{"gene":"PGRMC1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2016,"finding":"Crystal structure of the PGRMC1 cytosolic domain at 1.95 Å resolution reveals it forms a stable dimer through stacking interactions of two protruding heme molecules; the heme iron is five-coordinated by Tyr113. CO disrupts dimerization by binding to the sixth coordination site of heme. Haem-mediated dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation, and chemoresistance.","method":"X-ray crystallography, CO treatment, mutagenesis, co-immunoprecipitation, cell-based functional assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis, multiple orthogonal methods (crystallography, CO interference, protein interaction assays, cellular phenotype readouts) in one rigorous study","pmids":["26988023"],"is_preprint":false},{"year":2008,"finding":"PGRMC1 binds heme as its sole biochemical activity, shares homology with cytochrome b5-related proteins, and activates the P450 protein CYP51/lanosterol demethylase to regulate cholesterol synthesis. Binding partners include multiple P450 proteins, PAIR-BP1, and Insig.","method":"Biochemical binding assays, protein interaction studies (co-precipitation), enzymatic activity assays","journal":"Pharmacology & Therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple replicated interaction findings from independent work reviewed, but primary data in this paper is review-level","pmids":["18992768"],"is_preprint":false},{"year":2007,"finding":"PGRMC1 directly binds progesterone at a single site (apparent Kd ~35 nM), requiring the entire molecule including transmembrane domain and initial C-terminus for maximal binding. PGRMC1 siRNA knockdown reduced [3H]P4 binding by 60% and abolished progesterone's antiapoptotic action in granulosa cells. PAIRBP1 binds PGRMC1 at C-terminal residues 70-130, distal to the putative P4 binding site.","method":"siRNA knockdown, [3H]progesterone binding assay with GFP-PGRMC1 fusion protein, deletion mutagenesis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct radiolabeled binding with purified fusion protein and deletion mutants in a single lab, two orthogonal methods","pmids":["17991724"],"is_preprint":false},{"year":2015,"finding":"Human PGRMC1 binds heme in a five-coordinate high-spin configuration with an axial tyrosinate ligand at Y95. Y95C or Y95F mutations dramatically reduce heme binding. Progesterone binds to heme-loaded hPGRMC1 and induces spectral changes indicating conformational changes to the heme, providing direct evidence for progesterone-binding activity.","method":"Spectroscopy (UV-vis, EPR), site-directed mutagenesis, redox potential measurement, progesterone binding assay with purified protein","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified protein plus mutagenesis, multiple spectroscopic methods; single lab but rigorous","pmids":["25675345"],"is_preprint":false},{"year":2010,"finding":"PGRMC1 co-precipitates with EGFR, increases plasma membrane EGFR levels, co-localizes with EGFR in cytoplasmic vesicles, and co-fractionates with EGFR in high density microsomes. PGRMC1 increases susceptibility to EGFR inhibitors erlotinib and AG-1478. A PGRMC1 small molecule ligand destabilizes EGFR in tumor cell lines.","method":"Co-immunoprecipitation, subcellular fractionation, immunofluorescence co-localization, cell viability assays with EGFR inhibitors","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and fractionation in a single lab with multiple orthogonal methods","pmids":["20538600"],"is_preprint":false},{"year":2011,"finding":"A photoaffinity probe (WC-21) irreversibly labels sigma-2 receptors in rat liver membranes, and the labeled protein was identified as PGRMC1. Overexpression of PGRMC1 increases sigma-2 radioligand binding; knockdown decreases it. PGRMC1 and sigma-2 ligand SW120 co-localize with ER and mitochondrial markers in HeLa cells.","method":"Photoaffinity labeling, mass spectrometry identification, overexpression and siRNA knockdown with radioligand binding, immunocytochemistry","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical crosslinking plus genetic gain/loss-of-function, single lab with multiple orthogonal methods; sigma-2 identity later contested","pmids":["21730960"],"is_preprint":false},{"year":2016,"finding":"PGRMC1 interacts with ferrochelatase (FECH), the terminal enzyme of heme biosynthesis. This interaction was validated by reciprocal affinity purification/MS and confirmed in vitro and in HEK293T cells. In vitro, PGRMC1 decreases FECH activity in a dose-dependent manner, with strongest interaction for the FECH conformation associated with product release, suggesting PGRMC1 regulates heme release. PGRMC1 can donate heme to apo-cytochrome b5 in vitro.","method":"Affinity purification coupled with mass spectrometry, reciprocal co-IP/immunoblot, in vitro FECH activity assay, in vitro heme transfer assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of FECH activity modulation, reciprocal AP-MS, heme transfer assay; multiple orthogonal methods in one rigorous study","pmids":["27599036"],"is_preprint":false},{"year":2021,"finding":"PGRMC1 binds and stabilizes a broad range of cytochromes P450 (>13 identified) in a heme-independent manner in mouse liver. Pgrmc1 knockout reduces cytochrome P450 protein levels post-transcriptionally and reduces P450 enzyme activity. The Y113F mutation (lacking axial heme iron coordination) retains heme binding but abolishes binding to ferrochelatase.","method":"Pgrmc1 knockout mouse model, proteomics, transcriptomics, in vitro P450 activity assays, mutagenesis","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — KO mouse with proteomics + transcriptomics + in vitro activity assay + mutagenesis; multiple orthogonal methods","pmids":["34678314"],"is_preprint":false},{"year":2008,"finding":"PGRMC1 is differentially phosphorylated between ER-positive and ER-negative breast tumors. Simultaneous mutation of serine-56 and serine-180 fully abrogates sensitivity of MCF7 cells to peroxide-induced cell death, indicating these phosphorylation sites regulate PGRMC1's role in oxidative stress response.","method":"2D-PAGE proteomics, phosphatase treatment, site-directed mutagenesis of phosphorylation sites, oxidative stress survival assay in stable transfectants","journal":"Breast Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional phenotypic readout plus proteomic identification, single lab","pmids":["18922159"],"is_preprint":false},{"year":2008,"finding":"A missense mutation H165R in the cytochrome b5 domain of PGRMC1, associated with premature ovarian failure, abolishes binding of CYP7A1 to PGRMC1 and attenuates PGRMC1's ability to mediate the anti-apoptotic action of progesterone in ovarian cells.","method":"Mutation screening, protein binding assay (CYP7A1-PGRMC1 interaction), progesterone anti-apoptotic functional assay in ovarian cells","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — disease-associated mutation with direct protein interaction and functional apoptosis assay, single lab","pmids":["18782852"],"is_preprint":false},{"year":2021,"finding":"PGRMC1 acts as a size-selective cargo receptor for RTN3-dependent ER-phagy. Via its luminal domain, PGRMC1 binds misfolded prohormones (including mutant proinsulin and mutant POMC) and targets them for RTN3-dependent lysosomal degradation. PGRMC1 selectively recruits small oligomers rather than large aggregates. Chemical or genetic inactivation of PGRMC1 in pancreatic β-cells impairs mutant proinsulin turnover and restores WT proinsulin trafficking.","method":"Co-immunoprecipitation, proteomics (RTN3 interactome), siRNA knockdown, CRISPR knockout, confocal microscopy, cell-based ER-phagy assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, unbiased proteomics, genetic perturbation with defined cargo trafficking phenotype; multiple orthogonal methods, replicated in two papers (PMID 34645803 and 34779709)","pmids":["34645803","34779709"],"is_preprint":false},{"year":2014,"finding":"PGRMC1 acts as an adaptor protein that transports membrane progesterone receptor alpha (mPRα) to the cell surface. Stable overexpression of PGRMC1 increases cell-surface mPRα expression and specific [3H]progesterone binding characteristic of mPRα. PGRMC1 co-immunoprecipitates with mPRα. The antiapoptotic effects of progestins previously attributed to PGRMC1 were abolished by siRNA knockdown of mPRα, indicating they are mediated via mPRα.","method":"Stable transfection, [3H]progesterone binding assay, G-protein activation assay, co-immunoprecipitation, immunocytochemistry, siRNA knockdown of mPRα","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, binding assay, siRNA epistasis) in single lab","pmids":["24424068"],"is_preprint":false},{"year":2018,"finding":"PGRMC1, TMEM97, and LDL receptor form a ternary complex required for rapid internalization of LDL. CRISPR KO of PGRMC1 or TMEM97 individually reduced LDL uptake equally; double KO did not reduce it further. PGRMC1 KO reduced sigma-2 radioligand binding affinity but did not eliminate binding sites (TMEM97 KO eliminated [125I]RHM-4 binding), establishing TMEM97 as the primary sigma-2 receptor.","method":"CRISPR/Cas9 knockout, radioligand binding assays, confocal microscopy, proximity ligation assay, fluorescent/radiolabeled LDL internalization assay","journal":"Scientific Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with multiple orthogonal readouts (radioligand binding, LDL uptake, PLA), clean genetic epistasis","pmids":["30443021"],"is_preprint":false},{"year":2014,"finding":"PGRMC1 and PGRMC2 interact with each other (demonstrated by pull-down assays, co-localization, and proximity ligation assays) and both localize to the mitotic spindle. Depletion of either protein increases entry into the cell cycle and causes metaphase arrest and apoptosis. Both PGRMC1 and PGRMC2 bind GTPase-activating protein-binding