{"gene":"NREP","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2000,"finding":"P311 encodes an 8-kDa polypeptide that is rapidly degraded by the lactacystin-sensitive ubiquitin/proteasome system and an unidentified metalloprotease, resulting in a protein half-life of approximately 5 minutes. P311 mRNA expression is decreased by co-expression of oncogenic Met receptor tyrosine kinase and its ligand HGF/scatter factor.","method":"Proteasome inhibitor (lactacystin) treatment, protein half-life measurement, mRNA expression analysis in transformed cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical demonstration of proteasomal degradation with pharmacological inhibitor and half-life measurement, single lab but two orthogonal methods","pmids":["10660586"],"is_preprint":false},{"year":2001,"finding":"P311 supports migration of malignant glioma cells; antisense oligodeoxynucleotide knockdown of P311 reduces glioblastoma cell migration, and the protein localizes at focal adhesions in invasive cells.","method":"Antisense oligodeoxynucleotides, integrin activation assays, immunochemistry, laser capture microdissection followed by quantitative RT-PCR","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific migration phenotype, multiple orthogonal methods (antisense KD, integrin activation, immunohistochemistry), single lab","pmids":["11358844"],"is_preprint":false},{"year":2002,"finding":"P311 transfection into fibroblast cell lines induces a TGF-β1-independent myofibroblast phenotype characterized by upregulation of SM alpha-actin, SM22, FGF-2, VEGF, PDGF, PDGF receptors, and integrins α3/α5, while simultaneously inhibiting TGF-β1, TGF-β receptor 2, MMP-2, MMP-9, and collagen 1/3 expression.","method":"Plasmid transfection into NIH 3T3 and C3H10 T1/2 fibroblasts, Western blot, RT-PCR, exogenous TGF-β1 rescue experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function in two cell lines with multiple orthogonal readouts plus rescue experiment; independently replicated in subsequent studies","pmids":["12417574"],"is_preprint":false},{"year":2004,"finding":"P311 binds to the TGF-β latency-associated protein (LAP) of TGF-β1 and TGF-β2 (but not TGF-β3) as shown by yeast two-hybrid and co-immunoprecipitation. P311 downregulates TGF-β1 and TGF-β2 expression but not TGF-β3. Deletion of P311's PEST domain reverses its effect on TGF-β isoforms. P311 decreases Smad3 activity, consistent with reduced TGF-β autoinduction.","method":"Yeast two-hybrid, co-immunoprecipitation, Western blot, deletion mutagenesis of PEST domain, Smad3 activity reporter","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus PEST domain mutagenesis plus functional Smad3 readout; multiple orthogonal methods in single study","pmids":["14985127"],"is_preprint":false},{"year":2004,"finding":"Ectopically expressed P311 localizes in the cytoplasm and nucleus of neurons; overexpression of P311 induces p21(WAF1/Cip1) expression leading to PC12 cell differentiation with neuron-like morphology; adenoviral P311 gene transfer promotes neurite outgrowth of dorsal root ganglion and hippocampal neurons in vitro, an effect abolished by Rho kinase activation.","method":"Adenovirus-mediated gene transfer, immunofluorescence localization, PC12 differentiation assay, Rho kinase inhibitor, in vivo facial nerve axotomy model","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in multiple neuronal cell types with pharmacological pathway validation and in vivo confirmation, single lab","pmids":["15485502"],"is_preprint":false},{"year":2005,"finding":"P311 is constitutively serine-phosphorylated; dephosphorylation at S59 (near the PEST domain) stabilizes P311 protein and induces glioma cell motility (S59A mutation), while a phosphomimetic S59D mutation causes rapid P311 degradation and reduces migration. P311 binds Filamin A (identified by Co-IP/MALDI-TOF MS) and both colocalize at the cell periphery. P311-induced migration is abolished by β1 integrin dominant-negative inhibitor and requires Rac1 GTPase activity.","method":"Site-directed mutagenesis (S59A, S59D), co-immunoprecipitation, MALDI-TOF mass spectrometry, immunofluorescence colocalization, dominant-negative β1 integrin, siRNA knockdown of Rac1","journal":"Neoplasia (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis, Co-IP/MS, dominant-negative and siRNA epistasis with specific migration phenotype; multiple orthogonal methods in one study","pmids":["16229809"],"is_preprint":false},{"year":2006,"finding":"P311-induced myofibroblasts migrate in an ameboid pattern (lacking focal adhesions, stress fibers, integrins/MMPs clustering) through activation of GTPase RalA; RalA RNAi reverts migration to mesenchymal type. Ameboid migration is supported by fibrin matrix but is switched to mesenchymal migration by collagen I or TGF-β1.","method":"RalA siRNA, cell migration assays, matrix composition experiments (fibrin vs collagen I), immunofluorescence for focal adhesions/stress fibers","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi epistasis with defined phenotypic reversal and matrix-dependent switching; single lab, multiple orthogonal readouts","pmids":["16934802"],"is_preprint":false},{"year":2008,"finding":"P311 functions in an alternative pathway of lipid-droplet accumulation induced by retinoic acid; P311 upregulates genes associated with lipid synthesis and increases intracellular cholesterol, triglyceride, and lipid droplets. P311 is not required for lipogenesis in the canonical NIH3T3-L1 adipogenic differentiation model.","method":"P311 overexpression/knockdown, lipid staining, cholesterol and triglyceride quantification, gene expression profiling, NIH3T3-L1 differentiation assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple lipid readouts; pathway specificity established via negative NIH3T3-L1 result; single lab","pmids":["18664493"],"is_preprint":false},{"year":2008,"finding":"P311-knockout mice show impaired contextual and cued fear conditioning, social transmission of food preference, Morris water maze performance, and altered emotional responses (reduced fear-potentiated startle), establishing P311 as required for normal learning/memory and emotional responses without affecting motor coordination, balance, hearing, or olfactory discrimination.","method":"Gene-targeted P311-knockout mice, behavioral battery (Morris water maze, fear conditioning, fear-potentiated startle, social transmission of food preference)","journal":"Genes, brain, and behavior","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with specific behavioral phenotypic readouts and normal controls for sensorimotor function; single lab","pmids":["18616608"],"is_preprint":false},{"year":2008,"finding":"P311-knockout mice show normal heat and mechanical pain sensitivity and normal inflammatory pain responses, but exhibit significantly attenuated formalin-induced pain avoidance behavior (affective pain component), placing P311 specifically in the affective but not sensory pain pathway.","method":"P311-knockout mice, formalin pain test (sensory vs. affective components), heat and mechanical sensitivity tests","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with dissociated sensory/affective phenotype using multiple pain modalities; single lab","pmids":["18549486"],"is_preprint":false},{"year":2013,"finding":"P311 is an RNA-binding protein that stimulates translation of TGF-β1, TGF-β2, and TGF-β3 under steady-state conditions. P311-null mice are markedly hypotensive with defects in vascular smooth muscle contractility due to decreased TGF-β1/β2/β3 protein (but not mRNA) levels; this is fully rescued by exogenous TGF-β1–β3. P311-transgenic mice have elevated TGF-β levels and hypertension, establishing a P311–TGF-β translational axis for blood pressure regulation.","method":"P311-knockout and P311-transgenic mice, blood pressure measurement, vascular contractility assays, polysome fractionation, rescue with exogenous TGF-β1–β3, Western blot","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — both KO and transgenic models with rescue experiments; mechanistic translational control demonstrated by polysome analysis; multiple orthogonal methods","pmids":["24091331"],"is_preprint":false},{"year":2014,"finding":"P311 is an intrinsically disordered protein that directly binds eIF3 subunit b (eIF3b) with Kd of 1.26 µM via a central 11-amino acid eIF3b binding motif. P311 also directly binds TGF-β1, -β2, and -β3 5'UTR mRNAs via