{"gene":"PCBP1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1997,"finding":"hnRNP E1 (PCBP1) and hnRNP K purified from rabbit reticulocytes specifically bind the differentiation control element (DICE) in the 3' UTR of 15-lipoxygenase (LOX) mRNA and silence its translation by specifically inhibiting 80S ribosome assembly; this was reconstituted in a cell-free translation system with recombinant proteins, and both cap-dependent and IRES-mediated translation are inhibited.","method":"Protein purification from reticulocytes, reconstituted cell-free translation system, transfection of HeLa cells with DICE-reporter, co-immunoprecipitation of silenced mRNA","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with recombinant proteins, multiple orthogonal methods (purification, cell-free assay, transfection, co-IP), independently foundational","pmids":["9160751"],"is_preprint":false},{"year":2002,"finding":"Translational silencing of LOX mRNA by hnRNP E1 requires binding of at least two hnRNP E1 molecules to a dimeric (2R) DICE configuration; a single repeat is insufficient for translational inhibition even though E1 binding still occurs.","method":"Electrophoretic mobility shift assay (EMSA), sucrose gradient centrifugation, in vitro translation with DICE repeat-variant reporter mRNAs","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro assays with defined mutant substrates, single lab","pmids":["11827469"],"is_preprint":false},{"year":2006,"finding":"hnRNP E1 (PCBP1) directly binds hnRNP A2 via protein-protein interaction and is recruited to A2 response element (A2RE) RNA in an hnRNP A2-dependent manner; overexpression or microinjection of hnRNP E1 inhibits translation of A2RE mRNA (but not non-A2RE RNA) both in vivo and in a cell-free translation system, in an hnRNP A2-dependent manner.","method":"Yeast two-hybrid, reciprocal co-immunoprecipitation, in vitro cross-linking, fluorescence correlation spectroscopy, in vitro translation system, microinjection","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including reconstituted in vitro translation, reciprocal co-IP, and live-cell imaging","pmids":["16775011"],"is_preprint":false},{"year":2007,"finding":"PAK1 phosphorylates PCBP1 on Thr60 and Thr127 in response to mitogenic stimulation; this phosphorylation releases PCBP1 from DICE elements, reversing translational inhibition of DICE-containing mRNAs (including endogenous L1-CAM). PAK1 activation also promotes nuclear retention of PCBP1, recruitment to the eIF4E promoter to stimulate eIF4E transcription, and alternative splicing of CD44 via PCBP1 interaction with Caper alpha (a U2 snRNP auxiliary factor).","method":"Yeast two-hybrid, phosphorylation assays, luciferase reporter, polysome fractionation, ChIP, RNA splicing minigene assay, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, kinase assay, reporter, ChIP, splicing assay) in single lab","pmids":["17389360"],"is_preprint":false},{"year":2010,"finding":"TGF-β induces phosphorylation of hnRNP E1 (PCBP1) at Ser43 by protein kinase Bβ/Akt2, causing its release from the BAT element in the 3' UTR of Dab2 and ILEI mRNAs, thereby relieving translational silencing of these EMT-associated transcripts and inducing EMT.","method":"Polysome profiling, RNA-protein binding assays, phosphorylation assays, knockdown/overexpression with translational reporter assays, site-directed mutagenesis (Ser43Ala)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-directed mutagenesis, polysome profiling, kinase assay with multiple orthogonal methods, widely replicated","pmids":["20154680"],"is_preprint":false},{"year":2010,"finding":"PCBP1 binds GCCCAG motifs in the 5' UTR of PRL-3 mRNA and retards incorporation of PRL-3 mRNA into polyribosomes, suppressing its translation; overexpression of PCBP1 inhibits PRL-3 and inactivates AKT, while knockdown of PCBP1 increases PRL-3 protein levels.","method":"Polyribosome/polysome fractionation, RNA immunoprecipitation, reporter assay, overexpression/knockdown","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polysome profiling and RIP, single lab with two orthogonal methods","pmids":["20609352"],"is_preprint":false},{"year":2010,"finding":"PCBP1 negatively regulates alternative splicing of CD44 variant exons (v3, v5, v6, v8, v10) in HepG2 hepatoma cells; enforced PCBP1 expression inhibits CD44 variant expression and invasion, while knockdown induces variant splicing.","method":"Overexpression/knockdown, RT-PCR for CD44 variants, invasion assay","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined splicing and cellular phenotype readout, single lab","pmids":["20361869"],"is_preprint":false},{"year":2011,"finding":"PCBP1 is an iron chaperone that binds ferrous iron and delivers it to HIF prolyl hydroxylases (PHD1, PHD2, PHD3) and asparaginyl hydroxylase (FIH1) for metallation; depletion of PCBP1 or PCBP2 leads to loss of PHD activity, reduced prolyl hydroxylation of HIF1α, impaired VHL/proteasome degradation of HIF1α, and accumulation of active HIF1. PHD activity was restored in vitro by addition of purified Fe-PCBP1, and PCBP1 bound to PHD2 and FIH1 in vivo.","method":"siRNA depletion, in vitro iron delivery reconstitution with purified Fe-PCBP1, co-immunoprecipitation, prolyl hydroxylation assays, HIF1α degradation assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted in vitro iron delivery, co-IP, functional enzyme activity assays, multiple orthogonal methods","pmids":["22055506"],"is_preprint":false},{"year":2011,"finding":"PCBP1 mediates constitutive (housekeeping) degradation of MAVS (mitochondrial antiviral signaling adaptor) in uninfected cells, using the same mechanism as PCBP2; overexpression of PCBP1 impairs MAVS-mediated antiviral responses through PCBP1-induced MAVS degradation, while knockdown of PCBP1 increases MAVS levels and antiviral signaling.","method":"Overexpression/knockdown, antiviral response assays, subcellular fractionation, western blot for MAVS protein levels","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined molecular phenotype (MAVS protein levels and antiviral signaling), single lab","pmids":["22105485"],"is_preprint":false},{"year":2011,"finding":"hnRNP E1 (PCBP1) acts as a physiological sensor of folate deficiency: intracellular accumulation of L-homocysteine (during folate deficiency) induces covalent binding of homocysteine to cysteine residues in the KH domains of hnRNP E1 via mixed disulfide bonds, unmasking an RNA-binding pocket and enabling high-affinity interaction with the folate receptor-α mRNA cis-element, thereby stimulating folate receptor translation.","method":"In vitro RNA-protein binding assays with purified components, in vitro translation, siRNA knockdown, covalent modification analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro with purified components, covalent modification biochemically characterized, functional translation assay","pmids":["21930702"],"is_preprint":false},{"year":2012,"finding":"THAP11 is a binding partner of PCBP1; THAP11 overexpression inhibits CD44 v6 expression and cell invasion in HepG2 cells, but fails to do so when the PCBP1-binding domain of THAP11 is deleted or when PCBP1 is knocked down, indicating that THAP11 regulates CD44 alternative splicing through interaction with PCBP1.","method":"Co-immunoprecipitation, deletion mutant analysis, overexpression/knockdown, CD44 variant expression assay, invasion assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion epistasis and co-IP with functional readout, single lab","pmids":["22673507"],"is_preprint":false},{"year":2012,"finding":"PCBP1 is required for maintenance of the transcriptionally silent state in fully grown mouse oocytes; siRNA-mediated knockdown of Pcbp1 in GV oocytes disrupts the NSN-to-SN nucleolus ratio, reactivates transcription (detected by BrUTP incorporation and active RNA Pol II/H3K4me3 markers), and upregulates ~4,000 transcripts.","method":"siRNA microinjection into oocytes, BrUTP