protein 2 (G3BP2), and G3BP2 siRNA similarly promotes cell cycle entry.","method":"siRNA knockdown, pull-down assay, proximity ligation assay, immunofluorescence co-localization, FUCCI cell cycle sensor","journal":"Biology of Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal interaction assays with functional cell cycle readout in single lab","pmids":["25253729"],"is_preprint":false},{"year":2012,"finding":"Progesterone (P4) induces SUMOylation of PGRMC1 (interaction with SUMO-1 detected by co-immunoprecipitation and proximity ligation assay); SUMOylated PGRMC1 localizes to the nucleus. PGRMC1 mediates P4 suppression of Tcf/Lef transcriptional activity, and mutation of all PGRMC1 SUMOylation sites abolishes P4's ability to suppress Tcf/Lef activity.","method":"Co-immunoprecipitation with SUMO-1, proximity ligation assay, nuclear fractionation, Tcf/Lef reporter assay, PGRMC1 sumoylation site mutagenesis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/PLA for SUMO interaction plus mutagenesis with transcriptional readout, single lab","pmids":["22719051"],"is_preprint":false},{"year":2012,"finding":"Progesterone-induced BDNF release from glia requires Pgrmc1. siRNA knockdown of Pgrmc1 in C6 glial cells and primary astrocytes abolished P4-induced BDNF release. P4-induced BDNF release was mediated by ERK5 (not ERK1/2), placing Pgrmc1 upstream of ERK5 in this signaling cascade.","method":"siRNA knockdown, BDNF ELISA/measurement, pharmacological inhibition of PR vs. Pgrmc1-dependent signaling, ERK5 inhibition","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with functional BDNF release readout plus kinase inhibitor pathway positioning, single lab","pmids":["22778217"],"is_preprint":false},{"year":2016,"finding":"PGRMC1 participates in late mitotic and meiotic events by directly interacting with Aurora Kinase B (AURKB) at the central spindle of dividing cells. PGRMC1 siRNA silencing in bovine granulosa cells caused G2/M arrest and defects in karyokinesis. PGRMC1 inhibition or silencing in oocytes impaired first polar body extrusion and caused meiotic figure aberrations.","method":"siRNA knockdown, time-lapse imaging, co-localization of PGRMC1 with AURKB, pharmacological inhibition with AG205, flow cytometry cell cycle analysis","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus time-lapse imaging plus AURKB co-localization evidence, single lab","pmids":["27260975"],"is_preprint":false},{"year":2015,"finding":"PGRMC1 co-localizes with mPRα and mPRα-dependent EGFR signaling in zebrafish oocytes. Pharmacological inhibition of PGRMC1 with AG205 blocks estradiol/GPER-mediated inhibition of oocyte maturation and decreases EGFR expression on oocyte plasma membranes, indicating Pgrmc1 is required for cell-surface EGFR expression and function in normal cells.","method":"Pharmacological inhibition (AG205), western blot of plasma membrane fractions, oocyte maturation functional assay, EGFR inhibitor co-treatment","journal":"Journal of Endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological perturbation with consistent functional readouts; no direct genetic KO used here","pmids":["25720537"],"is_preprint":false},{"year":2003,"finding":"HPR6.6/PGRMC1 expression in MCF-7 breast cancer cells sensitizes them to oxidative damage-induced cell death (H2O2 treatment). Cell death was not through typical apoptosis and corresponded with hyperphosphorylation of Akt and IκB, but inhibition of Akt or IκB degradation had no effect on HPR6.6-mediated death, indicating a novel oxidative damage response pathway.","method":"Overexpression of HPR6.6/PGRMC1, H2O2 treatment, pharmacological inhibition of Akt/IκB, cell death assays","journal":"Journal of Cellular Biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment with pharmacological inhibitors, pathway defined by exclusion only","pmids":["14523988"],"is_preprint":false},{"year":2019,"finding":"Cell surface-expressed PGRMC1 (csPGRMC1) displays a non-conventional plasma membrane topology in which the C-terminal cytoplasmic domain (residues 171-195) is exposed extracellularly, as determined by epitope mapping of anti-PGRMC1 monoclonal antibodies and trypsin sensitivity assays.","method":"Flow cytometry, trypsin treatment, GST-fused PGRMC1 deletion/mutant epitope mapping, polyclonal antibody binding assays","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple antibody epitope mapping experiments with trypsin accessibility controls establishing membrane topology","pmids":["30679694"],"is_preprint":false},{"year":2022,"finding":"PGRMC1 promotes store-operated Ca2+ entry (SOCE) by directly binding to the coiled-coil domain of STIM1 and promoting STIM1 conformational switch. PGRMC1 depletion decreased SOCE, impaired NFAT pathway activation, and disrupted EGF-induced focal adhesion turnover and actomyosin formation in breast cancer cells.","method":"Complementation-dependent in situ labeling (co-IP discovery), genetic depletion (PGRMC1 KD), Ca2+ imaging, NFAT reporter assay, focal adhesion and actin cytoskeleton imaging","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding to STIM1 coiled-coil domain with multiple functional readouts; single lab","pmids":["35045297"],"is_preprint":false},{"year":2021,"finding":"PGRMC1 promotes ferroptosis in paclitaxel-tolerant persister cancer cells by increasing fatty acid oxidation and lipophagy via autophagosome formation. PGRMC1 silencing reduced ferroptosis sensitivity to xCT inhibitors; PGRMC1 overexpression in parental cells enhanced ferroptosis. PGRMC1 co-localized with LC3B-II.","method":"siRNA silencing, PGRMC1 overexpression, lipid ROS measurement, autophagosome imaging, mouse xenograft experiments","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function with multiple biochemical and in vivo readouts; single lab","pmids":["34749765"],"is_preprint":false},{"year":2025,"finding":"PGRMC1, localized to the ER membrane, interacts with PERK through their ER luminal domains. This interaction activates PERK in an ER stress-independent manner, leading to eIF2α phosphorylation and consequent inhibition of c-Myc protein translation, blocking hepatocellular carcinoma formation.","method":"Co-immunoprecipitation (ER luminal domain interaction), PERK phosphorylation assays, eIF2α phosphorylation assays, orthotopic HCC mouse model, ER localization confirmed by subcellular fractionation/imaging","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping plus kinase activation readout and in vivo tumor model; single lab","pmids":["39747098"],"is_preprint":false},{"year":2021,"finding":"PGRMC1 promotes progestin-dependent breast cancer cell proliferation by binding prohibitin-1 (PHB1) and prohibitin-2 (PHB2) in a manner dependent on S181 phosphorylation. PGRMC1-PHB interaction competitively displaces PHBs from ERα, allowing ERα transcriptional activation. Inhibition of PGRMC1 or ERα abolished this proliferative effect.","method":"Co-immunoprecipitation with mass spectrometry, phosphorylation mutant (S181A) analysis, ERα activity assays, cell proliferation assays, inhibitor experiments","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/MS discovery with mutagenesis and functional receptor activation readout, single lab","pmids":["34830790"],"is_preprint":false},{"year":2018,"finding":"Pgrmc1 knockout in zebrafish reduces mPRα protein expression and reduces oocyte sensitivity to progestin, resulting in impaired meiotic maturation and reduced fertility. This provides in vivo evidence that Pgrmc1 regulates oocyte maturation via regulation of mPRα expression.","method":"CRISPR/Cas9 global knockout in zebrafish, in vivo and in vitro oocyte maturation assays, western blot for mPRα levels","journal":"Frontiers in Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vertebrate model with defined molecular mechanism (mPRα reduction) and physiological phenotype","pmids":["30319543"],"is_preprint":false},{"year":2020,"finding":"Manipulation of PGRMC1 phosphorylation status (S57A/S181A double mutant or S57A/Y180F/S181A triple mutant) in cancer cells broadly alters energy metabolism, glycolysis, PI3K/AKT activity, cell shape, actin cytoskeleton, mitochondrial properties, and tumor growth. Y180F mutation strongly attenuates xenograft tumor growth, indicating Y180 phosphorylation is required for full tumorigenic activity.","method":"PGRMC1 phosphorylation site mutagenesis, proteomics, metabolic assays, PI3K/AKT phosphorylation assays, xenograft tumor growth in NOD-SCID gamma mice","journal":"BMC Molecular and Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with multiple orthogonal functional readouts including in vivo tumor model; single lab","pmids":["32245408"],"is_preprint":false},{"year":2013,"finding":"P4 antagonism of E2-induced neurite outgrowth requires microglial expression of Pgrmc1/S2R. siRNA knockdown of Pgrmc1 in microglia suppressed P4-E2 antagonism of neurite outgrowth. Conditioned media from activated (LPS or wound-stimulated) microglia restored P4-E2 antagonism, but only if Pgrmc1 was present, indicating Pgrmc1 mediates microglial activation and the release of soluble factors that antagonize neurite growth.","method":"siRNA knockdown, co-culture system (neurons/astrocytes/microglia), conditioned media transfer, LPS/wound activation, neurite outgrowth quantification","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with epistatic co-culture and conditioned media experiments, single lab","pmids":["23653459"],"is_preprint":false},{"year":2018,"finding":"PGRMC1 colocalizes with nucleolin (NCL) in the nucleolus of bovine granulosa cells and oocytes. PGRMC1 siRNA depletion causes NCL translocation from the nucleolus to the nucleoplasm; oxidative stress also reduces nucleolar PGRMC1 and redistributes NCL. However, direct PGRMC1-NCL interaction was not detected by proximity ligation assay, suggesting additional mediators.","method":"Immunofluorescence, siRNA knockdown, proximity