an RNA recognition motif-like motif. Disruption of P311–eIF3b interaction inhibits TGF-β1/2/3 translation as demonstrated by luciferase reporter assays, polysome fractionation, and Western blot.","method":"Immunoprecipitation/mass spectrometry, GST pulldown, surface plasmon resonance (Kd measurement), immunohistochemical colocalization, luciferase reporter assays, polysome fractionation, RNA-protein EMSA, UV cross-linking RNA precipitation, CD spectroscopy (PONDR disorder analysis)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with Kd measurement by SPR, mutagenesis of binding motif, polysome fractionation, EMSA; multiple orthogonal methods in single rigorous study","pmids":["25336651"],"is_preprint":false},{"year":2012,"finding":"Integrin β4 binding protein (ITGB4BP) is a direct interaction partner of P311, confirmed by yeast two-hybrid screening, co-immunoprecipitation in HEK293 cells, and fluorescence resonance energy transfer (FRET) in tissue sections.","method":"Yeast two-hybrid, co-immunoprecipitation, FRET in tissue sections, immunohistochemistry","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal methods (Y2H, Co-IP, FRET) confirming direct interaction; single lab","pmids":["22365962"],"is_preprint":false},{"year":2015,"finding":"P311 promotes renal fibrosis in vivo; P311 knockout mice subjected to unilateral ureteral obstruction show significantly reduced interstitial collagen deposition, α-SMA, TGF-β1, and macrophage infiltration. The pro-fibrotic effect operates via TGF-β1/Smad signaling.","method":"P311-knockout mice, unilateral ureteral obstruction model, histology, immunohistochemistry, Western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined fibrosis phenotype and pathway placement via TGF-β/Smad; single lab","pmids":["26616407"],"is_preprint":false},{"year":2016,"finding":"P311 induces epidermal stem cell (EpSC) to myofibroblast-like cell transdifferentiation via TGF-β1/Smad2/3 signaling. P311 increases TGF-β1 protein without increasing TGF-β1 mRNA (consistent with translational regulation), upregulates TGF-β receptors I/II, and activates Smad2/3. P311 promotes TGF-β1 5'/3'UTR activity. TGF-βRI/II inhibitor LY2109761 and Smad3 siRNA reverse P311-induced transdifferentiation.","method":"Adenoviral P311 overexpression in human/mouse EpSCs, Western blot, immunofluorescence, real-time PCR, bisulfite sequencing, luciferase reporter assays, pharmacological (LY2109761) and siRNA (Smad3) pathway blockade, P311-KO mouse wound model","journal":"Stem cell research & therapy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (overexpression, KO mouse, pharmacological and siRNA epistasis, UTR luciferase), replication in human and mouse cells","pmids":["27906099"],"is_preprint":false},{"year":2017,"finding":"P311 accelerates epidermal stem cell (EpSC) migration and skin wound reepithelialization through activation of RhoA and Rac1 GTPases (but not Cdc42). Specific RhoA and Rac1 inhibitors (but not Cdc42 inhibitor) suppress P311-induced EpSC migration. P311-knockout mouse wounds show impaired reepithelialization.","method":"Adenoviral P311 overexpression in human EpSCs, P311-KO mouse wound model, Rho GTPase activity assays, pharmacological inhibitors of RhoA, Rac1, and Cdc42, cell migration assays","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with pharmacological dissection of GTPase specificity; single lab, multiple methods","pmids":["27927130"],"is_preprint":false},{"year":2019,"finding":"P311 stimulates TGF-β1, -β2, and -β3 translation in lung fibroblasts. P311-knockout mice subjected to bleomycin-induced pulmonary fibrosis show significantly reduced fibrotic changes and decreased TGF-β1/2/3 levels. Forced P311 expression increases TGF-β levels and collagen production in human and mouse lung fibroblasts. TGF-β-neutralizing antibodies abrogate P311-induced collagen production. Rescue of P311-KO mice with recombinant TGF-β1/2/3 restores fibrosis to wild-type levels.","method":"P311-knockout mice with bleomycin lung fibrosis model, adenoviral P311 overexpression in lung fibroblasts, Western blot, TGF-β neutralizing antibodies, cytokine rescue experiments","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with rescue experiments, antibody blockade of TGF-β, overexpression in human and mouse cells; multiple orthogonal approaches","pmids":["30230348"],"is_preprint":false},{"year":2019,"finding":"P311 binds to the PPARγ2 promoter and its knockdown inhibits adipogenic differentiation of 3T3-L1 cells; P311 expression is induced at the onset of adipogenesis and correlates with PPARγ2 and C/EBPα induction.","method":"siRNA knockdown, 3T3-L1 adipogenesis model, chromatin immunoprecipitation (ChIP) for PPARγ2 promoter binding, Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence of promoter binding plus siRNA loss-of-function with differentiation phenotype; single lab","pmids":["31146912"],"is_preprint":false},{"year":2020,"finding":"Meox1 (mesenchyme homeobox 1), induced by TGF-β1, binds the P311 core promoter and increases P311 transcriptional activity. This Meox1-mediated P311 transcription contributes to altered migration and proliferation of human dermal fibroblasts.","method":"Bioinformatics promoter analysis, luciferase reporter assays, chromatin immunoprecipitation (ChIP), siRNA knockdown of Meox1, cell migration and proliferation assays","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence of Meox1 binding P311 promoter plus luciferase reporter and siRNA functional validation; single lab","pmids":["32411720"],"is_preprint":false},{"year":2020,"finding":"miR-7a-5p directly targets the 3'UTR of P311 mRNA and suppresses P311 expression; butyrate alleviates diabetic kidney fibrosis in part by inducing miR-7a-5p, which suppresses P311, thereby reducing TGF-β1 translation. Overexpression of P311 offsets butyrate's inhibition of TGF-β1.","method":"3'UTR luciferase reporter assay, miRNA sequencing, miR-7a-5p agomir in db/db mice, Western blot, RT-PCR, P311 overexpression rescue","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR targeting validated by luciferase assay plus in vivo agomir rescue and P311 overexpression epistasis; single lab","pmids":["32539181"],"is_preprint":false},{"year":2022,"finding":"P311 promotes M2 polarization of macrophages by upregulating IL-4 receptor expression and activating the IL-4 receptor–STAT6 signaling pathway. P311 regulation of IL-4 receptor expression involves the mTOR signaling pathway.","method":"P311-knockout mice, macrophage polarization assays, Western blot, flow cytometry for IL-4R/STAT6, mTOR inhibitor experiments, wound healing model","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with pathway dissection using mTOR inhibitor; defined cellular phenotype with mechanistic pathway placement; single lab","pmids":["36309321"],"is_preprint":false},{"year":2022,"finding":"P311 promotes angiogenesis in mesenchymal stem cells by increasing VEGF production through the mTOR signaling pathway.","method":"P311 overexpression in MSCs, VEGF ELISA, tube formation assay, mTOR inhibitor, in vivo wound model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with pharmacological pathway validation (mTOR inhibitor) and in vitro/in vivo corroboration; single lab","pmids":["35154140"],"is_preprint":false},{"year":2022,"finding":"P311 enhances angiogenesis in human microvascular endothelial cells by activating the VEGFR2/ERK1/2 signaling pathway; siRNA knockdown of VEGFR2 or ERK1/2 inhibitor treatment abolishes P311-induced tube formation.","method":"Adenoviral P311 overexpression in HMEC-1 cells, Western blot for p-VEGFR2 and p-ERK1/2, siRNA-VEGFR2 knockdown, ERK1/2 inhibitor, tube formation assay, scratch migration assay","journal":"Zhonghua shao shang yu chuang mian xiu fu za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal pathway blockade strategies (siRNA VEGFR2 and pharmacological ERK inhibitor) with defined angiogenesis phenotype; single lab","pmids":["35220700"],"is_preprint":false},{"year":2022,"finding":"P311 promotes fibroblast differentiation and granulation tissue formation by upregulating TGF-βRII (type II TGF-β receptor) expression and activating the TGF-βRII–Smad signaling pathway via the mTOR pathway.","method":"P311-knockout and wild-type mice with full-thickness excisional wounds, Western blot for TGF-βRII and Smad proteins, mTOR inhibitor, in vitro fibroblast differentiation assays","journal":"Burns & trauma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model plus pharmacological mTOR inhibition with defined TGF-βRII/Smad pathway placement; single lab","pmids":["37469904"],"is_preprint":false},{"year":2023,"finding":"NREP knockdown in primary human hepatocytes alters one-carbon metabolism, increases cholesterol esters and triglycerides, decreases phosphatidylcholine levels, and activates calcium signaling pathways, implicating NREP in hepatic lipid/metabolic homeostasis.","method":"siRNA knockdown in primary human hepatocytes, RNA-sequencing, lipidomics, antibody microarray (signalomics)","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omic profiling (transcriptomics, lipidomics, signalomics) in human primary cells with direct KD; single lab","pmids":["37354909"],"is_preprint":false},{"year":2023,"finding":"NREP knockdown in chondrocytes inactivates the TGF-β1/Smad2/3 signaling pathway, resulting in downregulation of anabolic markers Col2a1 and Sox9 and upregulation of catabolic markers MMP3 and MMP13, and reduced chondrocyte proliferation.","method":"siRNA knockdown of NREP in chondrocytes, Western blot for p-Smad2/3, RT-qPCR, CCK-8 and EdU proliferation assays, OA mouse model with IHC","journal":"Journal of orthopaedic translation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with defined TGF-β/Smad pathway placement and multiple phenotypic readouts; single lab","pmids":["38179126"],"is_preprint":false},{"year":2023,"finding":"YTHDF1 binds m6A-modified NREP mRNA and promotes its translation; YTHDF1 depletion reduces NREP protein levels and impairs TGF-β–Smad signaling, keratocyte proliferation, migration, and fibroblast-to-myofibroblast differentiation in corneal fibrosis.","method":"siRNA knockdown of NREP and YTHDF1, SRAMP m6A site prediction, LC-MS m6A profiling, CCK-8, scratch assay, immunofluorescence, Western blot, in vivo alkali burn corneal fibrosis model, YTHDF1 inhibitor (SKLB-Y13)","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two siRNA KDs plus pharmacological YTHDF1 inhibitor with defined m6A-translational mechanism; single lab","pmids":["42153780"],"is_preprint":false},{"year":2024,"finding":"HIF-1α directly binds to the NREP promoter to increase NREP transcriptional activity under hypoxia. NREP promotes breast cancer cell glycolysis (increased glucose consumption, ATP, lactate, glucose transporter expression), cell proliferation, migration, invasion, and EMT.","method":"Luciferase reporter system, chromatin immunoprecipitation (ChIP), siRNA/overexpression of NREP, HIF-1α inhibition, Seahorse glycolysis assay, cell cycle analysis, apoptosis assay, in vivo xenograft","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct ChIP confirmation of HIF-1α binding NREP promoter plus loss/gain-of-function with metabolic and functional readouts; single lab","pmids":["38697993"],"is_preprint":false},{"year":2024,"finding":"Structural variations disrupting the TAD boundary in the Epb41l4a/EPB41L4A locus cause dysregulation of Nrep gene expression, as demonstrated in mouse models with deletion and inversion mutations analyzed by RNA-seq.","method":"CRISPR/engineered mouse models (deletion and inversion), RNA-seq, 3D genome/TAD analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic engineering of TAD boundary with RNA-seq confirmation of Nrep dysregulation; single lab","pmids":["38438377"],"is_preprint":false}],"current_model":"NREP/P311 is a small (8 kDa), intrinsically disordered, rapidly proteasome-degraded RNA-binding protein that acts as the primary translational stimulator of TGF-β1, TGF-β2, and TGF-β3 by binding their 5'UTRs and directly interacting with eIF3b; it also binds the TGF-β latency-associated protein (LAP) and, through this translational axis, controls blood pressure homeostasis, promotes myofibroblast transformation, and drives fibrosis in lung, kidney, skin, and liver; additionally, P311 activates Rac1/RhoA GTPases (and RalA in ameboid migration) downstream of β1 integrin to drive cell migration, and is regulated transcriptionally by HIF-1α and Meox1 and post-transcriptionally by miR-7a-5p targeting its 3'UTR and by YTHDF1-mediated m6A-dependent translation enhancement."},"narrative":{"mechanistic_narrative":"NREP (P311) is a small, intrinsically disordered, rapidly proteasome-degraded RNA-binding protein that acts as the central translational activator of the TGF-β system and, through it, governs myofibroblast biology, fibrosis, and cell migration [PMID:10660586, PMID:24091331, PMID:25336651]. Mechanistically, NREP directly binds the 5'UTR mRNAs of TGF-β1, TGF-β2, and TGF-β3 through an RNA-recognition-motif-like element and recruits the translation initiation machinery by directly engaging eIF3 subunit b (eIF3b, Kd ≈ 1.26 µM) via a defined 11-residue motif, thereby stimulating TGF-β translation without altering TGF-β mRNA levels; disrupting the NREP–eIF3b interaction abolishes this output [PMID:25336651]. This translational axis is physiologically decisive: NREP-null mice are hypotensive with impaired vascular smooth muscle contractility and reduced TGF-β protein, both fully rescued by exogenous TGF-β, while transgenic mice are hypertensive [PMID:24091331]. The same axis drives fibrosis across organs—renal, pulmonary, dermal—operating through TGF-β/Smad2/3 signaling, upregulation of TGF-β receptors, and conversion of fibroblasts and epidermal stem cells into α-SMA-positive myofibroblast-like cells [PMID:26616407, PMID:27906099, PMID:30230348, PMID:37469904]. Independent of translation, NREP promotes cell migration downstream of β1 integrin by activating Rac1 and RhoA GTPases (and RalA in ameboid migration), with stability governed by serine phosphorylation at S59 near its PEST domain and an interaction with Filamin A at the cell periphery [PMID:16229809, PMID:16934802, PMID:27927130]. NREP expression is itself tightly controlled—transcriptionally activated by HIF-1α under hypoxia and by TGF-β-induced Meox1, and post-transcriptionally repressed by miR-7a-5p targeting its 3'UTR and enhanced by YTHDF1-mediated m6A-dependent translation [PMID:32411720, PMID:32539181, PMID:42153780, PMID:38697993]. Beyond fibrosis, NREP is required in vivo for normal learning, memory, and the affective component of pain [PMID:18616608, PMID:18549486].","teleology":[{"year":2000,"claim":"Established NREP/P311 as a short-lived protein, defining proteostatic control as a built-in regulatory feature before any function was known.","evidence":"Lactacystin treatment and half-life measurement in transformed cells","pmids":["10660586"],"confidence":"Medium","gaps":["Identity of the metalloprotease was not determined","Functional consequence of rapid turnover unknown at this stage"]},{"year":2001,"claim":"First functional role: linked NREP to glioma cell migration and focal-adhesion localization, framing it as a motility regulator.","evidence":"Antisense knockdown, integrin activation assays, immunochemistry in invasive glioma cells","pmids":["11358844"],"confidence":"Medium","gaps":["Molecular mechanism connecting NREP to adhesion machinery not defined","No interacting partner identified"]},{"year":2002,"claim":"Showed NREP drives a myofibroblast phenotype while paradoxically suppressing TGF-β1, suggesting a complex, isoform-selective relationship to TGF-β rather than simple agonism.","evidence":"Gain-of-function transfection in NIH3T3 and C3H10T1/2 fibroblasts with rescue experiments","pmids":["12417574"],"confidence":"High","gaps":["Reconciling phenotype with TGF-β1 suppression unresolved at the time","No molecular mechanism for TGF-β regulation"]},{"year":2004,"claim":"Provided a physical handle on TGF-β control by showing NREP binds the latency-associated protein of TGF-β1/β2 and that its PEST domain mediates the effect, while implicating reduced Smad3 autoinduction.","evidence":"Yeast two-hybrid, Co-IP, PEST-deletion mutagenesis, Smad3 reporter","pmids":["14985127"],"confidence":"High","gaps":["TGF-β3 not bound, leaving isoform selectivity unexplained","Did not resolve whether regulation was transcriptional, translational, or via LAP"]},{"year":2004,"claim":"Extended NREP to the nervous system, showing it promotes neurite outgrowth and PC12 differentiation in a Rho-kinase-sensitive manner, linking it to cytoskeletal/neuronal programs.","evidence":"Adenoviral overexpression, PC12 differentiation, Rho kinase inhibition, facial nerve axotomy model","pmids":["15485502"],"confidence":"Medium","gaps":["Direct molecular target in