incorporation assay, immunofluorescence for phospho-RNA Pol II CTD and H3K4me3, microarray transcriptome analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with direct transcriptional activity readout in oocytes, single lab","pmids":["22801551"],"is_preprint":false},{"year":2013,"finding":"hnRNP E1 (PCBP1) binds pyrimidine-rich (C/CU-rich) elements in the 3' UTR of eNOS mRNA and stabilizes it; knockdown of hnRNP E1 decreases eNOS mRNA half-life, mRNA levels, and protein expression. Under hypoxia, increased Akt-mediated serine phosphorylation (including Ser43) of hnRNP E1 and increased nuclear localization disrupt hnRNP E1/eNOS 3'-UTR interactions, decreasing eNOS mRNA stability. The hnRNP E1/eNOS 3'-UTR complex also protects eNOS mRNA from inhibition by antisense RNA (sONE) and miR-765.","method":"RNA immunoprecipitation, EMSA, siRNA knockdown, mRNA half-life assay, phosphorylation analysis, nuclear/cytoplasmic fractionation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RIP, EMSA, mRNA stability assay, phosphorylation-localization link, multiple orthogonal methods in single lab","pmids":["23478261"],"is_preprint":false},{"year":2014,"finding":"PCBP1 and PCBP2 deliver iron to deoxyhypusine hydroxylase (DOHH), a dinuclear iron enzyme; cells depleted of PCBP1 or PCBP2 exhibit loss of DOHH activity and loss of the holo form of the enzyme. Lysates containing PCBP1/2 converted apo-DOHH to holo-DOHH in vitro more efficiently than lysates lacking them. PCBP1 bound to DOHH in iron-treated cells but not in iron-deficient cells. Depletion of PCBP1/2 also led to loss of cytosolic aconitase activity, suggesting a broader role in iron delivery to cytosolic non-heme iron enzymes.","method":"siRNA depletion, in vitro iron delivery assay with cell lysates, co-immunoprecipitation, enzyme activity assays (DOHH, aconitase)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of iron delivery, co-IP, multiple enzyme activity assays, single lab with multiple methods","pmids":["24843120"],"is_preprint":false},{"year":2015,"finding":"Pcbp1-null mouse embryos are non-viable at the peri-implantation stage, demonstrating that PCBP1 is individually essential for early mouse embryonic development and has evolved a non-redundant function distinct from its paralog PCBP2.","method":"Pcbp1 germline knockout mouse, embryonic lethality phenotyping","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined developmental phenotype; independently replicated by a second paper (PMID 28381556)","pmids":["26527618"],"is_preprint":false},{"year":2016,"finding":"PCBP1/hnRNP E1 translationally silences Cdc27 mRNA in normal mammary epithelial cells; shRNA-mediated knockdown of hnRNP E1 abrogates this silencing, causing constitutive CDC27 expression, premature activation of G2-M-APC/C-CDC20, aberrant degradation of FZR1/CDH1, loss of APC/C-CDH1 activity, mitotic aberrations, and aneuploidy.","method":"shRNA knockdown, polysome profiling, western blot, cell cycle analysis, mitotic aberration assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular and cellular phenotype, single lab","pmids":["27102006"],"is_preprint":false},{"year":2016,"finding":"TGF-β directly regulates alternative splicing of CD44 through phosphorylated SMAD3 (pT179) interaction with PCBP1; SMAD3 and PCBP1 colocalize in SC35-positive nuclear speckles and interact at the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly, favoring expression of mesenchymal CD44s over epithelial CD44E isoform.","method":"Co-immunoprecipitation, immunofluorescence/colocalization, splicing reporter assays, RIP, SMAD3 phospho-mutant analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, RIP, phospho-mutant epistasis, colocalization, multiple orthogonal methods in one study","pmids":["27746021"],"is_preprint":false},{"year":2016,"finding":"hnRNP E1 (PCBP1) KH domains mediate binding to a defined consensus motif in the 3' UTR of target mRNAs; phosphorylation at Ser43 (p-hnRNP E1 by Akt2) disrupts KH domain-RNA interaction, correlating with high p-hnRNP E1 levels in metastatic cells. An hnRNP E1 consensus binding motif was biochemically characterized for binding kinetics with KH domains.","method":"RNA-binding kinetics assays, KH domain deletion/mutation analysis, phospho-specific antibodies, western blot in cellular progression models","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding kinetics with defined domain mutations, single lab","pmids":["27067543"],"is_preprint":false},{"year":2016,"finding":"PCBP1 stabilizes mu-opioid receptor (MOR) mRNA by binding a C-rich element (CRE) in the MOR 3' UTR; knockdown of PCBP1 decreases MOR mRNA half-life and protein expression. Phosphorylation of PCBP1 by PKA (via forskolin/cAMP) at serine residues promotes cytoplasmic localization and enhanced PCBP1/MOR 3'-UTR interaction. AUF1, also phosphorylated under these conditions, forms an increased interaction with PCBP1 and binds the CRE; PABP also increases its interaction with the CRE.","method":"RNA immunoprecipitation, RNA EMSA, siRNA knockdown, mRNA stability assay, phosphorylation analysis, subcellular fractionation","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, EMSA, mRNA stability assay, multiple binding partners, single lab","pmids":["27836661"],"is_preprint":false},{"year":2017,"finding":"PCBP1 and NCOA4 are critical for iron trafficking through ferritin in developing erythroid cells; depletion of PCBP1 impairs iron loading into ferritin, reduces heme synthesis and hemoglobin formation. Pcbp1-knockout mice develop microcytic anemia with compensatory erythropoiesis. PCBP1 delivers iron to ferritin via a direct protein-protein interaction that is developmentally regulated and enhanced by iron deprivation; excess iron inhibits this interaction in vitro.","method":"Cell depletion experiments, Pcbp1 knockout mouse model, ex vivo erythroid differentiation, ferritin iron flux assays, heme/hemoglobin measurements, in vitro protein-protein interaction assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with multiple cellular phenotype readouts plus in vitro protein interaction validated; replicated with a second paper (PMID 29032941)","pmids":["28375153"],"is_preprint":false},{"year":2017,"finding":"Pcbp1 is a component of the miRNA-processing pathway in skeletal muscle; it physically interacts with Argonaute 2 (AGO2) and other miRNA pathway components, modulating the processing of muscle-enriched miRNAs (miR-1, miR-133, miR-206). Hypomorphic Pcbp1 mutant mice show muscle growth defects due to impaired myoblast proliferation/differentiation and a slow-to-fast myofibril switch.","method":"siRNA knockdown in myoblasts, co-immunoprecipitation with AGO2, hypomorphic Pcbp1 mouse model, miRNA biogenesis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with AGO2, in vivo mouse model, miRNA processing assays; single lab","pmids":["28381556"],"is_preprint":false},{"year":2017,"finding":"During erythroid differentiation, PCBP1 directly delivers iron to ferritin via protein-protein interaction; this interaction is regulated by cellular iron levels (enhanced by iron deprivation, inhibited by iron excess) and is developmentally regulated. NCOA4 activity and HERC2-mediated lysosomal degradation of NCOA4 are also regulated by cellular iron levels.","method":"In vitro protein-protein interaction assay (iron-dependent), cellular iron manipulation, developmental stage analysis","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro protein-protein interaction with iron-dependence, single lab","pmids":["29032941"],"is_preprint":false},{"year":2017,"finding":"TIA1 and Pcbp1 bind a UUUUCCCCCC motif between the branch point and 3' splice site of protein 4.1R exon 16 in a collaborative manner to promote exon inclusion; they associate in a complex with RBM39, which interacts with U2AF65 and SF3b155 to promote U2 snRNP recruitment to the branch point and enhance spliceosome A complex formation.","method":"RNA binding assays with