ligation assay (negative for direct interaction), H2O2 oxidative stress treatment","journal":"Reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization and siRNA phenotype without confirmed direct protein interaction; negative PLA result","pmids":["29339453"],"is_preprint":false},{"year":2021,"finding":"PGRMC1 loss in a diethylnitrosamine-induced murine HCC model suppresses hepatocarcinogenesis by reducing NF-κB-dependent IL-6 production, which reduces compensatory hepatocyte proliferation. The anti-pro-inflammatory effect is mediated through reduced EGFR levels, as EGFR inhibitor erlotinib abolished the additional effect of PGRMC1 loss.","method":"Global Pgrmc1 knockout mouse, DEN-induced HCC model, NF-κB activity assay, IL-6 ELISA, EGFR protein measurement, pharmacological EGFR inhibition epistasis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined molecular pathway (EGFR-NF-κB-IL-6) and in vivo phenotype; single lab","pmids":["34069911"],"is_preprint":false}],"current_model":"PGRMC1 is an ER/membrane-associated heme-binding protein (coordinating heme via Tyr113/Y95) that functions as a multivalent scaffold: it forms haem-stacking dimers that bind and stabilize cytochromes P450 (in a heme-independent manner for stability) and EGFR at the plasma membrane, acts as a size-selective ER-phagy cargo receptor (via its luminal domain binding misfolded prohormones and coupling to RTN3), regulates heme biosynthesis by modulating ferrochelatase activity and acting as a heme donor, mediates progesterone's antiapoptotic and antimitotic signaling (in part through mPRα trafficking to the cell surface and SUMOylation-dependent suppression of Tcf/Lef transcription), promotes SOCE by binding the STIM1 coiled-coil domain, activates PERK in an ER stress-independent manner to inhibit c-Myc translation, and is regulated by phosphorylation at multiple sites (Y113, Y180, S57, S181) that govern its dimerization state, protein interactions, and tumorigenic activity."},"narrative":{"mechanistic_narrative":"PGRMC1 is a heme-binding cytochrome b5-related membrane protein that functions as a multivalent scaffold coupling heme chemistry to protein stabilization, organelle quality control, and growth signaling [PMID:18992768, PMID:27599036]. Its cytosolic domain coordinates heme via an axial tyrosinate (Y95/Y113) in a five-coordinate high-spin configuration and uses the two protruding heme groups to form stacking dimers; CO binding to the vacant sixth coordination site disrupts dimerization, and this heme-mediated dimerization is required for productive interactions with EGFR and cytochromes P450 [PMID:26988023, PMID:25675345]. Through these interactions PGRMC1 stabilizes a broad range of cytochromes P450 post-transcriptionally and in a heme-independent manner, raises plasma-membrane EGFR levels, and regulates cellular sensitivity to EGFR-targeted drugs [PMID:34678314, PMID:20538600]. PGRMC1 also engages the terminal heme-biosynthetic enzyme ferrochelatase—an interaction that requires Y113 axial coordination—modulating ferrochelatase activity and acting as a heme donor to apo-cytochrome b5, thereby placing it at the interface of heme production and distribution [PMID:27599036, PMID:34678314]. In the ER lumen, PGRMC1 serves as a size-selective cargo receptor that recognizes misfolded prohormones such as mutant proinsulin and POMC and routes small oligomers for RTN3-dependent ER-phagy [PMID:34645803, PMID:34779709]. PGRMC1 transduces progesterone responses chiefly by chaperoning membrane progesterone receptor alpha (mPRα) to the cell surface, an activity confirmed in vivo where Pgrmc1 loss reduces mPRα and impairs oocyte maturation [PMID:24424068, PMID:30319543]. Additional outputs include progesterone-induced SUMOylation that suppresses Tcf/Lef transcription [PMID:22719051], promotion of store-operated Ca2+ entry through direct binding to the STIM1 coiled-coil [PMID:35045297], and ER-stress-independent activation of PERK to phosphorylate eIF2α and block c-Myc translation [PMID:39747098]. PGRMC1 activity is governed by phosphorylation at multiple sites (S57, Y180, S181), which control dimerization, partner interactions including prohibitin binding, and tumorigenic capacity [PMID:32245408, PMID:34830790]. A disease-associated H165R missense mutation in the cytochrome b5 domain, linked to premature ovarian failure, abolishes CYP7A1 binding and attenuates progesterone's anti-apoptotic action [PMID:18782852].","teleology":[{"year":2003,"claim":"Established an early functional readout linking PGRMC1 expression to a non-canonical oxidative-stress death pathway in breast cancer cells, before its biochemistry was known.","evidence":"HPR6.6/PGRMC1 overexpression with H2O2 challenge and Akt/IκB inhibitor exclusion in MCF-7 cells","pmids":["14523988"],"confidence":"Low","gaps":["Pathway defined only by exclusion of Akt/IκB","No molecular mechanism for the death signal","Single overexpression system"]},{"year":2007,"claim":"Tested whether PGRMC1 itself binds progesterone and mediates progesterone's antiapoptotic action, addressing whether it is a direct steroid sensor.","evidence":"[3H]progesterone binding with GFP-PGRMC1 fusion, deletion mutagenesis, and siRNA in granulosa cells","pmids":["17991724"],"confidence":"Medium","gaps":["Did not resolve whether binding is direct vs. via partners","Structural basis of binding unknown","PAIRBP1 contribution not separated"]},{"year":2008,"claim":"Defined PGRMC1's core biochemical identity as a heme-binding, cytochrome b5-related protein that activates P450 enzymes, framing it as a P450-coupling factor.","evidence":"Biochemical binding and enzymatic activity assays (review-level synthesis) implicating CYP51, PAIR-BP1, Insig","pmids":["18992768"],"confidence":"Medium","gaps":["Primary data are review-level","Heme coordination geometry not defined here","Mechanism of P450 activation unresolved"]},{"year":2008,"claim":"Showed phosphorylation regulates PGRMC1's stress function, introducing post-translational control as a determinant of activity.","evidence":"2D-PAGE phosphoproteomics and S56/S180 mutagenesis with peroxide-survival assays in MCF7 tumors and cells","pmids":["18922159"],"confidence":"Medium","gaps":["Kinases responsible not identified","Link between phospho-state and molecular interactions not yet mapped"]},{"year":2008,"claim":"Connected a PGRMC1 missense mutation to premature ovarian failure and to loss of a specific P450 interaction, providing the first human disease link.","evidence":"H165R mutation screening with CYP7A1-binding and progesterone anti-apoptosis assays in ovarian cells","pmids":["18782852"],"confidence":"Medium","gaps":["Causality vs. association not fully established","Effect on other P450 partners untested"]},{"year":2010,"claim":"Defined PGRMC1 as an EGFR-stabilizing partner that raises plasma-membrane EGFR and modulates EGFR-inhibitor sensitivity, linking it to growth-factor signaling.","evidence":"Reciprocal co-IP, fractionation, immunofluorescence, and EGFR inhibitor viability assays","pmids":["20538600"],"confidence":"Medium","gaps":["Whether binding is direct not established","Mechanism of EGFR stabilization unresolved"]},{"year":2011,"claim":"Identified PGRMC1 as the protein labeled by a sigma-2 photoaffinity probe, an assignment later partly reassigned.","evidence":"Photoaffinity labeling, MS identification, and gain/loss-of-function radioligand binding in HeLa cells","pmids":["21730960"],"confidence":"Medium","gaps":["Sigma-2 identity later contested (see 2018)","Functional consequence of sigma-2 ligand binding unclear"]},{"year":2012,"claim":"Showed progesterone drives PGRMC1 SUMOylation and nuclear localization to suppress Tcf/Lef transcription, revealing a transcriptional output.","evidence":"Co-IP/PLA with SUMO-1, nuclear fractionation, Tcf/Lef reporter, and SUMO-site mutagenesis","pmids":["22719051"],"confidence":"Medium","gaps":["SUMO E3 ligase not identified","Direct DNA/transcription-machinery contacts unknown"]},{"year":2012,"claim":"Placed Pgrmc1 upstream of ERK5 in progesterone-induced BDNF release from glia, extending its signaling role to the nervous system.","evidence":"siRNA knockdown with BDNF measurement and ERK5 vs. ERK1/2 inhibition in glial cells/astrocytes","pmids":["22778217"],"confidence":"Medium","gaps":["Receptor coupling to ERK5 not defined","Whether mPRα participates not tested"]},{"year":2014,"claim":"Reframed PGRMC1's progesterone signaling as adaptor-mediated, showing it traffics mPRα to the cell surface and that antiapoptotic effects require mPRα.","evidence":"Stable overexpression, [3H]progesterone binding, co-IP, and mPRα siRNA epistasis","pmids":["24424068"],"confidence":"Medium","gaps":["Direct PGRMC1-mPRα binding interface unmapped","Reconciliation with direct-progesterone-binding model incomplete"]},{"year":2014,"claim":"Established PGRMC1/PGRMC2 as mitotic-spindle proteins that restrain cell-cycle entry, implicating it in division control via G3BP2.","evidence":"siRNA, pull-down, PLA, immunofluorescence, and FUCCI cell-cycle sensing","pmids":["25253729"],"confidence":"Medium","gaps":["Molecular role at the spindle unclear","G3BP2 functional contribution undefined"]},{"year":2015,"claim":"Resolved PGRMC1's heme coordination chemistry (five-coordinate high-spin, axial Y95 tyrosinate) and demonstrated progesterone-induced spectral changes in heme-loaded protein.","evidence":"UV-vis/EPR spectroscopy, Y95 mutagenesis, and progesterone binding with purified protein","pmids":["25675345"],"confidence":"High","gaps":["Physiological redox role of heme not established","Single-lab spectroscopic study"]},{"year":2015,"claim":"Showed Pgrmc1 is required for cell-surface EGFR and mPRα-dependent EGFR signaling in normal oocytes, generalizing its EGFR role beyond cancer.","evidence":"AG205 pharmacological inhibition, plasma-membrane fractionation, and oocyte maturation assays in