neurons not identified","Relationship to TGF-β axis in neurons unaddressed"]},{"year":2005,"claim":"Defined the migration mechanism: S59 phosphorylation controls NREP stability, and migration requires β1 integrin and Rac1 GTPase, with Filamin A as a peripheral binding partner.","evidence":"S59A/S59D mutagenesis, Co-IP/MALDI-TOF MS, dominant-negative β1 integrin, Rac1 siRNA, colocalization","pmids":["16229809"],"confidence":"High","gaps":["Kinase/phosphatase acting on S59 not identified","How Filamin A binding couples to Rac1 activation unclear"]},{"year":2006,"claim":"Showed NREP-induced migration can adopt a RalA-dependent ameboid mode switchable by matrix composition, revealing plasticity in its motility output.","evidence":"RalA siRNA, fibrin vs collagen I matrices, focal adhesion/stress fiber imaging","pmids":["16934802"],"confidence":"Medium","gaps":["Upstream signal selecting RalA vs Rac1 not defined","Single-lab phenotype"]},{"year":2008,"claim":"Genetic knockouts established organismal roles in learning/memory and the affective component of pain, dissociating these from sensorimotor function.","evidence":"P311-knockout mice, behavioral batteries and formalin pain testing","pmids":["18616608","18549486"],"confidence":"Medium","gaps":["Molecular basis of behavioral phenotypes not connected to TGF-β or migration mechanisms","Cell types and circuits involved not defined"]},{"year":2008,"claim":"Identified a non-canonical, retinoic-acid-linked role in lipid-droplet accumulation, distinguishing it from classical adipogenic differentiation.","evidence":"Overexpression/knockdown, lipid quantification, gene profiling, NIH3T3-L1 negative control","pmids":["18664493"],"confidence":"Medium","gaps":["Direct molecular mediators of lipid synthesis not identified","Relationship to later adipogenesis findings unresolved"]},{"year":2013,"claim":"Resolved the central mechanism: NREP is an RNA-binding protein that stimulates translation of all three TGF-β isoforms, and this axis controls blood pressure, with KO/transgenic phenotypes rescued by exogenous TGF-β.","evidence":"KO and transgenic mice, blood pressure and contractility assays, polysome fractionation, TGF-β rescue","pmids":["24091331"],"confidence":"High","gaps":["Molecular details of translational activation not yet resolved","Did not identify initiation-factor partner"]},{"year":2014,"claim":"Provided the molecular mechanism of translational activation: NREP binds TGF-β 5'UTRs and directly engages eIF3b through a defined motif, with disruption abolishing translation.","evidence":"IP/MS, GST pulldown, SPR Kd, EMSA, UV cross-linking, luciferase reporters, polysome fractionation, CD/PONDR","pmids":["25336651"],"confidence":"High","gaps":["Structural basis of the disordered NREP–eIF3b/RNA complex not determined","How NREP discriminates TGF-β transcripts from other mRNAs unclear"]},{"year":2012,"claim":"Added ITGB4BP as a direct interaction partner, expanding the NREP interactome beyond eIF3b and Filamin A.","evidence":"Yeast two-hybrid, Co-IP in HEK293, FRET in tissue","pmids":["22365962"],"confidence":"Medium","gaps":["Functional consequence of the ITGB4BP interaction not established","No epistasis or phenotype linked to this binding"]},{"year":2019,"claim":"Generalized the NREP–TGF-β translational axis to organ fibrosis (renal, pulmonary, dermal), establishing it as a pro-fibrotic driver reversible by TGF-β blockade or rescue.","evidence":"KO mice in UUO and bleomycin models, overexpression in human/mouse fibroblasts and EpSCs, TGF-β neutralization and rescue, UTR luciferase, Smad pathway blockade","pmids":["26616407","27906099","30230348","37469904"],"confidence":"High","gaps":["Why a normally short-lived protein achieves sustained pro-fibrotic output in vivo not fully explained","Cell-type-specific differences across organs not dissected"]},{"year":2020,"claim":"Mapped upstream control of NREP itself, identifying TGF-β-induced Meox1 as a transcriptional activator and miR-7a-5p as a 3'UTR repressor, embedding NREP in feedback regulation.","evidence":"ChIP, luciferase reporters, siRNA, in vivo miR-7a-5p agomir with P311-overexpression rescue","pmids":["32411720","32539181"],"confidence":"Medium","gaps":["Interplay between transcriptional and miRNA control not integrated","Other regulatory inputs likely incomplete"]},{"year":2022,"claim":"Implicated an mTOR-dependent branch through which NREP modulates macrophage M2 polarization, angiogenesis (VEGF/VEGFR2/ERK), and TGF-βRII expression in wound healing.","evidence":"KO and overexpression models, mTOR/ERK/VEGFR2 inhibition and siRNA, polarization, tube-formation, and wound assays","pmids":["36309321","35154140","35220700","37469904"],"confidence":"Medium","gaps":["How NREP connects mechanistically to mTOR signaling not defined","Whether mTOR effects depend on TGF-β translational axis unclear"]},{"year":2023,"claim":"Broadened the axis to chondrocyte and hepatic homeostasis and showed NREP is itself an m6A-regulated translational target of YTHDF1, adding an epitranscriptomic control layer.","evidence":"siRNA in chondrocytes and primary hepatocytes, multi-omics, m6A profiling, YTHDF1 knockdown and inhibitor, corneal fibrosis model","pmids":["38179126","37354909","42153780"],"confidence":"Medium","gaps":["Direct molecular basis of hepatic metabolic effects not resolved","m6A site mapping on NREP largely predictive"]},{"year":2024,"claim":"Placed NREP in hypoxic and oncogenic contexts: HIF-1α directly drives NREP transcription to promote breast cancer glycolysis and EMT, and TAD-boundary disruption dysregulates Nrep expression.","evidence":"ChIP, luciferase, loss/gain-of-function, Seahorse, xenograft; engineered TAD deletion/inversion mouse models with RNA-seq","pmids":["38697993","38438377"],"confidence":"Medium","gaps":["Whether tumor glycolytic phenotype requires the TGF-β translational axis untested","Functional consequence of TAD-driven Nrep dysregulation not characterized"]},{"year":null,"claim":"How a disordered, rapidly degraded protein achieves selective, high-fidelity translational activation of TGF-β transcripts, and how its diverse outputs (migration, mTOR, metabolism, neuronal function) are mechanistically partitioned, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of NREP bound to RNA or eIF3b","Mechanistic link between mTOR/metabolic roles and the TGF-β translational axis undefined","Molecular basis of neuronal and affective-pain phenotypes uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10,11]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[10,11,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,14,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of 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Ectopic expression augments motility of gliomas. Also promotes axonal regeneration (By similarity). May also have functions in cellular differentiation (By similarity). Induces differentiation of fibroblast into myofibroblast and myofibroblast ameboid migration. Increases retinoic-acid regulation of lipid-droplet biogenesis (By similarity). Down-regulates the expression of TGFB1 and TGFB2 but not of TGFB3 (By similarity). May play a role in the regulation of alveolar generation","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q16612/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NREP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NREP","total_profiled":1310},"omim":[{"mim_id":"607332","title":"NEURONAL REGENERATION-RELATED PROTEIN; NREP","url":"https://www.omim.org/entry/607332"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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Network Reveals Its New Functions.","date":"2019","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31762773","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.28.625899","title":"Mature tuft cell phenotypes are sequentially expressed along the intestinal crypt-villus axis following cytokine-induced tuft cell hyperplasia","date":"2024-11-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.28.625899","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38090,"output_tokens":7657,"usd":0.114562,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17204,"output_tokens":5418,"usd":0.110735,"stage2_stop_reason":"end_turn"},"total_usd":0.225297,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"P311 encodes an 8-kDa polypeptide that is rapidly degraded by the lactacystin-sensitive ubiquitin/proteasome system and an unidentified metalloprotease, resulting in a protein half-life of approximately 5 minutes. P311 mRNA expression is decreased by co-expression of oncogenic Met receptor tyrosine kinase and its ligand HGF/scatter factor.