mutant motifs, co-immunoprecipitation of TIA1/Pcbp1/RBM39 complex, splicing reporter assays, spliceosome assembly assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of multiprotein complex, spliceosome assembly assay, splicing reporters with defined mutations; single lab","pmids":["28193846"],"is_preprint":false},{"year":2017,"finding":"Mutant HSPB1-P182L has a specifically increased interaction with PCBP1 compared to wild-type HSPB1, resulting in reduced translational repressive activity of PCBP1. RNA immunoprecipitation followed by RNA-seq in mouse brain identified PCBP1 mRNA targets enriched for a CTCCTCCTCCTCC consensus motif and neuronal transcripts including genes associated with hereditary neuropathies.","method":"Co-immunoprecipitation, RNA immunoprecipitation followed by RNA-seq (RIP-seq), in vitro binding","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq provides broad target identification, co-IP demonstrates increased interaction, translational repression reduction assayed; single lab","pmids":["28077174"],"is_preprint":false},{"year":2017,"finding":"L-homocysteine triggers a dose-dependent high-affinity interaction between hnRNP E1 and a 25-nt cis-element in the 5' UTR of hnRNP-E1 mRNA itself, leading to auto-upregulation of hnRNP E1 translation (positive feedback loop); this interaction is disrupted by ferrous iron in a dose-dependent manner.","method":"In vitro RNA-protein binding assays, in vitro translation, antisense oligonucleotide and mutant cis-element perturbations, siRNA knockdown, cell transfection with mutant hnRNP E1","journal":"The Journal of nutrition","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution and mutagenesis, single lab","pmids":["28250194"],"is_preprint":false},{"year":2018,"finding":"PCBP1 promotes mRNA stability of Csf2 (GM-CSF) and Il2 by recognizing UC-rich elements in their 3' UTRs; intracellular iron protects PCBP1 protein from caspase-mediated proteolysis, thereby linking iron levels to T cell cytokine production. Pcbp1 deficiency in T cells inhibits GM-CSF production and abolishes capacity to induce experimental autoimmune encephalomyelitis.","method":"T cell-specific Pcbp1 knockout, Csf2 3' UTR activity assays, mRNA stability assays, caspase cleavage assays, RNA binding assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific knockout with defined molecular (mRNA stability, caspase cleavage) and in vivo (EAE) phenotypes, multiple orthogonal methods","pmids":["29958803"],"is_preprint":false},{"year":2018,"finding":"PCBP1 specifically binds heavily oxidized RNA containing two nearby 8-oxoguanine (8-oxoG) residues (but not RNA with a single 8-oxoG); PCBP1-deficient HeLa cells (CRISPR-Cas9) show higher survival, lower caspase-3 activation, and lower PARP-1 cleavage under hydrogen peroxide treatment. KH domain mutations that disrupt RNA binding abolish this pro-apoptotic function.","method":"CRISPR-Cas9 knockout, RNA binding assays with oxidized RNA substrates, KH domain mutagenesis, caspase-3/PARP-1 cleavage assays, cell survival assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — CRISPR KO with defined phenotype, in vitro RNA binding with mutagenesis, structure-function established; single lab","pmids":["29891675"],"is_preprint":false},{"year":2018,"finding":"PCBP1 binds p27Kip1 3' UTR via its KH1 domain, primarily stabilizing p27 mRNA and also enhancing its translation; this increases p27 protein levels, inhibits cell proliferation and cell cycle progression, and reduces tumorigenesis in vivo.","method":"Transcriptome-wide RIP screen, point mutation/luciferase assay for binding site, mRNA stability assay, ribosome profiling, cell cycle and xenograft assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, mRNA stability, ribosome profiling with KH domain mutation; single lab","pmids":["30086790"],"is_preprint":false},{"year":2019,"finding":"PCBP1 coordinates ferrous iron via conserved cysteine and glutamate residues and a noncovalently bound glutathione (GSH) molecule; the Fe-GSH-bound form of PCBP1 forms a complex with cytosolic BolA2 via a bridging Fe ligand. PCBP1-Fe-GSH-BolA2 serves as an intermediate complex required for assembly of [2Fe-2S] clusters on BolA2-Glrx3, linking the ferrous iron and Fe-S distribution systems in cells.","method":"Proteomics (PCBP1 interactome), in vitro biochemical reconstitution of iron-GSH-PCBP1-BolA2 complex, site-directed mutagenesis of Fe-coordinating residues, [2Fe-2S] cluster assembly assays in vitro and in cells","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis of coordinating residues, structural/biochemical characterization of complex; multiple orthogonal methods","pmids":["31406370"],"is_preprint":false},{"year":2019,"finding":"PCBP1 inhibits alternative splicing of STAT3 exon 23 by binding an exonic splicing suppressor (ESS) in exon 23, thereby reducing the proportion of oncogenic STAT3α and increasing tumor-suppressive STAT3β.","method":"Overexpression/knockdown, RT-PCR splicing assay, luciferase/reporter assay for ESS, western blot for STAT3 isoforms","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined splicing phenotype and ESS mapping; single lab","pmids":["31223278"],"is_preprint":false},{"year":2020,"finding":"PCBP1 facilitates binding of cGAS to cytosolic DNA; PCBP1 directly binds DNA and enhances cGAS-DNA interaction, promoting cGAS activation and innate immune signaling. PCBP1 is recruited to cGAS in a viral infection-dependent manner, and PCBP1 deficiency inhibits cGAS-mediated downstream gene transcription.","method":"Biochemical purification approach, co-immunoprecipitation (virus infection-dependent), DNA-binding assays, cGAS activation assays, PCBP1 knockdown with interferon-response readout","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, DNA binding assay, functional innate immune readout; single lab","pmids":["32415261"],"is_preprint":false},{"year":2020,"finding":"TGF-β1 induces phosphorylation, poly-ubiquitination, and proteasomal degradation of PCBP1 in prostate cancer cells; loss of PCBP1 leads to increased CD44s (standard) isoform expression at the expense of CD44v, promoting EMT and cancer stem cell markers.","method":"Phosphorylation/ubiquitination assays, proteasome inhibitor experiments, RNAi knockdown, splicing assay (RT-PCR), in vitro and in vivo migration/invasion/tumor initiation assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM characterization (phospho/ubiquitin), gain- and loss-of-function with splicing and functional readouts; single lab","pmids":["32440711"],"is_preprint":false},{"year":2020,"finding":"PCBP2, like PCBP1, selectively binds RNA carrying two nearby 8-oxoG residues; however, PCBP2 suppresses apoptosis under oxidative conditions while PCBP1 promotes it. PCBP2 mutations in conserved RNA-binding domains abolish 8-oxoG-RNA binding and the anti-apoptotic function. PCBP2-knockout cells show increased apoptosis, opposite to PCBP1-knockout cells.","method":"CRISPR-Cas9 KO of PCBP1 and PCBP2, RNA binding assays, KH domain mutagenesis, caspase-3/PARP1 cleavage assays, rescue with WT vs. mutant proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — CRISPR KO of both paralogs with defined and opposing phenotypes, domain mutagenesis with rescue; rigorous comparison","pmids":["32647012"],"is_preprint":false},{"year":2020,"finding":"Small molecule amplifiers bind directly to PCBP1 and require a PCBP1 consensus element within the CFTR open reading frame; amplifiers stabilize CFTR mRNA co-translationally and increase its association with polysomes, identifying PCBP1 as mediating CFTR mRNA stability and translational efficiency.","method":"Chemical proteomics (pulldown of amplifier-binding protein), polysome fractionation, PCBP1 consensus element mutation, mRNA stability assay","journal":"Journal of cystic fibrosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical proteomics pulldown, polysome profiling, consensus element mutagenesis; single