; PROK1","url":"https://www.omim.org/entry/606233"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"ovary","ntpm":190.8},{"tissue":"placenta","ntpm":47.2},{"tissue":"testis","ntpm":56.2}],"url":"https://www.proteinatlas.org/search/PROK1"},"hgnc":{"alias_symbol":["PK1","PRK1","EGVEGF","EG-VEGF"],"prev_symbol":[]},"alphafold":{"accession":"P58294","domains":[{"cath_id":"2.10.80.10","chopping":"21-105","consensus_level":"medium","plddt":89.4501,"start":21,"end":105}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P58294","model_url":"https://alphafold.ebi.ac.uk/files/AF-P58294-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P58294-F1-predicted_aligned_error_v6.png","plddt_mean":90.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PROK1","jax_strain_url":"https://www.jax.org/strain/search?query=PROK1"},"sequence":{"accession":"P58294","fasta_url":"https://rest.uniprot.org/uniprotkb/P58294.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P58294/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P58294"}},"corpus_meta":[{"pmid":"11912244","id":"PMC_11912244","title":"Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways.","date":"2002","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/11912244","citation_count":229,"is_preprint":false},{"pmid":"9227644","id":"PMC_9227644","title":"Protein kinase A phosphorylation is involved in regulated exocytosis of aquaporin-2 in transfected LLC-PK1 cells.","date":"1997","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9227644","citation_count":187,"is_preprint":false},{"pmid":"3985161","id":"PMC_3985161","title":"Biochemical characterization of renal epithelial cell cultures (LLC-PK1 and MDCK).","date":"1985","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/3985161","citation_count":142,"is_preprint":false},{"pmid":"10619026","id":"PMC_10619026","title":"The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1.","date":"1999","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/10619026","citation_count":142,"is_preprint":false},{"pmid":"7673228","id":"PMC_7673228","title":"Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. 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biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7513902","citation_count":15,"is_preprint":false},{"pmid":"25788276","id":"PMC_25788276","title":"The anti-tumor effect is enhanced by simultaneously targeting VEGF and PROK1 in colorectal cancer.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25788276","citation_count":14,"is_preprint":false},{"pmid":"16427251","id":"PMC_16427251","title":"The very C-terminus of PRK1/PKN is essential for its activation by RhoA and downstream signaling.","date":"2006","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/16427251","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52739,"output_tokens":3004,"usd":0.101639},"stage2":{"model":"claude-opus-4-6","input_tokens":6134,"output_tokens":2562,"usd":0.14208},"total_usd":0.243719,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about PROK1 (Prokineticin-1/EG-VEGF) versus other genes that happen to share similar symbols (like PRK1/PKN1 - protein kinase C-related kinase 1, LLC-PK1 - a cell line, or plant PRK1). \n\nPROK1 (Prokineticin-1) is a secreted protein that signals through G protein-coupled receptors PROKR1 and PROKR2. Papers about PRK1/PKN1 (a serine/threonine kinase activated by RhoA) are about a different protein. LLC-PK1 is a kidney cell line, not the gene. Plant PRK1 is a receptor-like kinase - symbol collision.\n\nLet me extract mechanistic findings specifically about PROK1 (Prokineticin-1/EG-VEGF):\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"PROK1 signals through PROKR1 (a G protein-coupled receptor) to induce IL-11 expression in endometrial cells via a Gq/11, ERK, Ca2+, and calcineurin-NFAT-dependent pathway; RCAN1-4 acts as a negative regulator of this calcineurin-mediated signaling.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibitors of Gq, PLC, ERK, calcineurin; adenoviral overexpression of RCAN1-4; lentiviral miRNA to knock down endogenous PROK1; PROKR1-stably transfected Ishikawa cells\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (receptor knockdown, pathway inhibitors, gain/loss of function) in a single study with defined signaling cascade\",\n      \"pmids\": [\"19801577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EG-VEGF (PROK1) inhibits extravillous trophoblast migration, invasion, and tube-like organization via its receptors PROKR1 and PROKR2 in human placenta; siRNA knockdown of PROKR2 reversed these inhibitory effects, and EG-VEGF decreases MMP-2 and MMP-9 production.