\",\n      \"method\": \"Proteasome inhibitor (lactacystin) treatment, protein half-life measurement, mRNA expression analysis in transformed cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical demonstration of proteasomal degradation with pharmacological inhibitor and half-life measurement, single lab but two orthogonal methods\",\n      \"pmids\": [\"10660586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"P311 supports migration of malignant glioma cells; antisense oligodeoxynucleotide knockdown of P311 reduces glioblastoma cell migration, and the protein localizes at focal adhesions in invasive cells.\",\n      \"method\": \"Antisense oligodeoxynucleotides, integrin activation assays, immunochemistry, laser capture microdissection followed by quantitative RT-PCR\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific migration phenotype, multiple orthogonal methods (antisense KD, integrin activation, immunohistochemistry), single lab\",\n      \"pmids\": [\"11358844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"P311 transfection into fibroblast cell lines induces a TGF-β1-independent myofibroblast phenotype characterized by upregulation of SM alpha-actin, SM22, FGF-2, VEGF, PDGF, PDGF receptors, and integrins α3/α5, while simultaneously inhibiting TGF-β1, TGF-β receptor 2, MMP-2, MMP-9, and collagen 1/3 expression.\",\n      \"method\": \"Plasmid transfection into NIH 3T3 and C3H10 T1/2 fibroblasts, Western blot, RT-PCR, exogenous TGF-β1 rescue experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function in two cell lines with multiple orthogonal readouts plus rescue experiment; independently replicated in subsequent studies\",\n      \"pmids\": [\"12417574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"P311 binds to the TGF-β latency-associated protein (LAP) of TGF-β1 and TGF-β2 (but not TGF-β3) as shown by yeast two-hybrid and co-immunoprecipitation. P311 downregulates TGF-β1 and TGF-β2 expression but not TGF-β3. Deletion of P311's PEST domain reverses its effect on TGF-β isoforms. P311 decreases Smad3 activity, consistent with reduced TGF-β autoinduction.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, Western blot, deletion mutagenesis of PEST domain, Smad3 activity reporter\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid plus reciprocal Co-IP plus PEST domain mutagenesis plus functional Smad3 readout; multiple orthogonal methods in single study\",\n      \"pmids\": [\"14985127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ectopically expressed P311 localizes in the cytoplasm and nucleus of neurons; overexpression of P311 induces p21(WAF1/Cip1) expression leading to PC12 cell differentiation with neuron-like morphology; adenoviral P311 gene transfer promotes neurite outgrowth of dorsal root ganglion and hippocampal neurons in vitro, an effect abolished by Rho kinase activation.\",\n      \"method\": \"Adenovirus-mediated gene transfer, immunofluorescence localization, PC12 differentiation assay, Rho kinase inhibitor, in vivo facial nerve axotomy model\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in multiple neuronal cell types with pharmacological pathway validation and in vivo confirmation, single lab\",\n      \"pmids\": [\"15485502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"P311 is constitutively serine-phosphorylated; dephosphorylation at S59 (near the PEST domain) stabilizes P311 protein and induces glioma cell motility (S59A mutation), while a phosphomimetic S59D mutation causes rapid P311 degradation and reduces migration. P311 binds Filamin A (identified by Co-IP/MALDI-TOF MS) and both colocalize at the cell periphery. P311-induced migration is abolished by β1 integrin dominant-negative inhibitor and requires Rac1 GTPase activity.\",\n      \"method\": \"Site-directed mutagenesis (S59A, S59D), co-immunoprecipitation, MALDI-TOF mass spectrometry, immunofluorescence colocalization, dominant-negative β1 integrin, siRNA knockdown of Rac1\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis, Co-IP/MS, dominant-negative and siRNA epistasis with specific migration phenotype; multiple orthogonal methods in one study\",\n      \"pmids\": [\"16229809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"P311-induced myofibroblasts migrate in an ameboid pattern (lacking focal adhesions, stress fibers, integrins/MMPs clustering) through activation of GTPase RalA; RalA RNAi reverts migration to mesenchymal type. Ameboid migration is supported by fibrin matrix but is switched to mesenchymal migration by collagen I or TGF-β1.\",\n      \"method\": \"RalA siRNA, cell migration assays, matrix composition experiments (fibrin vs collagen I), immunofluorescence for focal adhesions/stress fibers\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi epistasis with defined phenotypic reversal and matrix-dependent switching; single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"16934802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"P311 functions in an alternative pathway of lipid-droplet accumulation induced by retinoic acid; P311 upregulates genes associated with lipid synthesis and increases intracellular cholesterol, triglyceride, and lipid droplets. P311 is not required for lipogenesis in the canonical NIH3T3-L1 adipogenic differentiation model.\",\n      \"method\": \"P311 overexpression/knockdown, lipid staining, cholesterol and triglyceride quantification, gene expression profiling, NIH3T3-L1 differentiation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple lipid readouts; pathway specificity established via negative NIH3T3-L1 result; single lab\",\n      \"pmids\": [\"18664493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"P311-knockout mice show impaired contextual and cued fear conditioning, social transmission of food preference, Morris water maze performance, and altered emotional responses (reduced fear-potentiated startle), establishing P311 as required for normal learning/memory and emotional responses without affecting motor coordination, balance, hearing, or olfactory discrimination.\",\n      \"method\": \"Gene-targeted P311-knockout mice, behavioral battery (Morris water maze, fear conditioning, fear-potentiated startle, social transmission of food preference)\",\n      \"journal\": \"Genes, brain, and behavior\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with specific behavioral phenotypic readouts and normal controls for sensorimotor function; single lab\",\n      \"pmids\": [\"18616608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"P311-knockout mice show normal heat and mechanical pain sensitivity and normal inflammatory pain responses, but exhibit significantly attenuated formalin-induced pain avoidance behavior (affective pain component), placing P311 specifically in the affective but not sensory pain pathway.\",\n      \"method\": \"P311-knockout mice, formalin pain test (sensory vs. affective components), heat and mechanical sensitivity tests\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with dissociated sensory/affective phenotype using multiple pain modalities; single lab\",\n      \"pmids\": [\"18549486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"P311 is an RNA-binding protein that stimulates translation of TGF-β1, TGF-β2, and TGF-β3 under steady-state conditions. P311-null mice are markedly hypotensive with defects in vascular smooth muscle contractility due to decreased TGF-β1/β2/β3 protein (but not mRNA) levels; this is fully rescued by exogenous TGF-β1–β3. P311-transgenic mice have elevated TGF-β levels and hypertension, establishing a P311–TGF-β translational axis for blood pressure regulation.\",\n      \"method\": \"P311-knockout and P311-transgenic mice, blood pressure measurement, vascular contractility assays, polysome fractionation, rescue with exogenous TGF-β1–β3, Western blot\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — both KO and transgenic models with rescue experiments; mechanistic translational control demonstrated by polysome analysis; multiple orthogonal methods\",\n      \"pmids\": [\"24091331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"P311 is an intrinsically disordered protein that directly binds eIF3 subunit b (eIF3b) with Kd of 1.26 µM via a central 11-amino acid eIF3b binding motif. P311 also directly binds TGF-β1, -β2, and -β3 5'UTR mRNAs via an RNA recognition motif-like motif. Disruption of P311–eIF3b interaction inhibits TGF-β1/2/3 translation as demonstrated by luciferase reporter assays, polysome fractionation, and Western blot.