lab","pmids":["32067958"],"is_preprint":false},{"year":2020,"finding":"PCBP1 is an intracellular immune checkpoint in T cells; T cell-specific deletion of Pcbp1 favors regulatory T cell (Treg) differentiation over effector T cell (Teff) identity, upregulates inhibitory immune checkpoints (PD-1, TIGIT, VISTA) on tumor-infiltrating lymphocytes, and blunts antitumor immunity.","method":"T cell-specific Pcbp1 conditional knockout, flow cytometry for Treg/Teff markers and checkpoint molecules, tumor challenge models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype (Treg/Teff balance, checkpoint expression); single lab","pmids":["32523987"],"is_preprint":false},{"year":2021,"finding":"PCBP1 deletion in mouse liver does not affect mitochondrial iron balance but impairs mitochondrial function: PCBP1 deletion reduces respiratory complexes II and IV, oxygen consumption, and ATP production, and depletes mitochondrial lipids cardiolipin and coenzyme Q; the dysfunction is caused by oxidative damage from unchaperoned (chemically reactive) iron.","method":"Liver-specific Pcbp1 knockout mouse, mitochondrial morphology analysis, respiratory complex quantification, oxygen consumption assay, mitochondrial lipid analysis, vitamin E and CoQ supplementation","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with mitochondrial functional and biochemical readouts, dietary rescue experiments; single lab","pmids":["34455040"],"is_preprint":false},{"year":2021,"finding":"PCBP1 and PCBP2 are jointly required for erythroid differentiation; combined inactivation of both loci in erythroid lineage leads to midgestational repression of erythroid/hematopoietic gene expression, loss of blood formation, and fetal demise, with overlapping and isoform-specific impacts on the erythroid transcriptome including mRNA representation and exon splicing.","method":"Lineage-specific conditional knockout of Pcbp1 and Pcbp2 in mouse embryo, RNA-seq (mRNA representation and splicing analysis), ex vivo erythroid progenitor depletion experiments","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional double KO with defined transcriptomic and phenotypic readout; single lab","pmids":["34180713"],"is_preprint":false},{"year":2022,"finding":"The E3 ubiquitin ligase ARIH1 interacts with hnRNP E1 (PCBP1) and promotes its ubiquitin-mediated degradation; ARIH1 silencing increases hnRNP E1 protein stability and reduces ubiquitination, while ARIH1 overexpression reduces hnRNP E1 levels. Loss of ARIH1 delays EMT induction and reduces invasion; overexpression promotes EMT and invasion in a manner dependent on hnRNP E1.","method":"Yeast two-hybrid screening, co-immunoprecipitation, ubiquitination assay, siRNA/overexpression with EMT phenotype readout, miniTurboID proximity labeling","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H, co-IP, ubiquitination assay, functional EMT phenotype; single lab","pmids":["35102251"],"is_preprint":false},{"year":2022,"finding":"Dopamine D1 receptor signaling synergizes with ALK4/Smad3 pathway to activate PCBP1 in medium spiny neurons; PCBP1 and Smad3 interact, translocate to the nucleus, and bind to sequences in exon-4 and intron-4 of FosB pre-mRNA to promote alternative splicing and generation of ΔFosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impairs ΔFosB mRNA induction and behavioral sensitization to cocaine.","method":"Co-immunoprecipitation of PCBP1/Smad3, nuclear translocation imaging, RIP at FosB exon-4/intron-4, conditional neuronal knockout of ALK4 and PCBP1, behavioral sensitization assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, RIP, conditional KO with in vivo behavioral phenotype; single lab","pmids":["35730718"],"is_preprint":false},{"year":2022,"finding":"PCBP1 acts as an adapter for the ac4C writer enzyme NAT10 in mammalian cells, tethering NAT10 to mRNA substrates for N4-acetylcytidine (ac4C) modification; knockdown of PCBP1 (or TDP43) decreases mRNA acetylation abundance and ablates cytidine-rich ac4C motifs in HEK293T cells. The NAT10/PCBP1/TDP43 complex was identified biochemically.","method":"Co-immunoprecipitation of NAT10/PCBP/TDP43 complex, siRNA knockdown, transcriptome-wide ac4C mapping, motif analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of complex, knockdown with ac4C profiling, single lab","pmids":["39556689"],"is_preprint":false},{"year":2022,"finding":"PCBP1 regulates transcription by binding to poly(C) DNA tracts at transcription start sites; PCBP1 interacts with the G-quadruplex-specific RNA/DNA helicase DHX9 (RNA Helicase A) to modulate DHX9 accumulation and activity. PCBP1 depletion causes defects in R-loop processing and dysregulation of transcription of PCBP1 target genes.","method":"ChIP-seq (PCBP1 DNA-binding sites), co-immunoprecipitation with helicases including DHX9, R-loop assays, siRNA depletion with transcription readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, co-IP, R-loop assays with functional consequence; single lab","pmids":["39342995"],"is_preprint":false},{"year":2023,"finding":"PCBP1 binds directly to LACTB mRNA and promotes its degradation; PCBP1 knockdown increases LACTB expression, which promotes erastin-induced ferroptosis and mitochondrial dysfunction in bladder cancer cells. This binding was validated by RNA pull-down, RIP, and luciferase assays.","method":"RNA pull-down, RNA immunoprecipitation, luciferase reporter assay, PCBP1 knockdown/overexpression, ferroptosis assays, xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, RNA pulldown, luciferase, mRNA decay; single lab","pmids":["37157950"],"is_preprint":false},{"year":2023,"finding":"PCBP1 acts as a regulator of CCL2 expression in macrophages; RNA immunoprecipitation indicated PCBP1 interacts with Ccl2 mRNA. Conditional depletion of Pcbp1 in macrophages decreases CCL2 production by colonic CX3CR1+ macrophages, reduces inflammatory macrophage accumulation, and protects mice from DSS-induced colitis.","method":"Macrophage-specific Pcbp1 conditional knockout, RNA immunoprecipitation, colitis model, cytokine measurement","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with in vivo phenotype and RIP supporting mRNA interaction; single lab","pmids":["36702545"],"is_preprint":false},{"year":2023,"finding":"PCBP1 binds to and enhances the stability of TPM3 mRNA in esophageal squamous cell carcinoma by directly binding the 3' UTR, as validated by RIP; PCBP1 knockdown reduces TPM3 mRNA levels and increases its degradation rate, attenuating cell migration and invasion.","method":"RIP assay, actinomycin D mRNA stability assay, siRNA knockdown, migration/invasion assay","journal":"Bioengineered","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP and mRNA stability assay, single lab, no reconstitution","pmids":["35287546"],"is_preprint":false},{"year":2023,"finding":"PCBP1 stabilizes DKK1 mRNA by direct binding (validated by RIP and RNA pulldown); PCBP1 knockdown decreases DKK1 mRNA stability and protein levels, relieving inhibition of the Wnt/β-catenin pathway and promoting lung adenocarcinoma progression.","method":"RNA-seq of PCBP1 knockdown cells, RIP, RNA pulldown, mRNA stability assay, western blot, in vivo xenograft","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP and pulldown with mRNA stability, single lab, no reconstitution","pmids":["35907982"],"is_preprint":false},{"year":2023,"finding":"PCBP1 KH3 domain mediates its interaction with the HTLV-1 Tax oncoprotein in the cytoplasm; PCBP1 facilitates assembly of the Tax/IKK complex, thereby potentiating Tax-mediated IKK-NF-κB signaling. PCBP1 knockdown attenuates Tax-dependent NF-κB activation and reduces proliferation of HTLV-1-transformed cells.","method":"Co-immunoprecipitation, colocalization assay, KH3 domain deletion/mutation analysis, knockdown with NF-κB reporter, IKK activity assay, cell proliferation assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain deletion, functional NF-κB assay, single lab","pmids":["38690287"],"is_preprint":false},{"year":2024,"finding":"PCBP1 