\",\n      \"method\": \"Human villous explants, HTR-8/SVneo trophoblast cell line, siRNA against PROKR2, invasion and migration assays, MMP measurement\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor-specific siRNA knockdown with defined functional phenotype (invasion, MMP production) in both primary tissue and cell line\",\n      \"pmids\": [\"19602057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EG-VEGF (PROK1) stimulates proliferation, migration, and survival of placental microvascular endothelial cells (HPEC) and increases permeability; angiogenic effects are mediated by PROKR1, while cellular permeability effects are mediated by PROKR2.\",\n      \"method\": \"siRNA knockdown of PROKR1 vs PROKR2, neutralizing antibodies, proliferation/migration/survival/permeability assays in HPEC and HUVEC\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor-specific knockdown with orthogonal antibody strategy differentiating PROKR1 vs PROKR2 contributions to distinct cellular functions\",\n      \"pmids\": [\"20587779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"hCG upregulates EG-VEGF (PROK1), PROKR1, and PROKR2 mRNA and protein expression in trophoblasts via cAMP and cAMP response elements in the EG-VEGF promoter; effects are both transcriptional and post-transcriptional and mediated through the LH/CG receptor.\",\n      \"method\": \"Placental explants and primary trophoblast cultures, dose/time-response experiments, cAMP pathway analysis, promoter-CRE element mapping\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods but single lab; transcriptional and post-transcriptional mechanisms defined\",\n      \"pmids\": [\"22138749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PROK1 (Prok-1) cooperates with GDNF/RET signaling to promote proliferation and differentiation of enteric neural crest cells; GDNF upregulates prokineticin receptor 1 (PK-R1) expression, and Prok-1 can induce proliferation and differentiation markers even in c-Ret-deficient neural crest cells, sharing downstream targets with GDNF.\",\n      \"method\": \"Microarray analysis, isolated enteric NCCs, gene knockdown experiments, c-Ret-deficient mice, functional assays for proliferation and differentiation markers\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with c-Ret knockouts and gene knockdown, but single lab\",\n      \"pmids\": [\"18006159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PROK1 regulates CTGF expression in early pregnancy decidua via the Gq, PLC, cSrc, EGFR, MAPK/ERK kinase pathway through PROKR1; CTGF in turn promotes trophoblast adhesion to collagen IV and tube-like structure formation.\",\n      \"method\": \"qPCR, siRNA/miRNA knockdown of PROK1, pharmacological inhibitors of Gq/PLC/cSrc/EGFR/ERK pathways, HTR-8/SVneo cell adhesion and network formation assays\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pathway inhibitors with defined signaling cascade, and endogenous PROK1 knockdown confirms pathway in primary tissue\",\n      \"pmids\": [\"21098624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EG-VEGF (PROK1) promotes trophoblast invasion through PROKR1 localized to primary cilia; EG-VEGF activates ERK1/2 signaling and upregulates MMP2 and MMP9; depletion of the ciliogenesis factor IFT88 inhibits primary cilium growth and abrogates EG-VEGF-induced ERK1/2 activation, MMP upregulation, and invasion.\",\n      \"method\": \"siRNA knockdown of IFT88, ERK1/2 inhibition, PROKR1 immunolocalization to primary cilia in HTR-8/SVneo cells and first-trimester placental tissue, invasion assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor localized to primary cilia by direct imaging, functional consequence confirmed by ciliogenesis knockdown with pathway readouts\",\n      \"pmids\": [\"27736039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PPARγ transcriptionally activates EG-VEGF (PROK1) expression; rosiglitazone (PPARγ agonist) increases EG-VEGF secretion and receptor expression in trophoblasts; PPARγ-null mouse placentas have significantly decreased EG-VEGF levels; EG-VEGF mediates PPARγ effects on trophoblast vascularization (via PROKR1/PROKR2) and inhibition of invasion (via PROKR2).\",\n      \"method\": \"PPARγ agonist treatment in human trophoblast cells and placental explants, PROKR1/PROKR2 antagonists, PPARγ-deficient mouse placentas (in vivo), receptor-specific antagonism\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro pharmacology combined with PPARγ knockout mouse validation and receptor-specific antagonist strategy\",\n      \"pmids\": [\"26081281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EG-VEGF (PROK1) promotes choriocarcinoma (JEG3) cell proliferation, migration, and invasion through PROKR1 and PROKR2; antagonism of these receptors reduces tumor development and metastasis in a placental SCID mouse model.