zebrafish","pmids":["25720537"],"confidence":"Medium","gaps":["Pharmacological inhibitor specificity","No genetic KO in this study"]},{"year":2016,"claim":"Provided the structural basis for PGRMC1 function: heme-stacking dimerization required for EGFR and P450 interactions, proliferation, and chemoresistance, with CO as a dimer disruptor.","evidence":"1.95 Å crystal structure, CO interference, mutagenesis, co-IP, and cellular phenotype assays","pmids":["26988023"],"confidence":"High","gaps":["Full-length/membrane context not crystallized","Dynamics of dimer-to-monomer switching in cells not quantified"]},{"year":2016,"claim":"Linked PGRMC1 to heme biosynthesis by showing it binds and modulates ferrochelatase and can donate heme to apo-cytochrome b5.","evidence":"Reciprocal AP-MS, in vitro FECH activity assay, and in vitro heme-transfer assay","pmids":["27599036"],"confidence":"High","gaps":["In vivo significance of FECH modulation not established here","Directionality of heme flux in cells unresolved"]},{"year":2016,"claim":"Identified a direct interaction of PGRMC1 with Aurora Kinase B at the central spindle, tying it to karyokinesis and meiotic progression.","evidence":"siRNA, time-lapse imaging, AURKB co-localization, and AG205 inhibition in granulosa cells and oocytes","pmids":["27260975"],"confidence":"Medium","gaps":["Direct biochemical AURKB binding not isolated","Role in spindle assembly mechanism undefined"]},{"year":2018,"claim":"Resolved the sigma-2 identity question, establishing TMEM97 as the primary sigma-2 receptor and defining a PGRMC1-TMEM97-LDLR ternary complex for LDL internalization.","evidence":"CRISPR KO with radioligand binding, PLA, and LDL uptake epistasis","pmids":["30443021"],"confidence":"High","gaps":["Stoichiometry of the ternary complex undefined","Mechanism by which PGRMC1 promotes LDL uptake unclear"]},{"year":2018,"claim":"Provided in vivo genetic evidence that Pgrmc1 controls oocyte maturation through regulation of mPRα expression.","evidence":"CRISPR global KO in zebrafish with oocyte maturation assays and mPRα western blot","pmids":["30319543"],"confidence":"Medium","gaps":["Mechanism linking PGRMC1 to mPRα stability not defined","Mammalian generalizability untested here"]},{"year":2018,"claim":"Reported a non-conventional plasma-membrane topology for cell-surface PGRMC1 with the C-terminal cytoplasmic domain exposed extracellularly.","evidence":"Flow cytometry, trypsin sensitivity, and GST-fusion epitope mapping with antibodies","pmids":["30679694"],"confidence":"Medium","gaps":["How the topology arises mechanistically unknown","Functional consequence of surface exposure undefined"]},{"year":2018,"claim":"Showed PGRMC1 colocalizes with and positions nucleolin in the nucleolus, though without a confirmed direct interaction.","evidence":"Immunofluorescence, siRNA, and PLA (negative for direct interaction) under oxidative stress","pmids":["29339453"],"confidence":"Low","gaps":["No direct PGRMC1-NCL interaction detected (negative PLA)","Mediating factor unidentified","Nucleolar function of PGRMC1 unclear"]},{"year":2020,"claim":"Demonstrated that PGRMC1 phosphorylation status broadly reprograms metabolism and tumor growth, with Y180 required for full tumorigenicity.","evidence":"Phospho-site mutagenesis (S57A/Y180F/S181A combinations), proteomics, metabolic assays, and xenografts in NSG mice","pmids":["32245408"],"confidence":"Medium","gaps":["Kinases targeting these sites not identified","Direct mechanistic link from phospho-state to metabolism unresolved"]},{"year":2021,"claim":"Defined PGRMC1 as a size-selective ER-phagy cargo receptor for misfolded prohormones coupling to RTN3, revealing an organelle quality-control function.","evidence":"Reciprocal co-IP, RTN3 interactome proteomics, CRISPR/siRNA, and ER-phagy/trafficking assays in β-cells (two papers)","pmids":["34645803","34779709"],"confidence":"High","gaps":["Structural basis of size selectivity unknown","Range of physiological cargoes incompletely defined"]},{"year":2021,"claim":"Showed PGRMC1 stabilizes a broad set of cytochromes P450 heme-independently and that Y113 axial coordination is required for ferrochelatase binding, dissociating stabilization from heme catalysis.","evidence":"Pgrmc1 KO mouse with proteomics, transcriptomics, in vitro P450 activity, and Y113F mutagenesis","pmids":["34678314"],"confidence":"High","gaps":["How heme-independent stabilization occurs mechanistically unclear","Which P450s are physiologically most dependent unresolved"]},{"year":2021,"claim":"Linked PGRMC1 to progestin-driven proliferation via S181-dependent prohibitin binding that frees ERα for transcription.","evidence":"Co-IP/MS, S181A mutant analysis, ERα activity and proliferation assays with inhibitors","pmids":["34830790"],"confidence":"Medium","gaps":["Direct PGRMC1-PHB binding interface unmapped","Generality beyond the cell models tested unknown"]},{"year":2021,"claim":"Showed PGRMC1 promotes ferroptosis in drug-tolerant persister cells via lipophagy and fatty-acid oxidation, identifying a context-dependent cell-death role.","evidence":"siRNA, overexpression, lipid-ROS measurement, autophagosome imaging, and xenografts","pmids":["34749765"],"confidence":"Medium","gaps":["Molecular trigger linking PGRMC1 to lipophagy undefined","Reconciliation with its protective stress roles unresolved"]},{"year":2021,"claim":"Connected Pgrmc1 to hepatocarcinogenesis through an EGFR-NF-κB-IL-6 axis driving compensatory proliferation.","evidence":"Global Pgrmc1 KO in DEN-induced HCC, NF-κB/IL-6 assays, and erlotinib epistasis","pmids":["34069911"],"confidence":"Medium","gaps":["Cell-type origin of the effect not isolated","Direct vs. indirect EGFR contribution incompletely separated"]},{"year":2022,"claim":"Identified PGRMC1 as a direct STIM1 coiled-coil binder that promotes store-operated Ca2+ entry and downstream NFAT and cytoskeletal signaling.","evidence":"Co-IP, PGRMC1 depletion, Ca2+ imaging, NFAT reporter, and focal-adhesion/actin imaging in breast cancer cells","pmids":["35045297"],"confidence":"Medium","gaps":["Structural basis of STIM1 conformational promotion undefined","Relationship to ER heme/P450 functions unclear"]},{"year":2025,"claim":"Showed PGRMC1 binds PERK via ER luminal domains to activate PERK independent of ER stress, phosphorylating eIF2α and suppressing c-Myc translation to block HCC.","evidence":"Co-IP with domain mapping, PERK/eIF2α phosphorylation assays, and orthotopic HCC mouse model","pmids":["39747098"],"confidence":"Medium","gaps":["How PGRMC1 binding activates PERK mechanistically undefined","Apparent contrast with tumor-promoting PGRMC1 roles unresolved"]},{"year":null,"claim":"It remains unresolved how PGRMC1's distinct activities—heme chemistry, P450/EGFR stabilization, ER-phagy cargo receptor function, progesterone/mPRα signaling, SOCE, and PERK activation—are coordinated within a single protein and switched between tumor-suppressive and tumor-promoting outputs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model of full-length membrane-embedded PGRMC1 in different complexes","Phospho-code-to-interaction mapping incomplete","Mechanism reconciling opposing roles in hepatocarcinogenesis unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,7,20]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[10]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10,22]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,11,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[13,16]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,6,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,20,22]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[13,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,10,22]}],"complexes":["PGRMC1-TMEM97-LDLR ternary complex"],"partners":["EGFR","FECH","RTN3","STIM1","PERK","MPRΑ","TMEM97","AURKB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00264","full_name":"Membrane-associated progesterone receptor component 1","aliases":["Dap1","IZA"],"length_aa":195,"mass_kda":21.7,"function":"Component of a progesterone-binding protein complex (PubMed:28396637). Binds progesterone (PubMed:25675345). Has many reported cellular functions (heme homeostasis, interaction with CYPs). Required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan (By similarity). Intracellular heme chaperone. Regulates heme synthesis via interactions with FECH and acts as a heme donor for at least some hemoproteins (PubMed:27599036). Forms a ternary complex with TMEM97 receptor and low density lipid receptor/LDLR, which increases LDLR-mediated LDL lipoprotein internalization (PubMed:30443021)","subcellular_location":"Microsome membrane; Smooth endoplasmic reticulum membrane; Mitochondrion outer membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/O00264/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PGRMC1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000101856","cell_line_id":"CID001733","localizations":[{"compartment":"er","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"DAD1","stoichiometry":10.0},{"gene":"OSTC","stoichiometry":10.0},{"gene":"VAPB","stoichiometry":10.0},{"gene":"STX18","stoichiometry":10.0},{"gene":"RER1","stoichiometry":10.0},{"gene":"SEC61B","stoichiometry":10.0},{"gene":"STT3B","stoichiometry":10.0},{"gene":"BNIP1","stoichiometry":4.0},{"gene":"CDS2","stoichiometry":4.0},{"gene":"TMCO1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001733","total_profiled":1310},"omim":[{"mim_id":"607735","title":"PROGESTERONE RECEPTOR MEMBRANE COMPONENT 2; PGRMC2","url":"https://www.omim.org/entry/607735"},{"mim_id":"300995","title":"KIAA1210 GENE; KIAA1210","url":"https://www.omim.org/entry/300995"},{"mim_id":"300435","title":"PROGESTERONE RECEPTOR MEMBRANE COMPONENT 1; PGRMC1","url":"https://www.omim.org/entry/300435"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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through stacking interactions of two protruding heme molecules; the heme iron is five-coordinated by Tyr113. CO disrupts dimerization by binding to the sixth coordination site of heme. Haem-mediated dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation, and chemoresistance.