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, GST pulldown, surface plasmon resonance (Kd measurement), immunohistochemical colocalization, luciferase reporter assays, polysome fractionation, RNA-protein EMSA, UV cross-linking RNA precipitation, CD spectroscopy (PONDR disorder analysis)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with Kd measurement by SPR, mutagenesis of binding motif, polysome fractionation, EMSA; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"25336651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Integrin β4 binding protein (ITGB4BP) is a direct interaction partner of P311, confirmed by yeast two-hybrid screening, co-immunoprecipitation in HEK293 cells, and fluorescence resonance energy transfer (FRET) in tissue sections.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, FRET in tissue sections, immunohistochemistry\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal methods (Y2H, Co-IP, FRET) confirming direct interaction; single lab\",\n      \"pmids\": [\"22365962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"P311 promotes renal fibrosis in vivo; P311 knockout mice subjected to unilateral ureteral obstruction show significantly reduced interstitial collagen deposition, α-SMA, TGF-β1, and macrophage infiltration. The pro-fibrotic effect operates via TGF-β1/Smad signaling.\",\n      \"method\": \"P311-knockout mice, unilateral ureteral obstruction model, histology, immunohistochemistry, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined fibrosis phenotype and pathway placement via TGF-β/Smad; single lab\",\n      \"pmids\": [\"26616407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"P311 induces epidermal stem cell (EpSC) to myofibroblast-like cell transdifferentiation via TGF-β1/Smad2/3 signaling. P311 increases TGF-β1 protein without increasing TGF-β1 mRNA (consistent with translational regulation), upregulates TGF-β receptors I/II, and activates Smad2/3. P311 promotes TGF-β1 5'/3'UTR activity. TGF-βRI/II inhibitor LY2109761 and Smad3 siRNA reverse P311-induced transdifferentiation.\",\n      \"method\": \"Adenoviral P311 overexpression in human/mouse EpSCs, Western blot, immunofluorescence, real-time PCR, bisulfite sequencing, luciferase reporter assays, pharmacological (LY2109761) and siRNA (Smad3) pathway blockade, P311-KO mouse wound model\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (overexpression, KO mouse, pharmacological and siRNA epistasis, UTR luciferase), replication in human and mouse cells\",\n      \"pmids\": [\"27906099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"P311 accelerates epidermal stem cell (EpSC) migration and skin wound reepithelialization through activation of RhoA and Rac1 GTPases (but not Cdc42). Specific RhoA and Rac1 inhibitors (but not Cdc42 inhibitor) suppress P311-induced EpSC migration. P311-knockout mouse wounds show impaired reepithelialization.\",\n      \"method\": \"Adenoviral P311 overexpression in human EpSCs, P311-KO mouse wound model, Rho GTPase activity assays, pharmacological inhibitors of RhoA, Rac1, and Cdc42, cell migration assays\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with pharmacological dissection of GTPase specificity; single lab, multiple methods\",\n      \"pmids\": [\"27927130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"P311 stimulates TGF-β1, -β2, and -β3 translation in lung fibroblasts. P311-knockout mice subjected to bleomycin-induced pulmonary fibrosis show significantly reduced fibrotic changes and decreased TGF-β1/2/3 levels. Forced P311 expression increases TGF-β levels and collagen production in human and mouse lung fibroblasts. TGF-β-neutralizing antibodies abrogate P311-induced collagen production. Rescue of P311-KO mice with recombinant TGF-β1/2/3 restores fibrosis to wild-type levels.\",\n      \"method\": \"P311-knockout mice with bleomycin lung fibrosis model, adenoviral P311 overexpression in lung fibroblasts, Western blot, TGF-β neutralizing antibodies, cytokine rescue experiments\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with rescue experiments, antibody blockade of TGF-β, overexpression in human and mouse cells; multiple orthogonal approaches\",\n      \"pmids\": [\"30230348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"P311 binds to the PPARγ2 promoter and its knockdown inhibits adipogenic differentiation of 3T3-L1 cells; P311 expression is induced at the onset of adipogenesis and correlates with PPARγ2 and C/EBPα induction.\",\n      \"method\": \"siRNA knockdown, 3T3-L1 adipogenesis model, chromatin immunoprecipitation (ChIP) for PPARγ2 promoter binding, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence of promoter binding plus siRNA loss-of-function with differentiation phenotype; single lab\",\n      \"pmids\": [\"31146912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Meox1 (mesenchyme homeobox 1), induced by TGF-β1, binds the P311 core promoter and increases P311 transcriptional activity. This Meox1-mediated P311 transcription contributes to altered migration and proliferation of human dermal fibroblasts.\",\n      \"method\": \"Bioinformatics promoter analysis, luciferase reporter assays, chromatin immunoprecipitation (ChIP), siRNA knockdown of Meox1, cell migration and proliferation assays\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence of Meox1 binding P311 promoter plus luciferase reporter and siRNA functional validation; single lab\",\n      \"pmids\": [\"32411720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-7a-5p directly targets the 3'UTR of P311 mRNA and suppresses P311 expression; butyrate alleviates diabetic kidney fibrosis in part by inducing miR-7a-5p, which suppresses P311, thereby reducing TGF-β1 translation. Overexpression of P311 offsets butyrate's inhibition of TGF-β1.\",\n      \"method\": \"3'UTR luciferase reporter assay, miRNA sequencing, miR-7a-5p agomir in db/db mice, Western blot, RT-PCR, P311 overexpression rescue\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR targeting validated by luciferase assay plus in vivo agomir rescue and P311 overexpression epistasis; single lab\",\n      \"pmids\": [\"32539181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"P311 promotes M2 polarization of macrophages by upregulating IL-4 receptor expression and activating the IL-4 receptor–STAT6 signaling pathway. P311 regulation of IL-4 receptor expression involves the mTOR signaling pathway.\",\n      \"method\": \"P311-knockout mice, macrophage polarization assays, Western blot, flow cytometry for IL-4R/STAT6, mTOR inhibitor experiments, wound healing model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with pathway dissection using mTOR inhibitor; defined cellular phenotype with mechanistic pathway placement; single lab\",\n      \"pmids\": [\"36309321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"P311 promotes angiogenesis in mesenchymal stem cells by increasing VEGF production through the mTOR signaling pathway.\",\n      \"method\": \"P311 overexpression in MSCs, VEGF ELISA, tube formation assay, mTOR inhibitor, in vivo wound model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with pharmacological pathway validation (mTOR inhibitor) and in vitro/in vivo corroboration; single lab\",\n      \"pmids\": [\"35154140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"P311 enhances angiogenesis in human microvascular endothelial cells by activating the VEGFR2/ERK1/2 signaling pathway; siRNA knockdown of VEGFR2 or ERK1/2 inhibitor treatment abolishes P311-induced tube formation.\",\n      \"method\": \"Adenoviral P311 overexpression in HMEC-1 cells, Western blot for p-VEGFR2 and p-ERK1/2, siRNA-VEGFR2 knockdown, ERK1/2 inhibitor, tube formation assay, scratch migration assay\",\n      \"journal\": \"Zhonghua shao shang yu chuang mian xiu fu za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal pathway blockade strategies (siRNA VEGFR2 and pharmacological ERK inhibitor) with defined angiogenesis phenotype; single lab\",\n      \"pmids\": [\"35220700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"P311 promotes fibroblast differentiation and granulation tissue formation by upregulating TGF-βRII (type II TGF-β receptor) expression and activating the TGF-βRII–Smad signaling pathway via the mTOR pathway.