\",\n      \"method\": \"2D and 3D cell culture invasion/migration assays, JEG3-luciferase placental xenograft mouse model, EG-VEGF receptor antagonists, antibody-array analysis\",\n      \"journal\": \"Clinical cancer research : an official journal of the American Association for Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo validation with receptor antagonists in a novel animal model\",\n      \"pmids\": [\"28899975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EG-VEGF/PK-1 promotes luteal endothelial cell (LEC) proliferation via MAPK activation and c-jun/fos mRNA expression, and inhibits apoptosis; PK-R2 expression is upregulated under stress conditions (serum withdrawal, TNFα, hypoxia) while PK-R1 remains unchanged, suggesting anti-apoptotic effects are mediated via PK-R2; EG-VEGF/PK-1 also upregulates VEGF mRNA in luteal steroidogenic cells that express only PK-R1.\",\n      \"method\": \"[3H]-thymidine incorporation, MAPK activation assays, apoptosis assays, RT-PCR for receptor expression under stress conditions in bovine/human corpus luteum cells\",\n      \"journal\": \"Annals of anatomy = Anatomischer Anzeiger\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab review with experimental data, indirect receptor-subtype assignment based on differential expression rather than direct knockdown\",\n      \"pmids\": [\"16320832\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PROK1 (Prokineticin-1/EG-VEGF) is a secreted cysteine-rich protein that signals through two G protein-coupled receptors, PROKR1 and PROKR2, to regulate angiogenesis (proliferation, migration, survival of endothelial cells primarily via PROKR1), vascular permeability (via PROKR2), and trophoblast invasion and placentation (inhibiting invasion via PROKR2, promoting vascularization via PROKR1); its downstream signaling involves Gq/11, PLC, ERK/MAPK, cSrc, EGFR, and calcineurin-NFAT pathways, and it is transcriptionally regulated by hCG (through cAMP/CRE) and PPARγ, with PROKR1 localizing to primary cilia to mediate EG-VEGF-induced ERK activation and MMP-driven trophoblast invasion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PROK1 (Prokineticin-1/EG-VEGF) is a secreted cysteine-rich ligand that signals through two G protein-coupled receptors, PROKR1 and PROKR2, to regulate angiogenesis, vascular permeability, trophoblast invasion, and enteric neural crest cell development. PROKR1 mediates proliferation, migration, and survival of endothelial cells and activates downstream Gq/11–PLC–ERK, cSrc–EGFR–MAPK, and calcineurin–NFAT cascades to induce target genes including IL-11, CTGF, and MMPs, while PROKR2 mediates vascular permeability and inhibition of trophoblast invasion with associated downregulation of MMP-2/MMP-9 [PMID:20587779, PMID:19801577, PMID:21098624, PMID:19602057]. PROKR1 localizes to primary cilia in trophoblasts, where ciliogenesis is required for EG-VEGF-induced ERK1/2 activation and MMP-dependent invasion [PMID:27736039]. PROK1 expression is transcriptionally regulated by hCG via cAMP/CRE elements and by PPARγ, as demonstrated by PPARγ-null mouse placentas showing decreased EG-VEGF levels [PMID:22138749, PMID:26081281].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Early work established that EG-VEGF/PK-1 is a mitogen and survival factor for endothelial cells acting through MAPK, and suggested receptor-subtype-specific roles based on differential expression under stress conditions.\",\n      \"evidence\": \"Proliferation, MAPK activation, and apoptosis assays in luteal endothelial and steroidogenic cells with RT-PCR-based receptor profiling\",\n      \"pmids\": [\"16320832\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Receptor-subtype assignment was based on expression patterns rather than direct knockdown or antagonism\",\n        \"Bovine system findings not validated in human cells\",\n        \"VEGF upregulation downstream of PK-R1 not confirmed by loss-of-function\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"PROK1 was shown to function beyond the vasculature, cooperating with GDNF/RET signaling to drive enteric neural crest cell proliferation and differentiation, establishing it as a neurodevelopmental factor.\",\n      \"evidence\": \"Microarray, enteric NCC cultures, and c-Ret-deficient mouse epistasis analysis\",\n      \"pmids\": [\"18006159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding without independent replication\",\n        \"Downstream signaling pathway in NCCs not fully dissected\",\n        \"In vivo enteric phenotype of Prok1 loss not characterized\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Two studies resolved receptor-specific functions: PROKR1 was identified as the conduit for Gq/11–ERK–calcineurin–NFAT signaling to IL-11 in endometrium, while PROKR2 was shown to mediate inhibition of trophoblast invasion and MMP-2/9 suppression.