\",\n      \"method\": \"X-ray crystallography, CO treatment, mutagenesis, co-immunoprecipitation, cell-based functional assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis, multiple orthogonal methods (crystallography, CO interference, protein interaction assays, cellular phenotype readouts) in one rigorous study\",\n      \"pmids\": [\"26988023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PGRMC1 binds heme as its sole biochemical activity, shares homology with cytochrome b5-related proteins, and activates the P450 protein CYP51/lanosterol demethylase to regulate cholesterol synthesis. Binding partners include multiple P450 proteins, PAIR-BP1, and Insig.\",\n      \"method\": \"Biochemical binding assays, protein interaction studies (co-precipitation), enzymatic activity assays\",\n      \"journal\": \"Pharmacology & Therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple replicated interaction findings from independent work reviewed, but primary data in this paper is review-level\",\n      \"pmids\": [\"18992768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PGRMC1 directly binds progesterone at a single site (apparent Kd ~35 nM), requiring the entire molecule including transmembrane domain and initial C-terminus for maximal binding. PGRMC1 siRNA knockdown reduced [3H]P4 binding by 60% and abolished progesterone's antiapoptotic action in granulosa cells. PAIRBP1 binds PGRMC1 at C-terminal residues 70-130, distal to the putative P4 binding site.\",\n      \"method\": \"siRNA knockdown, [3H]progesterone binding assay with GFP-PGRMC1 fusion protein, deletion mutagenesis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct radiolabeled binding with purified fusion protein and deletion mutants in a single lab, two orthogonal methods\",\n      \"pmids\": [\"17991724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human PGRMC1 binds heme in a five-coordinate high-spin configuration with an axial tyrosinate ligand at Y95. Y95C or Y95F mutations dramatically reduce heme binding. Progesterone binds to heme-loaded hPGRMC1 and induces spectral changes indicating conformational changes to the heme, providing direct evidence for progesterone-binding activity.\",\n      \"method\": \"Spectroscopy (UV-vis, EPR), site-directed mutagenesis, redox potential measurement, progesterone binding assay with purified protein\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified protein plus mutagenesis, multiple spectroscopic methods; single lab but rigorous\",\n      \"pmids\": [\"25675345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PGRMC1 co-precipitates with EGFR, increases plasma membrane EGFR levels, co-localizes with EGFR in cytoplasmic vesicles, and co-fractionates with EGFR in high density microsomes. PGRMC1 increases susceptibility to EGFR inhibitors erlotinib and AG-1478. A PGRMC1 small molecule ligand destabilizes EGFR in tumor cell lines.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, immunofluorescence co-localization, cell viability assays with EGFR inhibitors\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and fractionation in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20538600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A photoaffinity probe (WC-21) irreversibly labels sigma-2 receptors in rat liver membranes, and the labeled protein was identified as PGRMC1. Overexpression of PGRMC1 increases sigma-2 radioligand binding; knockdown decreases it. PGRMC1 and sigma-2 ligand SW120 co-localize with ER and mitochondrial markers in HeLa cells.\",\n      \"method\": \"Photoaffinity labeling, mass spectrometry identification, overexpression and siRNA knockdown with radioligand binding, immunocytochemistry\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical crosslinking plus genetic gain/loss-of-function, single lab with multiple orthogonal methods; sigma-2 identity later contested\",\n      \"pmids\": [\"21730960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PGRMC1 interacts with ferrochelatase (FECH), the terminal enzyme of heme biosynthesis. This interaction was validated by reciprocal affinity purification/MS and confirmed in vitro and in HEK293T cells. In vitro, PGRMC1 decreases FECH activity in a dose-dependent manner, with strongest interaction for the FECH conformation associated with product release, suggesting PGRMC1 regulates heme release. PGRMC1 can donate heme to apo-cytochrome b5 in vitro.\",\n      \"method\": \"Affinity purification coupled with mass spectrometry, reciprocal co-IP/immunoblot, in vitro FECH activity assay, in vitro heme transfer assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of FECH activity modulation, reciprocal AP-MS, heme transfer assay; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"27599036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PGRMC1 binds and stabilizes a broad range of cytochromes P450 (>13 identified) in a heme-independent manner in mouse liver. Pgrmc1 knockout reduces cytochrome P450 protein levels post-transcriptionally and reduces P450 enzyme activity. The Y113F mutation (lacking axial heme iron coordination) retains heme binding but abolishes binding to ferrochelatase.\",\n      \"method\": \"Pgrmc1 knockout mouse model, proteomics, transcriptomics, in vitro P450 activity assays, mutagenesis\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — KO mouse with proteomics + transcriptomics + in vitro activity assay + mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"34678314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PGRMC1 is differentially phosphorylated between ER-positive and ER-negative breast tumors. Simultaneous mutation of serine-56 and serine-180 fully abrogates sensitivity of MCF7 cells to peroxide-induced cell death, indicating these phosphorylation sites regulate PGRMC1's role in oxidative stress response.\",\n      \"method\": \"2D-PAGE proteomics, phosphatase treatment, site-directed mutagenesis of phosphorylation sites, oxidative stress survival assay in stable transfectants\",\n      \"journal\": \"Breast Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional phenotypic readout plus proteomic identification, single lab\",\n      \"pmids\": [\"18922159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A missense mutation H165R in the cytochrome b5 domain of PGRMC1, associated with premature ovarian failure, abolishes binding of CYP7A1 to PGRMC1 and attenuates PGRMC1's ability to mediate the anti-apoptotic action of progesterone in ovarian cells.\",\n      \"method\": \"Mutation screening, protein binding assay (CYP7A1-PGRMC1 interaction), progesterone anti-apoptotic functional assay in ovarian cells\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — disease-associated mutation with direct protein interaction and functional apoptosis assay, single lab\",\n      \"pmids\": [\"18782852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PGRMC1 acts as a size-selective cargo receptor for RTN3-dependent ER-phagy. Via its luminal domain, PGRMC1 binds misfolded prohormones (including mutant proinsulin and mutant POMC) and targets them for RTN3-dependent lysosomal degradation. PGRMC1 selectively recruits small oligomers rather than large aggregates. Chemical or genetic inactivation of PGRMC1 in pancreatic β-cells impairs mutant proinsulin turnover and restores WT proinsulin trafficking.\",\n      \"method\": \"Co-immunoprecipitation, proteomics (RTN3 interactome), siRNA knockdown, CRISPR knockout, confocal microscopy, cell-based ER-phagy assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, unbiased proteomics, genetic perturbation with defined cargo trafficking phenotype; multiple orthogonal methods, replicated in two papers (PMID 34645803 and 34779709)\",\n      \"pmids\": [\"34645803\", \"34779709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PGRMC1 acts as an adaptor protein that transports membrane progesterone receptor alpha (mPRα) to the cell surface. Stable overexpression of PGRMC1 increases cell-surface mPRα expression and specific [3H]progesterone binding characteristic of mPRα. PGRMC1 co-immunoprecipitates with mPRα. The antiapoptotic effects of progestins previously attributed to PGRMC1 were abolished by siRNA knockdown of mPRα, indicating they are mediated via mPRα.\",\n      \"method\": \"Stable transfection, [3H]progesterone binding assay, G-protein activation assay, co-immunoprecipitation, immunocytochemistry, siRNA knockdown of mPRα\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, binding assay, siRNA epistasis) in single lab\",\n      \"pmids\": [\"24424068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PGRMC1, TMEM97, and LDL receptor form a ternary complex required for rapid internalization of LDL. CRISPR KO of PGRMC1 or TMEM97 individually reduced LDL uptake equally; double KO did not reduce it further. PGRMC1 KO reduced sigma-2 radioligand binding affinity but did not eliminate binding sites (TMEM97 KO eliminated [125I]RHM-4 binding), establishing TMEM97 as the primary sigma-2 receptor.\",\n      \"method\": \"CRISPR/Cas9 knockout, radioligand binding assays, confocal microscopy, proximity ligation assay, fluorescent/radiolabeled LDL internalization assay\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with multiple orthogonal readouts (radioligand binding, LDL uptake, PLA), clean genetic epistasis\",\n      \"pmids\": [\"30443021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PGRMC1 and PGRMC2 interact with each other (demonstrated by pull-down assays, co-localization, and proximity ligation assays) and both localize to the mitotic spindle. Depletion of either protein increases entry into the cell cycle and causes metaphase arrest and apoptosis. Both PGRMC1 and PGRMC2 bind GTPase-activating protein-binding protein 2 (G3BP2), and G3BP2 siRNA similarly promotes cell cycle entry.