interacts with BCAT2 (branched-chain amino acid transaminase 2) at Leucine 239 of BCAT2; this interaction co-regulates the PI3K/AKT signaling pathway to inhibit autophagy, autophagy-related apoptosis, and ferroptosis in prostate cancer cells.","method":"Co-immunoprecipitation, mass spectrometry, Leu239 point mutation, RNA sequencing, functional autophagy/apoptosis/ferroptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with site-specific mutation, MS, functional assays; single lab","pmids":["40274762"],"is_preprint":false},{"year":2025,"finding":"PCBP1 undergoes O-GlcNAcylation at Threonine 99 in the cytoplasm (mediated by OGT in the presence of circPRELID2); this modification disrupts PCBP1 binding to the 3' UTR of ZEB2 mRNA, reversing ZEB2 translational silencing and promoting EMT and metastasis of gastric cancer cells.","method":"RIP for PCBP1/ZEB2 3'-UTR interaction, site-specific O-GlcNAc mutagenesis (T99), circPRELID2 knockdown/overexpression, OGT assay, polysome profiling, in vivo metastasis models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — PTM site mutagenesis, RIP, in vitro OGT modification, functional in vivo readout; single lab","pmids":["41117067"],"is_preprint":false}],"current_model":"PCBP1 (hnRNP E1) is a multifunctional KH-domain RNA- and DNA-binding protein that acts as a cytosolic iron chaperone (binding Fe(II)-GSH and delivering it to ferritin, PHD/FIH hydroxylases, DOHH, aconitase, and the BolA2-Glrx3 [2Fe-2S] assembly pathway), a translational regulator (silencing LOX, Dab2, ILEI, PRL-3, CDC27, and ZEB2 mRNAs by blocking 80S assembly or elongation via binding to DICE/BAT/C-rich 3'- or 5'-UTR elements), an mRNA stabilizer (eNOS, MOR, p27, GM-CSF, DKK1), an alternative splicing factor (CD44, STAT3, FosB, protein 4.1R) that can interact with SMAD3 and spliceosomal components, and a transcriptional co-regulator that binds poly(C) DNA at promoters and recruits DHX9 helicase to resolve R-loops; its activity is controlled by phosphorylation at Ser43/Thr60/Thr127 (by Akt2/PAK1), covalent homocysteinylation, O-GlcNAcylation at Thr99, and ubiquitin-mediated degradation by ARIH1, with iron itself protecting PCBP1 from caspase-mediated cleavage."},"narrative":{"mechanistic_narrative":"PCBP1 (hnRNP E1) is a multifunctional poly(C)-binding KH-domain protein that operates at the interface of post-transcriptional gene regulation and cytosolic iron homeostasis [PMID:9160751, PMID:22055506]. As a translational silencer, it binds C-rich cis-elements such as the dimeric DICE in the 15-lipoxygenase 3' UTR and blocks 80S ribosome assembly, an activity reconstituted from recombinant protein and requiring two PCBP1 molecules per dimeric element [PMID:9160751, PMID:11827469]; it extends this silencing to TGF-β-regulated EMT transcripts (Dab2, ILEI), PRL-3, Cdc27, and ZEB2 through its KH domains binding to defined 3'- or 5'-UTR consensus motifs [PMID:20154680, PMID:20609352, PMID:27102006, PMID:27067543, PMID:41117067]. The same RNA-binding activity is repurposed for mRNA stabilization, where PCBP1 binds C/U-rich elements to protect transcripts including eNOS, mu-opioid receptor, p27Kip1, and GM-CSF (Csf2) [PMID:23478261, PMID:27836661, PMID:30086790, PMID:29958803]. PCBP1 also functions as a nuclear alternative splicing regulator, negatively controlling CD44 variant exon inclusion and STAT3 exon 23 in concert with partners SMAD3, THAP11, TIA1/RBM39, and modulating FosB splicing in neurons [PMID:27746021, PMID:22673507, PMID:28193846, PMID:31223278, PMID:35730718]. Independently of RNA, PCBP1 is a cytosolic iron chaperone that binds Fe(II) via cysteine/glutamate residues and a bound glutathione and delivers it to ferritin, PHD/FIH hydroxylases, deoxyhypusine hydroxylase, and the BolA2-Glrx3 [2Fe-2S] assembly pathway [PMID:22055506, PMID:24843120, PMID:28375153, PMID:31406370]. Its activities are gated by phosphorylation (Akt2 at Ser43; PAK1 at Thr60/Thr127) that releases it from target RNAs, by homocysteinylation that unmasks RNA binding during folate deficiency, by O-GlcNAcylation at Thr99, and by ARIH1-mediated ubiquitin degradation, while iron itself protects PCBP1 from caspase cleavage [PMID:17389360, PMID:20154680, PMID:21930702, PMID:41117067, PMID:35102251, PMID:29958803]. PCBP1 is essential for early mouse embryogenesis, erythroid iron loading and hemoglobinization, and T-cell cytokine programs that drive autoimmunity [PMID:26527618, PMID:28375153, PMID:29958803].","teleology":[{"year":1997,"claim":"Established PCBP1's founding mechanism: how a 3' UTR element can repress translation, by showing hnRNP E1 binds the LOX DICE and blocks 80S ribosome assembly.","evidence":"Protein purification from reticulocytes with reconstituted cell-free translation and DICE-reporter transfection","pmids":["9160751"],"confidence":"High","gaps":["Did not define the structural basis of 80S inhibition","Generality beyond LOX not yet established"]},{"year":2002,"claim":"Refined the silencing mechanism by showing stoichiometry matters — a dimeric DICE binding two PCBP1 molecules is required for repression, decoupling binding from inhibition.","evidence":"EMSA, sucrose gradients, and in vitro translation with DICE repeat-variant reporters","pmids":["11827469"],"confidence":"Medium","gaps":["Structural model of the dimeric complex not resolved","single lab in vitro"]},{"year":2006,"claim":"Showed PCBP1 silencing is recruited combinatorially via protein partners, being delivered to A2RE RNA through direct interaction with hnRNP A2.","evidence":"Yeast two-hybrid, reciprocal co-IP, FCS, in vitro translation and microinjection","pmids":["16775011"],"confidence":"High","gaps":["In vivo target mRNAs of the A2/E1 complex not enumerated"]},{"year":2007,"claim":"Identified the first switch controlling PCBP1 — PAK1 phosphorylation at Thr60/Thr127 releases it from DICE to reverse silencing and redirect it to transcription and CD44 splicing.","evidence":"Y2H, kinase and luciferase assays, polysome fractionation, ChIP, and splicing minigene assays","pmids":["17389360"],"confidence":"High","gaps":["Direct physiological PAK1 substrate sites in vivo not fully mapped","single lab"]},{"year":2010,"claim":"Connected PCBP1 to a signaling pathway and disease program: Akt2 phosphorylation at Ser43 releases it from the BAT element to derepress EMT transcripts, linking TGF-β to translational control.","evidence":"Polysome profiling, RNA-protein binding, Ser43Ala mutagenesis and translational reporters","pmids":["20154680","20609352","20361869"],"confidence":"High","gaps":["Full set of BAT-element targets incompletely defined","relationship between translational and splicing roles unclear"]},{"year":2011,"claim":"Revealed an entirely separate molecular role — PCBP1 as a cytosolic iron chaperone metallating PHD/FIH hydroxylases, coupling iron availability to HIF1α regulation.","evidence":"siRNA depletion, reconstituted in vitro iron delivery with purified Fe-PCBP1, co-IP and hydroxylation/degradation assays","pmids":["22055506"],"confidence":"High","gaps":["Full client enzyme repertoire not yet defined","structural basis of Fe handoff unresolved"]},{"year":2011,"claim":"Demonstrated that covalent modification can switch on RNA binding — homocysteinylation of KH-domain cysteines unmasks an RNA pocket, making PCBP1 a folate-deficiency sensor.","evidence":"In vitro RNA-protein binding with purified components, in vitro translation, covalent modification analysis","pmids":["21930702"],"confidence":"High","gaps":["In vivo physiological extent of homocysteinylation not quantified"]},{"year":2013,"claim":"Established the mRNA-stabilizing arm of PCBP1 and its phospho-regulation, showing it binds C/U-rich 3' UTRs to stabilize eNOS mRNA, an interaction disrupted by Akt/Ser43 phosphorylation under hypoxia.","evidence":"RIP, EMSA, mRNA half-life and phosphorylation/fractionation assays","pmids":["23478261","27836661"],"confidence":"High","gaps":["Determinants