\",\n      \"evidence\": \"siRNA knockdown of PROKR1/PROKR2, pathway inhibitors, and gain/loss-of-function in Ishikawa cells, HTR-8/SVneo cells, and villous explants\",\n      \"pmids\": [\"19801577\", \"19602057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"NFAT-target gene repertoire beyond IL-11 not defined\",\n        \"Whether PROKR1 and PROKR2 signal independently or form heterodimers in trophoblasts is unknown\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Receptor dichotomy was extended to placental endothelial cells: PROKR1 drives angiogenic responses (proliferation, migration, survival) while PROKR2 controls permeability, and a PROKR1-specific Gq–PLC–cSrc–EGFR–ERK cascade inducing CTGF was mapped in decidua.\",\n      \"evidence\": \"siRNA and neutralizing antibody approaches in HPEC/HUVEC; pharmacological inhibitor cascade dissection with functional trophoblast adhesion and tube-formation readouts\",\n      \"pmids\": [\"20587779\", \"21098624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"EGFR transactivation mechanism (ligand shedding vs. intracellular) not resolved\",\n        \"In vivo confirmation of receptor-specific angiogenic vs. permeability functions lacking\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"hCG was identified as a major upstream regulator of PROK1 transcription via cAMP and CRE elements in the EG-VEGF promoter, linking gonadotropin signaling to prokineticin expression in early pregnancy.\",\n      \"evidence\": \"Placental explants and primary trophoblast cultures with dose–time responses, cAMP pathway analysis, and promoter element mapping\",\n      \"pmids\": [\"22138749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"CRE element identity not confirmed by mutagenesis\",\n        \"Post-transcriptional regulatory mechanism not molecularly defined\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PPARγ was established as a second transcriptional activator of EG-VEGF, with PPARγ-null mouse placentas showing reduced EG-VEGF levels and PPARγ-mediated effects on trophoblast vascularization and invasion routed through PROKR1 and PROKR2 respectively.\",\n      \"evidence\": \"PPARγ agonist treatment in human trophoblasts, receptor-specific antagonists, and PPARγ-knockout mouse placental analysis\",\n      \"pmids\": [\"26081281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct PPARγ binding to PROK1 promoter not demonstrated (e.g., ChIP)\",\n        \"Relative contributions of hCG vs. PPARγ to PROK1 expression in vivo not determined\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"PROKR1 was found to localize to primary cilia in trophoblasts, and ciliary integrity (via IFT88) was shown to be required for EG-VEGF-induced ERK1/2 activation and MMP-dependent invasion, revealing a novel subcellular compartment for prokineticin signaling.\",\n      \"evidence\": \"PROKR1 immunolocalization to cilia in HTR-8/SVneo and first-trimester placenta; IFT88 siRNA abrogated ciliary growth, ERK activation, MMP upregulation, and invasion\",\n      \"pmids\": [\"27736039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of ciliary enrichment of PROKR1 not defined\",\n        \"Whether ciliary PROKR1 signaling differs qualitatively from non-ciliary signaling is unclear\",\n        \"In vivo ciliary requirement not tested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The PROK1–PROKR1/R2 axis was shown to drive choriocarcinoma cell proliferation, migration, and invasion, and receptor antagonism reduced tumor growth and metastasis in vivo, establishing PROK1 as a potential therapeutic target in gestational trophoblastic neoplasia.\",\n      \"evidence\": \"JEG3 2D/3D assays and luciferase-labeled placental xenograft SCID mouse model with receptor antagonists\",\n      \"pmids\": [\"28899975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Antagonist specificity and off-target effects not fully characterized\",\n        \"Human clinical relevance beyond xenograft model not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of PROKR1 vs. PROKR2 signaling selectivity, the identity of the full downstream transcriptional program of PROK1 in different tissues, and the in vivo requirement for PROK1 in human placental development and enteric nervous system formation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of PROK1–receptor complexes exists\",\n        \"Prok1-knockout phenotype in mouse placenta and ENS not reported in the literature\",\n        \"Comprehensive transcriptomic profiling of PROK1 target genes across tissues is lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 3, 8]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PROKR1\",\n      \"PROKR2\",\n      \"CTGF\",\n      \"EGFR\",\n      \"IFT88\",\n      \"RCAN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}