\",\n      \"method\": \"siRNA knockdown, pull-down assay, proximity ligation assay, immunofluorescence co-localization, FUCCI cell cycle sensor\",\n      \"journal\": \"Biology of Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal interaction assays with functional cell cycle readout in single lab\",\n      \"pmids\": [\"25253729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Progesterone (P4) induces SUMOylation of PGRMC1 (interaction with SUMO-1 detected by co-immunoprecipitation and proximity ligation assay); SUMOylated PGRMC1 localizes to the nucleus. PGRMC1 mediates P4 suppression of Tcf/Lef transcriptional activity, and mutation of all PGRMC1 SUMOylation sites abolishes P4's ability to suppress Tcf/Lef activity.\",\n      \"method\": \"Co-immunoprecipitation with SUMO-1, proximity ligation assay, nuclear fractionation, Tcf/Lef reporter assay, PGRMC1 sumoylation site mutagenesis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/PLA for SUMO interaction plus mutagenesis with transcriptional readout, single lab\",\n      \"pmids\": [\"22719051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Progesterone-induced BDNF release from glia requires Pgrmc1. siRNA knockdown of Pgrmc1 in C6 glial cells and primary astrocytes abolished P4-induced BDNF release. P4-induced BDNF release was mediated by ERK5 (not ERK1/2), placing Pgrmc1 upstream of ERK5 in this signaling cascade.\",\n      \"method\": \"siRNA knockdown, BDNF ELISA/measurement, pharmacological inhibition of PR vs. Pgrmc1-dependent signaling, ERK5 inhibition\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with functional BDNF release readout plus kinase inhibitor pathway positioning, single lab\",\n      \"pmids\": [\"22778217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PGRMC1 participates in late mitotic and meiotic events by directly interacting with Aurora Kinase B (AURKB) at the central spindle of dividing cells. PGRMC1 siRNA silencing in bovine granulosa cells caused G2/M arrest and defects in karyokinesis. PGRMC1 inhibition or silencing in oocytes impaired first polar body extrusion and caused meiotic figure aberrations.\",\n      \"method\": \"siRNA knockdown, time-lapse imaging, co-localization of PGRMC1 with AURKB, pharmacological inhibition with AG205, flow cytometry cell cycle analysis\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus time-lapse imaging plus AURKB co-localization evidence, single lab\",\n      \"pmids\": [\"27260975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PGRMC1 co-localizes with mPRα and mPRα-dependent EGFR signaling in zebrafish oocytes. Pharmacological inhibition of PGRMC1 with AG205 blocks estradiol/GPER-mediated inhibition of oocyte maturation and decreases EGFR expression on oocyte plasma membranes, indicating Pgrmc1 is required for cell-surface EGFR expression and function in normal cells.\",\n      \"method\": \"Pharmacological inhibition (AG205), western blot of plasma membrane fractions, oocyte maturation functional assay, EGFR inhibitor co-treatment\",\n      \"journal\": \"Journal of Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological perturbation with consistent functional readouts; no direct genetic KO used here\",\n      \"pmids\": [\"25720537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HPR6.6/PGRMC1 expression in MCF-7 breast cancer cells sensitizes them to oxidative damage-induced cell death (H2O2 treatment). Cell death was not through typical apoptosis and corresponded with hyperphosphorylation of Akt and IκB, but inhibition of Akt or IκB degradation had no effect on HPR6.6-mediated death, indicating a novel oxidative damage response pathway.\",\n      \"method\": \"Overexpression of HPR6.6/PGRMC1, H2O2 treatment, pharmacological inhibition of Akt/IκB, cell death assays\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment with pharmacological inhibitors, pathway defined by exclusion only\",\n      \"pmids\": [\"14523988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cell surface-expressed PGRMC1 (csPGRMC1) displays a non-conventional plasma membrane topology in which the C-terminal cytoplasmic domain (residues 171-195) is exposed extracellularly, as determined by epitope mapping of anti-PGRMC1 monoclonal antibodies and trypsin sensitivity assays.\",\n      \"method\": \"Flow cytometry, trypsin treatment, GST-fused PGRMC1 deletion/mutant epitope mapping, polyclonal antibody binding assays\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple antibody epitope mapping experiments with trypsin accessibility controls establishing membrane topology\",\n      \"pmids\": [\"30679694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PGRMC1 promotes store-operated Ca2+ entry (SOCE) by directly binding to the coiled-coil domain of STIM1 and promoting STIM1 conformational switch. PGRMC1 depletion decreased SOCE, impaired NFAT pathway activation, and disrupted EGF-induced focal adhesion turnover and actomyosin formation in breast cancer cells.\",\n      \"method\": \"Complementation-dependent in situ labeling (co-IP discovery), genetic depletion (PGRMC1 KD), Ca2+ imaging, NFAT reporter assay, focal adhesion and actin cytoskeleton imaging\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding to STIM1 coiled-coil domain with multiple functional readouts; single lab\",\n      \"pmids\": [\"35045297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PGRMC1 promotes ferroptosis in paclitaxel-tolerant persister cancer cells by increasing fatty acid oxidation and lipophagy via autophagosome formation. PGRMC1 silencing reduced ferroptosis sensitivity to xCT inhibitors; PGRMC1 overexpression in parental cells enhanced ferroptosis. PGRMC1 co-localized with LC3B-II.\",\n      \"method\": \"siRNA silencing, PGRMC1 overexpression, lipid ROS measurement, autophagosome imaging, mouse xenograft experiments\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function with multiple biochemical and in vivo readouts; single lab\",\n      \"pmids\": [\"34749765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PGRMC1, localized to the ER membrane, interacts with PERK through their ER luminal domains. This interaction activates PERK in an ER stress-independent manner, leading to eIF2α phosphorylation and consequent inhibition of c-Myc protein translation, blocking hepatocellular carcinoma formation.\",\n      \"method\": \"Co-immunoprecipitation (ER luminal domain interaction), PERK phosphorylation assays, eIF2α phosphorylation assays, orthotopic HCC mouse model, ER localization confirmed by subcellular fractionation/imaging\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping plus kinase activation readout and in vivo tumor model; single lab\",\n      \"pmids\": [\"39747098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PGRMC1 promotes progestin-dependent breast cancer cell proliferation by binding prohibitin-1 (PHB1) and prohibitin-2 (PHB2) in a manner dependent on S181 phosphorylation. PGRMC1-PHB interaction competitively displaces PHBs from ERα, allowing ERα transcriptional activation. Inhibition of PGRMC1 or ERα abolished this proliferative effect.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, phosphorylation mutant (S181A) analysis, ERα activity assays, cell proliferation assays, inhibitor experiments\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/MS discovery with mutagenesis and functional receptor activation readout, single lab\",\n      \"pmids\": [\"34830790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pgrmc1 knockout in zebrafish reduces mPRα protein expression and reduces oocyte sensitivity to progestin, resulting in impaired meiotic maturation and reduced fertility. This provides in vivo evidence that Pgrmc1 regulates oocyte maturation via regulation of mPRα expression.\",\n      \"method\": \"CRISPR/Cas9 global knockout in zebrafish, in vivo and in vitro oocyte maturation assays, western blot for mPRα levels\",\n      \"journal\": \"Frontiers in Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vertebrate model with defined molecular mechanism (mPRα reduction) and physiological phenotype\",\n      \"pmids\": [\"30319543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Manipulation of PGRMC1 phosphorylation status (S57A/S181A double mutant or S57A/Y180F/S181A triple mutant) in cancer cells broadly alters energy metabolism, glycolysis, PI3K/AKT activity, cell shape, actin cytoskeleton, mitochondrial properties, and tumor growth. Y180F mutation strongly attenuates xenograft tumor growth, indicating Y180 phosphorylation is required for full tumorigenic activity.\",\n      \"method\": \"PGRMC1 phosphorylation site mutagenesis, proteomics, metabolic assays, PI3K/AKT phosphorylation assays, xenograft tumor growth in NOD-SCID gamma mice\",\n      \"journal\": \"BMC Molecular and Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with multiple orthogonal functional readouts including in vivo tumor model; single lab\",\n      \"pmids\": [\"32245408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"P4 antagonism of E2-induced neurite outgrowth requires microglial expression of Pgrmc1/S2R. siRNA knockdown of Pgrmc1 in microglia suppressed P4-E2 antagonism of neurite outgrowth. Conditioned media from activated (LPS or wound-stimulated) microglia restored P4-E2 antagonism, but only if Pgrmc1 was present, indicating Pgrmc1 mediates microglial activation and the release of soluble factors that antagonize neurite growth.