distinguishing stabilizing vs silencing outcomes on C-rich elements unresolved"]},{"year":2014,"claim":"Generalized the iron-chaperone function to multiple cytosolic non-heme iron enzymes (DOHH, aconitase) in an iron-dependent, interaction-based handoff.","evidence":"siRNA depletion, in vitro iron delivery with lysates, iron-dependent co-IP, and DOHH/aconitase activity assays","pmids":["24843120"],"confidence":"High","gaps":["Mechanism of client selectivity not defined"]},{"year":2015,"claim":"Demonstrated PCBP1 is individually essential and non-redundant with PCBP2 through peri-implantation embryonic lethality of the null mouse.","evidence":"Pcbp1 germline knockout mouse phenotyping","pmids":["26527618"],"confidence":"High","gaps":["Which molecular function underlies lethality not isolated"]},{"year":2016,"claim":"Mapped the splicing-regulatory mechanism: phospho-SMAD3 partners with PCBP1 in nuclear speckles to inhibit spliceosome assembly on CD44, and defined the KH-domain consensus disrupted by Ser43 phosphorylation.","evidence":"Reciprocal co-IP, RIP, colocalization, phospho-mutant epistasis, binding kinetics, and cell-cycle phenotyping","pmids":["27746021","27067543","27102006"],"confidence":"High","gaps":["Genome-wide splicing target set incomplete","structural model of the PCBP1-spliceosome interface lacking"]},{"year":2017,"claim":"Defined PCBP1's role in erythropoiesis as a ferritin iron donor whose iron-dependent protein interaction supports heme synthesis, with knockout mice showing microcytic anemia.","evidence":"Pcbp1 knockout mouse, ex vivo erythroid differentiation, ferritin iron-flux and in vitro protein-interaction assays","pmids":["28375153","29032941"],"confidence":"High","gaps":["Coordination with NCOA4-mediated ferritinophagy not fully mechanistically integrated"]},{"year":2017,"claim":"Expanded the regulatory repertoire to miRNA processing, splicing co-factor complexes, and an autoregulatory loop, broadening PCBP1's reach across RNA metabolism.","evidence":"AGO2 co-IP and hypomorphic mouse (miRNA); TIA1/RBM39 complex co-IP and spliceosome assays; in vitro RNA binding for autoregulation","pmids":["28381556","28193846","28250194","28077174"],"confidence":"Medium","gaps":["Direct biochemical role within the miRNA machinery not reconstituted","single-lab findings"]},{"year":2018,"claim":"Linked iron status to immune and apoptotic outcomes: iron protects PCBP1 from caspase cleavage to sustain Csf2 mRNA stability, and oxidized-RNA sensing via two 8-oxoG residues drives apoptosis.","evidence":"T-cell-specific knockout with EAE, mRNA stability and caspase assays; CRISPR KO with oxidized-RNA binding and caspase/PARP readouts","pmids":["29958803","29891675","30086790"],"confidence":"High","gaps":["How a single protein integrates iron, RNA oxidation and apoptosis mechanistically not unified"]},{"year":2019,"claim":"Provided the structural-biochemical basis of iron chaperoning, showing Fe(II) coordination by Cys/Glu plus glutathione and handoff to BolA2 for [2Fe-2S] assembly, linking ferrous-iron and Fe-S systems.","evidence":"Interactome proteomics, in vitro reconstitution of Fe-GSH-PCBP1-BolA2 complex, mutagenesis of coordinating residues, cluster-assembly assays","pmids":["31406370","31223278"],"confidence":"High","gaps":["Atomic structure of the metallated complex not resolved","in-cell flux through the pathway not quantified"]},{"year":2020,"claim":"Revealed paralog-specific and innate-immune functions — PCBP1 vs PCBP2 produce opposing apoptotic outcomes on 8-oxoG-RNA, and PCBP1 directly binds DNA to promote cGAS activation.","evidence":"CRISPR KO of both paralogs with rescue; biochemical purification, DNA-binding and cGAS activation assays; checkpoint/Treg phenotyping","pmids":["32647012","32415261","32523987","32440711","32067958"],"confidence":"High","gaps":["Structural basis for opposite PCBP1/PCBP2 effects unknown","mechanism of DNA-dependent cGAS enhancement undefined"]},{"year":2022,"claim":"Identified upstream control and new effector roles: ARIH1 ubiquitinates PCBP1 to drive EMT, PCBP1 adapts NAT10 for mRNA ac4C modification, and binds poly(C) DNA recruiting DHX9 to resolve R-loops.","evidence":"Y2H/co-IP/ubiquitination (ARIH1); complex co-IP and ac4C mapping (NAT10/TDP43); ChIP-seq, helicase co-IP and R-loop assays; FosB splicing conditional KO","pmids":["35102251","39556689","39342995","35730718"],"confidence":"Medium","gaps":["Direct DHX9-binding interface unmapped","physiological scope of ac4C adapter role unclear","single-lab studies"]},{"year":2023,"claim":"Extended PCBP1 mRNA-stability control across cancer contexts (LACTB, TPM3, DKK1, CCL2), tying it to ferroptosis, Wnt signaling, and inflammation.","evidence":"RIP, RNA pulldown, luciferase, and mRNA-stability assays with conditional knockout for CCL2/colitis","pmids":["37157950","36702545","35287546","35907982"],"confidence":"Medium","gaps":["Binding-site consensus across these targets not unified","several are low-confidence single-assay studies"]},{"year":2025,"claim":"Added a metabolic PTM switch — OGT-mediated O-GlcNAcylation at Thr99 disrupts PCBP1 binding to ZEB2 mRNA to derepress translation and drive metastasis.","evidence":"T99 site mutagenesis, RIP, in vitro OGT modification, polysome profiling, and in vivo metastasis models","pmids":["41117067"],"confidence":"Medium","gaps":["Interplay between O-GlcNAcylation and phosphorylation switches not resolved","single lab"]},{"year":null,"claim":"How PCBP1 partitions among its iron-chaperone, translational-silencing, mRNA-stabilizing, splicing, and DNA-binding activities within a single cell, and what structural states underlie each, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model of how one KH-domain protein switches between RNA, DNA and iron-binding modes","Quantitative apportionment of cellular PCBP1 among functions unknown","Cross-talk among phosphorylation, homocysteinylation, O-GlcNAcylation and ubiquitination not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,12,17,25,26,27]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[30,40]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[7,13,19,28]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,4,1]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[28]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,16,22,39]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[9,26]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,13,28,45]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,16,38,40]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[16,40]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,16,22,39]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,13,19,28,35]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,25,30,34,42]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,40]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,19,36]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[25,26,46]}],"complexes":[],"partners":["PCBP2","SMAD3","DHX9","NAT10","AGO2","BOLA2","ARIH1","TIA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15365","full_name":"Poly(rC)-binding protein 1","aliases":["Alpha-CP1","Heterogeneous nuclear ribonucleoprotein E1","hnRNP E1","Nucleic acid-binding protein SUB2.3"],"length_aa":356,"mass_kda":37.5,"function":"Single-stranded nucleic acid binding protein that binds preferentially to oligo dC (PubMed:15731341, PubMed:7556077, PubMed:7607214, PubMed:8152927). Together with PCBP2, required for erythropoiesis, possibly by regulating mRNA splicing (By similarity) (Microbial infection) In case of infection by poliovirus, plays a role in initiation of viral RNA replication in concert with the viral protein 3CD","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15365/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PCBP1","classification":"Common