\",\n      \"method\": \"P311-knockout and wild-type mice with full-thickness excisional wounds, Western blot for TGF-βRII and Smad proteins, mTOR inhibitor, in vitro fibroblast differentiation assays\",\n      \"journal\": \"Burns & trauma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model plus pharmacological mTOR inhibition with defined TGF-βRII/Smad pathway placement; single lab\",\n      \"pmids\": [\"37469904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NREP knockdown in primary human hepatocytes alters one-carbon metabolism, increases cholesterol esters and triglycerides, decreases phosphatidylcholine levels, and activates calcium signaling pathways, implicating NREP in hepatic lipid/metabolic homeostasis.\",\n      \"method\": \"siRNA knockdown in primary human hepatocytes, RNA-sequencing, lipidomics, antibody microarray (signalomics)\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omic profiling (transcriptomics, lipidomics, signalomics) in human primary cells with direct KD; single lab\",\n      \"pmids\": [\"37354909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NREP knockdown in chondrocytes inactivates the TGF-β1/Smad2/3 signaling pathway, resulting in downregulation of anabolic markers Col2a1 and Sox9 and upregulation of catabolic markers MMP3 and MMP13, and reduced chondrocyte proliferation.\",\n      \"method\": \"siRNA knockdown of NREP in chondrocytes, Western blot for p-Smad2/3, RT-qPCR, CCK-8 and EdU proliferation assays, OA mouse model with IHC\",\n      \"journal\": \"Journal of orthopaedic translation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with defined TGF-β/Smad pathway placement and multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"38179126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YTHDF1 binds m6A-modified NREP mRNA and promotes its translation; YTHDF1 depletion reduces NREP protein levels and impairs TGF-β–Smad signaling, keratocyte proliferation, migration, and fibroblast-to-myofibroblast differentiation in corneal fibrosis.\",\n      \"method\": \"siRNA knockdown of NREP and YTHDF1, SRAMP m6A site prediction, LC-MS m6A profiling, CCK-8, scratch assay, immunofluorescence, Western blot, in vivo alkali burn corneal fibrosis model, YTHDF1 inhibitor (SKLB-Y13)\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two siRNA KDs plus pharmacological YTHDF1 inhibitor with defined m6A-translational mechanism; single lab\",\n      \"pmids\": [\"42153780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF-1α directly binds to the NREP promoter to increase NREP transcriptional activity under hypoxia. NREP promotes breast cancer cell glycolysis (increased glucose consumption, ATP, lactate, glucose transporter expression), cell proliferation, migration, invasion, and EMT.\",\n      \"method\": \"Luciferase reporter system, chromatin immunoprecipitation (ChIP), siRNA/overexpression of NREP, HIF-1α inhibition, Seahorse glycolysis assay, cell cycle analysis, apoptosis assay, in vivo xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct ChIP confirmation of HIF-1α binding NREP promoter plus loss/gain-of-function with metabolic and functional readouts; single lab\",\n      \"pmids\": [\"38697993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Structural variations disrupting the TAD boundary in the Epb41l4a/EPB41L4A locus cause dysregulation of Nrep gene expression, as demonstrated in mouse models with deletion and inversion mutations analyzed by RNA-seq.\",\n      \"method\": \"CRISPR/engineered mouse models (deletion and inversion), RNA-seq, 3D genome/TAD analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic engineering of TAD boundary with RNA-seq confirmation of Nrep dysregulation; single lab\",\n      \"pmids\": [\"38438377\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NREP/P311 is a small (8 kDa), intrinsically disordered, rapidly proteasome-degraded RNA-binding protein that acts as the primary translational stimulator of TGF-β1, TGF-β2, and TGF-β3 by binding their 5'UTRs and directly interacting with eIF3b; it also binds the TGF-β latency-associated protein (LAP) and, through this translational axis, controls blood pressure homeostasis, promotes myofibroblast transformation, and drives fibrosis in lung, kidney, skin, and liver; additionally, P311 activates Rac1/RhoA GTPases (and RalA in ameboid migration) downstream of β1 integrin to drive cell migration, and is regulated transcriptionally by HIF-1α and Meox1 and post-transcriptionally by miR-7a-5p targeting its 3'UTR and by YTHDF1-mediated m6A-dependent translation enhancement.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NREP (P311) is a small, intrinsically disordered, rapidly proteasome-degraded RNA-binding protein that acts as the central translational activator of the TGF-\\u03b2 system and, through it, governs myofibroblast biology, fibrosis, and cell migration [#0, #10, #11]. Mechanistically, NREP directly binds the 5'UTR mRNAs of TGF-\\u03b21, TGF-\\u03b22, and TGF-\\u03b23 through an RNA-recognition-motif-like element and recruits the translation initiation machinery by directly engaging eIF3 subunit b (eIF3b, Kd \\u2248 1.26 \\u00b5M) via a defined 11-residue motif, thereby stimulating TGF-\\u03b2 translation without altering TGF-\\u03b2 mRNA levels; disrupting the NREP\\u2013eIF3b interaction abolishes this output [#11]. This translational axis is physiologically decisive: NREP-null mice are hypotensive with impaired vascular smooth muscle contractility and reduced TGF-\\u03b2 protein, both fully rescued by exogenous TGF-\\u03b2, while transgenic mice are hypertensive [#10]. The same axis drives fibrosis across organs\\u2014renal, pulmonary, dermal\\u2014operating through TGF-\\u03b2/Smad2/3 signaling, upregulation of TGF-\\u03b2 receptors, and conversion of fibroblasts and epidermal stem cells into \\u03b1-SMA-positive myofibroblast-like cells [#13, #14, #16, #23]. Independent of translation, NREP promotes cell migration downstream of \\u03b21 integrin by activating Rac1 and RhoA GTPases (and RalA in ameboid migration), with stability governed by serine phosphorylation at S59 near its PEST domain and an interaction with Filamin A at the cell periphery [#5, #6, #15]. NREP expression is itself tightly controlled\\u2014transcriptionally activated by HIF-1\\u03b1 under hypoxia and by TGF-\\u03b2-induced Meox1, and post-transcriptionally repressed by miR-7a-5p targeting its 3'UTR and enhanced by YTHDF1-mediated m6A-dependent translation [#18, #19, #26, #27]. Beyond fibrosis, NREP is required in vivo for normal learning, memory, and the affective component of pain [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established NREP/P311 as a short-lived protein, defining proteostatic control as a built-in regulatory feature before any function was known.\",\n      \"evidence\": \"Lactacystin treatment and half-life measurement in transformed cells\",\n      \"pmids\": [\"10660586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the metalloprotease was not determined\", \"Functional consequence of rapid turnover unknown at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"First functional role: linked NREP to glioma cell migration and focal-adhesion localization, framing it as a motility regulator.\",\n      \"evidence\": \"Antisense knockdown, integrin activation assays, immunochemistry in invasive glioma cells\",\n      \"pmids\": [\"11358844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting NREP to adhesion machinery not defined\", \"No interacting partner identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed NREP drives a myofibroblast phenotype while paradoxically suppressing TGF-\\u03b21, suggesting a complex, isoform-selective relationship to TGF-\\u03b2 rather than simple agonism.\",\n      \"evidence\": \"Gain-of-function transfection in NIH3T3 and C3H10T1/2 fibroblasts with rescue experiments\",\n      \"pmids\": [\"12417574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling phenotype with TGF-\\u03b21 suppression unresolved at the time\", \"No molecular mechanism for TGF-\\u03b2 regulation\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Provided a physical handle on TGF-\\u03b2 control by showing NREP binds the latency-associated protein of TGF-\\u03b21/\\u03b22 and that its PEST domain mediates the effect, while implicating reduced Smad3 autoinduction.