\",\n      \"method\": \"siRNA knockdown, co-culture system (neurons/astrocytes/microglia), conditioned media transfer, LPS/wound activation, neurite outgrowth quantification\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with epistatic co-culture and conditioned media experiments, single lab\",\n      \"pmids\": [\"23653459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PGRMC1 colocalizes with nucleolin (NCL) in the nucleolus of bovine granulosa cells and oocytes. PGRMC1 siRNA depletion causes NCL translocation from the nucleolus to the nucleoplasm; oxidative stress also reduces nucleolar PGRMC1 and redistributes NCL. However, direct PGRMC1-NCL interaction was not detected by proximity ligation assay, suggesting additional mediators.\",\n      \"method\": \"Immunofluorescence, siRNA knockdown, proximity ligation assay (negative for direct interaction), H2O2 oxidative stress treatment\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization and siRNA phenotype without confirmed direct protein interaction; negative PLA result\",\n      \"pmids\": [\"29339453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PGRMC1 loss in a diethylnitrosamine-induced murine HCC model suppresses hepatocarcinogenesis by reducing NF-κB-dependent IL-6 production, which reduces compensatory hepatocyte proliferation. The anti-pro-inflammatory effect is mediated through reduced EGFR levels, as EGFR inhibitor erlotinib abolished the additional effect of PGRMC1 loss.\",\n      \"method\": \"Global Pgrmc1 knockout mouse, DEN-induced HCC model, NF-κB activity assay, IL-6 ELISA, EGFR protein measurement, pharmacological EGFR inhibition epistasis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined molecular pathway (EGFR-NF-κB-IL-6) and in vivo phenotype; single lab\",\n      \"pmids\": [\"34069911\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PGRMC1 is an ER/membrane-associated heme-binding protein (coordinating heme via Tyr113/Y95) that functions as a multivalent scaffold: it forms haem-stacking dimers that bind and stabilize cytochromes P450 (in a heme-independent manner for stability) and EGFR at the plasma membrane, acts as a size-selective ER-phagy cargo receptor (via its luminal domain binding misfolded prohormones and coupling to RTN3), regulates heme biosynthesis by modulating ferrochelatase activity and acting as a heme donor, mediates progesterone's antiapoptotic and antimitotic signaling (in part through mPRα trafficking to the cell surface and SUMOylation-dependent suppression of Tcf/Lef transcription), promotes SOCE by binding the STIM1 coiled-coil domain, activates PERK in an ER stress-independent manner to inhibit c-Myc translation, and is regulated by phosphorylation at multiple sites (Y113, Y180, S57, S181) that govern its dimerization state, protein interactions, and tumorigenic activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PGRMC1 is a heme-binding cytochrome b5-related membrane protein that functions as a multivalent scaffold coupling heme chemistry to protein stabilization, organelle quality control, and growth signaling [#1, #6]. Its cytosolic domain coordinates heme via an axial tyrosinate (Y95/Y113) in a five-coordinate high-spin configuration and uses the two protruding heme groups to form stacking dimers; CO binding to the vacant sixth coordination site disrupts dimerization, and this heme-mediated dimerization is required for productive interactions with EGFR and cytochromes P450 [#0, #3]. Through these interactions PGRMC1 stabilizes a broad range of cytochromes P450 post-transcriptionally and in a heme-independent manner, raises plasma-membrane EGFR levels, and regulates cellular sensitivity to EGFR-targeted drugs [#7, #4]. PGRMC1 also engages the terminal heme-biosynthetic enzyme ferrochelatase—an interaction that requires Y113 axial coordination—modulating ferrochelatase activity and acting as a heme donor to apo-cytochrome b5, thereby placing it at the interface of heme production and distribution [#6, #7]. In the ER lumen, PGRMC1 serves as a size-selective cargo receptor that recognizes misfolded prohormones such as mutant proinsulin and POMC and routes small oligomers for RTN3-dependent ER-phagy [#10]. PGRMC1 transduces progesterone responses chiefly by chaperoning membrane progesterone receptor alpha (mPRα) to the cell surface, an activity confirmed in vivo where Pgrmc1 loss reduces mPRα and impairs oocyte maturation [#11, #24]. Additional outputs include progesterone-induced SUMOylation that suppresses Tcf/Lef transcription [#14], promotion of store-operated Ca2+ entry through direct binding to the STIM1 coiled-coil [#20], and ER-stress-independent activation of PERK to phosphorylate eIF2α and block c-Myc translation [#22]. PGRMC1 activity is governed by phosphorylation at multiple sites (S57, Y180, S181), which control dimerization, partner interactions including prohibitin binding, and tumorigenic capacity [#25, #23]. A disease-associated H165R missense mutation in the cytochrome b5 domain, linked to premature ovarian failure, abolishes CYP7A1 binding and attenuates progesterone's anti-apoptotic action [#9].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established an early functional readout linking PGRMC1 expression to a non-canonical oxidative-stress death pathway in breast cancer cells, before its biochemistry was known.\",\n      \"evidence\": \"HPR6.6/PGRMC1 overexpression with H2O2 challenge and Akt/IκB inhibitor exclusion in MCF-7 cells\",\n      \"pmids\": [\"14523988\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway defined only by exclusion of Akt/IκB\", \"No molecular mechanism for the death signal\", \"Single overexpression system\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Tested whether PGRMC1 itself binds progesterone and mediates progesterone's antiapoptotic action, addressing whether it is a direct steroid sensor.\",\n      \"evidence\": \"[3H]progesterone binding with GFP-PGRMC1 fusion, deletion mutagenesis, and siRNA in granulosa cells\",\n      \"pmids\": [\"17991724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve whether binding is direct vs. via partners\", \"Structural basis of binding unknown\", \"PAIRBP1 contribution not separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined PGRMC1's core biochemical identity as a heme-binding, cytochrome b5-related protein that activates P450 enzymes, framing it as a P450-coupling factor.\",\n      \"evidence\": \"Biochemical binding and enzymatic activity assays (review-level synthesis) implicating CYP51, PAIR-BP1, Insig\",\n      \"pmids\": [\"18992768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary data are review-level\", \"Heme coordination geometry not defined here\", \"Mechanism of P450 activation unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed phosphorylation regulates PGRMC1's stress function, introducing post-translational control as a determinant of activity.\",\n      \"evidence\": \"2D-PAGE phosphoproteomics and S56/S180 mutagenesis with peroxide-survival assays in MCF7 tumors and cells\",\n      \"pmids\": [\"18922159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinases responsible not identified\", \"Link between phospho-state and molecular interactions not yet mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected a PGRMC1 missense mutation to premature ovarian failure and to loss of a specific P450 interaction, providing the first human disease link.\",\n      \"evidence\": \"H165R mutation screening with CYP7A1-binding and progesterone anti-apoptosis assays in ovarian cells\",\n      \"pmids\": [\"18782852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality vs. association not fully established\", \"Effect on other P450 partners untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined PGRMC1 as an EGFR-stabilizing partner that raises plasma-membrane EGFR and modulates EGFR-inhibitor sensitivity, linking it to growth-factor signaling.\",\n      \"evidence\": \"Reciprocal co-IP, fractionation, immunofluorescence, and EGFR inhibitor viability assays\",\n      \"pmids\": [\"20538600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether binding is direct not established\", \"Mechanism of EGFR stabilization unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified PGRMC1 as the protein labeled by a sigma-2 photoaffinity probe, an assignment later partly reassigned.\",\n      \"evidence\": \"Photoaffinity labeling, MS identification, and gain/loss-of-function radioligand binding in HeLa cells\",\n      \"pmids\": [\"21730960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sigma-2 identity later contested (see 2018)\", \"Functional consequence of sigma-2 ligand binding unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed progesterone drives PGRMC1 SUMOylation and nuclear localization to suppress Tcf/Lef transcription, revealing a transcriptional output.\",\n      \"evidence\": \"Co-IP/PLA with SUMO-1, nuclear fractionation, Tcf/Lef reporter, and SUMO-site mutagenesis\",\n      \"pmids\": [\"22719051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO E3 ligase not identified\", \"Direct DNA/transcription-machinery contacts unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed Pgrmc1 upstream of ERK5 in progesterone-induced BDNF release from glia, extending its signaling role to the nervous system.\",\n      \"evidence\": \"siRNA knockdown with BDNF measurement and ERK5 vs. ERK1/2 inhibition in glial cells/astrocytes\",\n      \"pmids\": [\"22778217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor coupling to ERK5 not defined\", \"Whether mPRα participates not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reframed PGRMC1's progesterone signaling as adaptor-mediated, showing it traffics mPRα to the cell surface and that antiapoptotic effects require mPRα.\",\n      \"evidence\": \"Stable overexpression, [3H]progesterone binding, co-IP, and mPRα siRNA epistasis\",\n      \"pmids\": [\"24424068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PGRMC1-mPRα binding interface unmapped\", \"Reconciliation with direct-progesterone-binding model incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established PGRMC1/PGRMC2 as mitotic-spindle proteins that restrain cell-cycle entry, implicating it in division control via G3BP2.