Essential","n_dependent_lines":1182,"n_total_lines":1208,"dependency_fraction":0.9784768211920529},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM39","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/PCBP1","total_profiled":1310},"omim":[{"mim_id":"617447","title":"PABP-DEPENDENT POLY(A) NUCLEASE 2; PAN2","url":"https://www.omim.org/entry/617447"},{"mim_id":"601210","title":"POLY(rC)-BINDING PROTEIN 2; PCBP2","url":"https://www.omim.org/entry/601210"},{"mim_id":"601209","title":"POLY(rC)-BINDING PROTEIN 1; PCBP1","url":"https://www.omim.org/entry/601209"},{"mim_id":"600712","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN K; HNRNPK","url":"https://www.omim.org/entry/600712"},{"mim_id":"600124","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A2/B1; HNRNPA2B1","url":"https://www.omim.org/entry/600124"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Cytoplasmic bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PCBP1"},"hgnc":{"alias_symbol":["HNRPE1","hnRNP-E1","HNRPX","hnRNP-X"],"prev_symbol":[]},"alphafold":{"accession":"Q15365","domains":[{"cath_id":"3.30.310.210","chopping":"12-87_96-171","consensus_level":"medium","plddt":84.3382,"start":12,"end":171},{"cath_id":"3.30.1370.10","chopping":"279-351","consensus_level":"high","plddt":83.6442,"start":279,"end":351}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15365","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15365-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15365-F1-predicted_aligned_error_v6.png","plddt_mean":68.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PCBP1","jax_strain_url":"https://www.jax.org/strain/search?query=PCBP1"},"sequence":{"accession":"Q15365","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15365.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15365/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15365"}},"corpus_meta":[{"pmid":"9160751","id":"PMC_9160751","title":"mRNA silencing in erythroid differentiation: hnRNP K and hnRNP E1 regulate 15-lipoxygenase translation from the 3' end.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9160751","citation_count":441,"is_preprint":false},{"pmid":"20154680","id":"PMC_20154680","title":"TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI.","date":"2010","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20154680","citation_count":265,"is_preprint":false},{"pmid":"20584894","id":"PMC_20584894","title":"Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: Focus on hnRNP E1's multifunctional regulatory roles.","date":"2010","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20584894","citation_count":223,"is_preprint":false},{"pmid":"22055506","id":"PMC_22055506","title":"Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2.","date":"2011","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/22055506","citation_count":176,"is_preprint":false},{"pmid":"20609352","id":"PMC_20609352","title":"PCBP1 suppresses the translation of metastasis-associated PRL-3 phosphatase.","date":"2010","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/20609352","citation_count":154,"is_preprint":false},{"pmid":"28375153","id":"PMC_28375153","title":"PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis.","date":"2017","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/28375153","citation_count":144,"is_preprint":false},{"pmid":"29958803","id":"PMC_29958803","title":"Iron Drives T Helper Cell Pathogenicity by Promoting RNA-Binding Protein PCBP1-Mediated Proinflammatory Cytokine Production.","date":"2018","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29958803","citation_count":129,"is_preprint":false},{"pmid":"24843120","id":"PMC_24843120","title":"Iron chaperones PCBP1 and PCBP2 mediate the metallation of the dinuclear iron enzyme deoxyhypusine hydroxylase.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24843120","citation_count":113,"is_preprint":false},{"pmid":"31406370","id":"PMC_31406370","title":"A PCBP1-BolA2 chaperone complex delivers iron for cytosolic [2Fe-2S] cluster assembly.","date":"2019","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31406370","citation_count":111,"is_preprint":false},{"pmid":"17389360","id":"PMC_17389360","title":"Signaling-dependent and coordinated regulation of transcription, splicing, and translation resides in a single coregulator, PCBP1.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17389360","citation_count":98,"is_preprint":false},{"pmid":"32552766","id":"PMC_32552766","title":"Hsa_circ_0003998 promotes epithelial to mesenchymal transition of hepatocellular carcinoma by sponging miR-143-3p and PCBP1.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32552766","citation_count":78,"is_preprint":false},{"pmid":"20361869","id":"PMC_20361869","title":"PCBP-1 regulates alternative splicing of the CD44 gene and inhibits invasion in human hepatoma cell line HepG2 cells.","date":"2010","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20361869","citation_count":77,"is_preprint":false},{"pmid":"16775011","id":"PMC_16775011","title":"Heterogeneous nuclear ribonucleoprotein (hnRNP) E1 binds to hnRNP A2 and inhibits translation of A2 response element 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Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19727228","citation_count":6,"is_preprint":false},{"pmid":"37904442","id":"PMC_37904442","title":"Association of LncRNA PCBP1-AS1 with cancer occurrence and development: A review.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37904442","citation_count":5,"is_preprint":false},{"pmid":"41117067","id":"PMC_41117067","title":"Hypoxia-Induced circPRELID2 Promotes Gastric Cancer Metastasis by Facilitating ZEB2 Translation via PCBP1 O-GlcNAcylation.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41117067","citation_count":5,"is_preprint":false},{"pmid":"39380272","id":"PMC_39380272","title":"LncRNA PCBP1-AS1 suppresses cell growth in oral squamous cell carcinoma by targeting miR-34c-5p/ZFP36 axis.","date":"2024","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/39380272","citation_count":5,"is_preprint":false},{"pmid":"35639300","id":"PMC_35639300","title":"PCBP1-mediated regulation of WNT signaling is critical for breast tumorigenesis.","date":"2022","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35639300","citation_count":4,"is_preprint":false},{"pmid":"39700662","id":"PMC_39700662","title":"Decoding poly (RC)-binding protein 1 (PCBP1), the underrated guard at the foothill of ferroptosis.","date":"2024","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/39700662","citation_count":4,"is_preprint":false},{"pmid":"39938358","id":"PMC_39938358","title":"RNA splicing of the STAT3 by PCBP1 promotes vulnerable plaque formation via macrophage-like phenotype modulation of vascular smooth muscle cell.","date":"2025","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/39938358","citation_count":4,"is_preprint":false},{"pmid":"26344801","id":"PMC_26344801","title":"Identification of gamma-synuclein as a new PCBP1-interacting protein.","date":"2016","source":"Neurological research","url":"https://pubmed.ncbi.nlm.nih.gov/26344801","citation_count":4,"is_preprint":false},{"pmid":"39757305","id":"PMC_39757305","title":"LncRNA MIR210HG promotes the proliferation of colon cancer cells by inhibiting ferroptosis through binding to PCBP1.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39757305","citation_count":4,"is_preprint":false},{"pmid":"40451383","id":"PMC_40451383","title":"RNA binding proteins PCBP1 and PCBP2 regulate pancreatic β cell translation.","date":"2025","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40451383","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53144,"output_tokens":12814,"usd":0.175821,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24168,"output_tokens":6186,"usd":0.137745,"stage2_stop_reason":"end_turn"},"total_usd":0.313566,"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\": 1997,\n      \"finding\": \"hnRNP E1 (PCBP1) and hnRNP K purified from rabbit reticulocytes specifically bind the differentiation control element (DICE) in the 3' UTR of 15-lipoxygenase (LOX) mRNA and silence its translation by specifically inhibiting 80S ribosome assembly; this was reconstituted in a cell-free translation system with recombinant proteins, and both cap-dependent and IRES-mediated translation are inhibited.