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, PEST-deletion mutagenesis, Smad3 reporter\",\n      \"pmids\": [\"14985127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TGF-\\u03b23 not bound, leaving isoform selectivity unexplained\", \"Did not resolve whether regulation was transcriptional, translational, or via LAP\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended NREP to the nervous system, showing it promotes neurite outgrowth and PC12 differentiation in a Rho-kinase-sensitive manner, linking it to cytoskeletal/neuronal programs.\",\n      \"evidence\": \"Adenoviral overexpression, PC12 differentiation, Rho kinase inhibition, facial nerve axotomy model\",\n      \"pmids\": [\"15485502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target in neurons not identified\", \"Relationship to TGF-\\u03b2 axis in neurons unaddressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the migration mechanism: S59 phosphorylation controls NREP stability, and migration requires \\u03b21 integrin and Rac1 GTPase, with Filamin A as a peripheral binding partner.\",\n      \"evidence\": \"S59A/S59D mutagenesis, Co-IP/MALDI-TOF MS, dominant-negative \\u03b21 integrin, Rac1 siRNA, colocalization\",\n      \"pmids\": [\"16229809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase/phosphatase acting on S59 not identified\", \"How Filamin A binding couples to Rac1 activation unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed NREP-induced migration can adopt a RalA-dependent ameboid mode switchable by matrix composition, revealing plasticity in its motility output.\",\n      \"evidence\": \"RalA siRNA, fibrin vs collagen I matrices, focal adhesion/stress fiber imaging\",\n      \"pmids\": [\"16934802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signal selecting RalA vs Rac1 not defined\", \"Single-lab phenotype\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic knockouts established organismal roles in learning/memory and the affective component of pain, dissociating these from sensorimotor function.\",\n      \"evidence\": \"P311-knockout mice, behavioral batteries and formalin pain testing\",\n      \"pmids\": [\"18616608\", \"18549486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of behavioral phenotypes not connected to TGF-\\u03b2 or migration mechanisms\", \"Cell types and circuits involved not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a non-canonical, retinoic-acid-linked role in lipid-droplet accumulation, distinguishing it from classical adipogenic differentiation.\",\n      \"evidence\": \"Overexpression/knockdown, lipid quantification, gene profiling, NIH3T3-L1 negative control\",\n      \"pmids\": [\"18664493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mediators of lipid synthesis not identified\", \"Relationship to later adipogenesis findings unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the central mechanism: NREP is an RNA-binding protein that stimulates translation of all three TGF-\\u03b2 isoforms, and this axis controls blood pressure, with KO/transgenic phenotypes rescued by exogenous TGF-\\u03b2.\",\n      \"evidence\": \"KO and transgenic mice, blood pressure and contractility assays, polysome fractionation, TGF-\\u03b2 rescue\",\n      \"pmids\": [\"24091331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular details of translational activation not yet resolved\", \"Did not identify initiation-factor partner\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the molecular mechanism of translational activation: NREP binds TGF-\\u03b2 5'UTRs and directly engages eIF3b through a defined motif, with disruption abolishing translation.\",\n      \"evidence\": \"IP/MS, GST pulldown, SPR Kd, EMSA, UV cross-linking, luciferase reporters, polysome fractionation, CD/PONDR\",\n      \"pmids\": [\"25336651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the disordered NREP\\u2013eIF3b/RNA complex not determined\", \"How NREP discriminates TGF-\\u03b2 transcripts from other mRNAs unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Added ITGB4BP as a direct interaction partner, expanding the NREP interactome beyond eIF3b and Filamin A.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP in HEK293, FRET in tissue\",\n      \"pmids\": [\"22365962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the ITGB4BP interaction not established\", \"No epistasis or phenotype linked to this binding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized the NREP\\u2013TGF-\\u03b2 translational axis to organ fibrosis (renal, pulmonary, dermal), establishing it as a pro-fibrotic driver reversible by TGF-\\u03b2 blockade or rescue.\",\n      \"evidence\": \"KO mice in UUO and bleomycin models, overexpression in human/mouse fibroblasts and EpSCs, TGF-\\u03b2 neutralization and rescue, UTR luciferase, Smad pathway blockade\",\n      \"pmids\": [\"26616407\", \"27906099\", \"30230348\", \"37469904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why a normally short-lived protein achieves sustained pro-fibrotic output in vivo not fully explained\", \"Cell-type-specific differences across organs not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped upstream control of NREP itself, identifying TGF-\\u03b2-induced Meox1 as a transcriptional activator and miR-7a-5p as a 3'UTR repressor, embedding NREP in feedback regulation.\",\n      \"evidence\": \"ChIP, luciferase reporters, siRNA, in vivo miR-7a-5p agomir with P311-overexpression rescue\",\n      \"pmids\": [\"32411720\", \"32539181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between transcriptional and miRNA control not integrated\", \"Other regulatory inputs likely incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated an mTOR-dependent branch through which NREP modulates macrophage M2 polarization, angiogenesis (VEGF/VEGFR2/ERK), and TGF-\\u03b2RII expression in wound healing.\",\n      \"evidence\": \"KO and overexpression models, mTOR/ERK/VEGFR2 inhibition and siRNA, polarization, tube-formation, and wound assays\",\n      \"pmids\": [\"36309321\", \"35154140\", \"35220700\", \"37469904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How NREP connects mechanistically to mTOR signaling not defined\", \"Whether mTOR effects depend on TGF-\\u03b2 translational axis unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened the axis to chondrocyte and hepatic homeostasis and showed NREP is itself an m6A-regulated translational target of YTHDF1, adding an epitranscriptomic control layer.\",\n      \"evidence\": \"siRNA in chondrocytes and primary hepatocytes, multi-omics, m6A profiling, YTHDF1 knockdown and inhibitor, corneal fibrosis model\",\n      \"pmids\": [\"38179126\", \"37354909\", \"42153780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular basis of hepatic metabolic effects not resolved\", \"m6A site mapping on NREP largely predictive\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed NREP in hypoxic and oncogenic contexts: HIF-1\\u03b1 directly drives NREP transcription to promote breast cancer glycolysis and EMT, and TAD-boundary disruption dysregulates Nrep expression.\",\n      \"evidence\": \"ChIP, luciferase, loss/gain-of-function, Seahorse, xenograft; engineered TAD deletion/inversion mouse models with RNA-seq\",\n      \"pmids\": [\"38697993\", \"38438377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether tumor glycolytic phenotype requires the TGF-\\u03b2 translational axis untested\", \"Functional consequence of TAD-driven Nrep dysregulation not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a disordered, rapidly degraded protein achieves selective, high-fidelity translational activation of TGF-\\u03b2 transcripts, and how its diverse outputs (migration, mTOR, metabolism, neuronal function) are mechanistically partitioned, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of NREP bound to RNA or eIF3b\", \"Mechanistic link between mTOR/metabolic roles and the TGF-\\u03b2 translational axis undefined\", \"Molecular basis of neuronal and affective-pain phenotypes uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [10, 11, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 14, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EIF3B\", \"FLNA\", \"ITGB4BP\", \"ITGB1\", \"YTHDF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}