\",\n      \"evidence\": \"siRNA, pull-down, PLA, immunofluorescence, and FUCCI cell-cycle sensing\",\n      \"pmids\": [\"25253729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular role at the spindle unclear\", \"G3BP2 functional contribution undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved PGRMC1's heme coordination chemistry (five-coordinate high-spin, axial Y95 tyrosinate) and demonstrated progesterone-induced spectral changes in heme-loaded protein.\",\n      \"evidence\": \"UV-vis/EPR spectroscopy, Y95 mutagenesis, and progesterone binding with purified protein\",\n      \"pmids\": [\"25675345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological redox role of heme not established\", \"Single-lab spectroscopic study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed Pgrmc1 is required for cell-surface EGFR and mPRα-dependent EGFR signaling in normal oocytes, generalizing its EGFR role beyond cancer.\",\n      \"evidence\": \"AG205 pharmacological inhibition, plasma-membrane fractionation, and oocyte maturation assays in zebrafish\",\n      \"pmids\": [\"25720537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inhibitor specificity\", \"No genetic KO in this study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural basis for PGRMC1 function: heme-stacking dimerization required for EGFR and P450 interactions, proliferation, and chemoresistance, with CO as a dimer disruptor.\",\n      \"evidence\": \"1.95 Å crystal structure, CO interference, mutagenesis, co-IP, and cellular phenotype assays\",\n      \"pmids\": [\"26988023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length/membrane context not crystallized\", \"Dynamics of dimer-to-monomer switching in cells not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked PGRMC1 to heme biosynthesis by showing it binds and modulates ferrochelatase and can donate heme to apo-cytochrome b5.\",\n      \"evidence\": \"Reciprocal AP-MS, in vitro FECH activity assay, and in vitro heme-transfer assay\",\n      \"pmids\": [\"27599036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of FECH modulation not established here\", \"Directionality of heme flux in cells unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a direct interaction of PGRMC1 with Aurora Kinase B at the central spindle, tying it to karyokinesis and meiotic progression.\",\n      \"evidence\": \"siRNA, time-lapse imaging, AURKB co-localization, and AG205 inhibition in granulosa cells and oocytes\",\n      \"pmids\": [\"27260975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical AURKB binding not isolated\", \"Role in spindle assembly mechanism undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the sigma-2 identity question, establishing TMEM97 as the primary sigma-2 receptor and defining a PGRMC1-TMEM97-LDLR ternary complex for LDL internalization.\",\n      \"evidence\": \"CRISPR KO with radioligand binding, PLA, and LDL uptake epistasis\",\n      \"pmids\": [\"30443021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the ternary complex undefined\", \"Mechanism by which PGRMC1 promotes LDL uptake unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided in vivo genetic evidence that Pgrmc1 controls oocyte maturation through regulation of mPRα expression.\",\n      \"evidence\": \"CRISPR global KO in zebrafish with oocyte maturation assays and mPRα western blot\",\n      \"pmids\": [\"30319543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PGRMC1 to mPRα stability not defined\", \"Mammalian generalizability untested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reported a non-conventional plasma-membrane topology for cell-surface PGRMC1 with the C-terminal cytoplasmic domain exposed extracellularly.\",\n      \"evidence\": \"Flow cytometry, trypsin sensitivity, and GST-fusion epitope mapping with antibodies\",\n      \"pmids\": [\"30679694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How the topology arises mechanistically unknown\", \"Functional consequence of surface exposure undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PGRMC1 colocalizes with and positions nucleolin in the nucleolus, though without a confirmed direct interaction.\",\n      \"evidence\": \"Immunofluorescence, siRNA, and PLA (negative for direct interaction) under oxidative stress\",\n      \"pmids\": [\"29339453\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct PGRMC1-NCL interaction detected (negative PLA)\", \"Mediating factor unidentified\", \"Nucleolar function of PGRMC1 unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that PGRMC1 phosphorylation status broadly reprograms metabolism and tumor growth, with Y180 required for full tumorigenicity.\",\n      \"evidence\": \"Phospho-site mutagenesis (S57A/Y180F/S181A combinations), proteomics, metabolic assays, and xenografts in NSG mice\",\n      \"pmids\": [\"32245408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinases targeting these sites not identified\", \"Direct mechanistic link from phospho-state to metabolism unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined PGRMC1 as a size-selective ER-phagy cargo receptor for misfolded prohormones coupling to RTN3, revealing an organelle quality-control function.\",\n      \"evidence\": \"Reciprocal co-IP, RTN3 interactome proteomics, CRISPR/siRNA, and ER-phagy/trafficking assays in β-cells (two papers)\",\n      \"pmids\": [\"34645803\", \"34779709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of size selectivity unknown\", \"Range of physiological cargoes incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PGRMC1 stabilizes a broad set of cytochromes P450 heme-independently and that Y113 axial coordination is required for ferrochelatase binding, dissociating stabilization from heme catalysis.\",\n      \"evidence\": \"Pgrmc1 KO mouse with proteomics, transcriptomics, in vitro P450 activity, and Y113F mutagenesis\",\n      \"pmids\": [\"34678314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How heme-independent stabilization occurs mechanistically unclear\", \"Which P450s are physiologically most dependent unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PGRMC1 to progestin-driven proliferation via S181-dependent prohibitin binding that frees ERα for transcription.\",\n      \"evidence\": \"Co-IP/MS, S181A mutant analysis, ERα activity and proliferation assays with inhibitors\",\n      \"pmids\": [\"34830790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PGRMC1-PHB binding interface unmapped\", \"Generality beyond the cell models tested unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PGRMC1 promotes ferroptosis in drug-tolerant persister cells via lipophagy and fatty-acid oxidation, identifying a context-dependent cell-death role.\",\n      \"evidence\": \"siRNA, overexpression, lipid-ROS measurement, autophagosome imaging, and xenografts\",\n      \"pmids\": [\"34749765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger linking PGRMC1 to lipophagy undefined\", \"Reconciliation with its protective stress roles unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected Pgrmc1 to hepatocarcinogenesis through an EGFR-NF-κB-IL-6 axis driving compensatory proliferation.\",\n      \"evidence\": \"Global Pgrmc1 KO in DEN-induced HCC, NF-κB/IL-6 assays, and erlotinib epistasis\",\n      \"pmids\": [\"34069911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type origin of the effect not isolated\", \"Direct vs. indirect EGFR contribution incompletely separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified PGRMC1 as a direct STIM1 coiled-coil binder that promotes store-operated Ca2+ entry and downstream NFAT and cytoskeletal signaling.\",\n      \"evidence\": \"Co-IP, PGRMC1 depletion, Ca2+ imaging, NFAT reporter, and focal-adhesion/actin imaging in breast cancer cells\",\n      \"pmids\": [\"35045297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of STIM1 conformational promotion undefined\", \"Relationship to ER heme/P450 functions unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed PGRMC1 binds PERK via ER luminal domains to activate PERK independent of ER stress, phosphorylating eIF2α and suppressing c-Myc translation to block HCC.\",\n      \"evidence\": \"Co-IP with domain mapping, PERK/eIF2α phosphorylation assays, and orthotopic HCC mouse model\",\n      \"pmids\": [\"39747098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PGRMC1 binding activates PERK mechanistically undefined\", \"Apparent contrast with tumor-promoting PGRMC1 roles unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PGRMC1's distinct activities—heme chemistry, P450/EGFR stabilization, ER-phagy cargo receptor function, progesterone/mPRα signaling, SOCE, and PERK activation—are coordinated within a single protein and switched between tumor-suppressive and tumor-promoting outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of full-length membrane-embedded PGRMC1 in different complexes\", \"Phospho-code-to-interaction mapping incomplete\", \"Mechanism reconciling opposing roles in hepatocarcinogenesis unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0020037\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 7, 20]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10, 22]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 11, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [13, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 20, 22]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 10, 22]}\n    ],\n    \"complexes\": [\n      \"PGRMC1-TMEM97-LDLR ternary complex\"\n    ],\n    \"partners\": [\n      \"EGFR\",\n      \"FECH\",\n      \"RTN3\",\n      \"STIM1\",\n      \"PERK\",\n      \"mPRα\",\n      \"TMEM97\",\n      \"AURKB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}