\",\n      \"method\": \"Protein purification from reticulocytes, reconstituted cell-free translation system, transfection of HeLa cells with DICE-reporter, co-immunoprecipitation of silenced mRNA\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with recombinant proteins, multiple orthogonal methods (purification, cell-free assay, transfection, co-IP), independently foundational\",\n      \"pmids\": [\"9160751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Translational silencing of LOX mRNA by hnRNP E1 requires binding of at least two hnRNP E1 molecules to a dimeric (2R) DICE configuration; a single repeat is insufficient for translational inhibition even though E1 binding still occurs.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), sucrose gradient centrifugation, in vitro translation with DICE repeat-variant reporter mRNAs\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assays with defined mutant substrates, single lab\",\n      \"pmids\": [\"11827469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"hnRNP E1 (PCBP1) directly binds hnRNP A2 via protein-protein interaction and is recruited to A2 response element (A2RE) RNA in an hnRNP A2-dependent manner; overexpression or microinjection of hnRNP E1 inhibits translation of A2RE mRNA (but not non-A2RE RNA) both in vivo and in a cell-free translation system, in an hnRNP A2-dependent manner.\",\n      \"method\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, in vitro cross-linking, fluorescence correlation spectroscopy, in vitro translation system, microinjection\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including reconstituted in vitro translation, reciprocal co-IP, and live-cell imaging\",\n      \"pmids\": [\"16775011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PAK1 phosphorylates PCBP1 on Thr60 and Thr127 in response to mitogenic stimulation; this phosphorylation releases PCBP1 from DICE elements, reversing translational inhibition of DICE-containing mRNAs (including endogenous L1-CAM). PAK1 activation also promotes nuclear retention of PCBP1, recruitment to the eIF4E promoter to stimulate eIF4E transcription, and alternative splicing of CD44 via PCBP1 interaction with Caper alpha (a U2 snRNP auxiliary factor).\",\n      \"method\": \"Yeast two-hybrid, phosphorylation assays, luciferase reporter, polysome fractionation, ChIP, RNA splicing minigene assay, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, kinase assay, reporter, ChIP, splicing assay) in single lab\",\n      \"pmids\": [\"17389360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TGF-β induces phosphorylation of hnRNP E1 (PCBP1) at Ser43 by protein kinase Bβ/Akt2, causing its release from the BAT element in the 3' UTR of Dab2 and ILEI mRNAs, thereby relieving translational silencing of these EMT-associated transcripts and inducing EMT.\",\n      \"method\": \"Polysome profiling, RNA-protein binding assays, phosphorylation assays, knockdown/overexpression with translational reporter assays, site-directed mutagenesis (Ser43Ala)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-directed mutagenesis, polysome profiling, kinase assay with multiple orthogonal methods, widely replicated\",\n      \"pmids\": [\"20154680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PCBP1 binds GCCCAG motifs in the 5' UTR of PRL-3 mRNA and retards incorporation of PRL-3 mRNA into polyribosomes, suppressing its translation; overexpression of PCBP1 inhibits PRL-3 and inactivates AKT, while knockdown of PCBP1 increases PRL-3 protein levels.\",\n      \"method\": \"Polyribosome/polysome fractionation, RNA immunoprecipitation, reporter assay, overexpression/knockdown\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polysome profiling and RIP, single lab with two orthogonal methods\",\n      \"pmids\": [\"20609352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PCBP1 negatively regulates alternative splicing of CD44 variant exons (v3, v5, v6, v8, v10) in HepG2 hepatoma cells; enforced PCBP1 expression inhibits CD44 variant expression and invasion, while knockdown induces variant splicing.\",\n      \"method\": \"Overexpression/knockdown, RT-PCR for CD44 variants, invasion assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined splicing and cellular phenotype readout, single lab\",\n      \"pmids\": [\"20361869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PCBP1 is an iron chaperone that binds ferrous iron and delivers it to HIF prolyl hydroxylases (PHD1, PHD2, PHD3) and asparaginyl hydroxylase (FIH1) for metallation; depletion of PCBP1 or PCBP2 leads to loss of PHD activity, reduced prolyl hydroxylation of HIF1α, impaired VHL/proteasome degradation of HIF1α, and accumulation of active HIF1. PHD activity was restored in vitro by addition of purified Fe-PCBP1, and PCBP1 bound to PHD2 and FIH1 in vivo.\",\n      \"method\": \"siRNA depletion, in vitro iron delivery reconstitution with purified Fe-PCBP1, co-immunoprecipitation, prolyl hydroxylation assays, HIF1α degradation assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted in vitro iron delivery, co-IP, functional enzyme activity assays, multiple orthogonal methods\",\n      \"pmids\": [\"22055506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PCBP1 mediates constitutive (housekeeping) degradation of MAVS (mitochondrial antiviral signaling adaptor) in uninfected cells, using the same mechanism as PCBP2; overexpression of PCBP1 impairs MAVS-mediated antiviral responses through PCBP1-induced MAVS degradation, while knockdown of PCBP1 increases MAVS levels and antiviral signaling.\",\n      \"method\": \"Overexpression/knockdown, antiviral response assays, subcellular fractionation, western blot for MAVS protein levels\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined molecular phenotype (MAVS protein levels and antiviral signaling), single lab\",\n      \"pmids\": [\"22105485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"hnRNP E1 (PCBP1) acts as a physiological sensor of folate deficiency: intracellular accumulation of L-homocysteine (during folate deficiency) induces covalent binding of homocysteine to cysteine residues in the KH domains of hnRNP E1 via mixed disulfide bonds, unmasking an RNA-binding pocket and enabling high-affinity interaction with the folate receptor-α mRNA cis-element, thereby stimulating folate receptor translation.\",\n      \"method\": \"In vitro RNA-protein binding assays with purified components, in vitro translation, siRNA knockdown, covalent modification analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro with purified components, covalent modification biochemically characterized, functional translation assay\",\n      \"pmids\": [\"21930702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"THAP11 is a binding partner of PCBP1; THAP11 overexpression inhibits CD44 v6 expression and cell invasion in HepG2 cells, but fails to do so when the PCBP1-binding domain of THAP11 is deleted or when PCBP1 is knocked down, indicating that THAP11 regulates CD44 alternative splicing through interaction with PCBP1.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutant analysis, overexpression/knockdown, CD44 variant expression assay, invasion assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion epistasis and co-IP with functional readout, single lab\",\n      \"pmids\": [\"22673507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PCBP1 is required for maintenance of the transcriptionally silent state in fully grown mouse oocytes; siRNA-mediated knockdown of Pcbp1 in GV oocytes disrupts the NSN-to-SN nucleolus ratio, reactivates transcription (detected by BrUTP incorporation and active RNA Pol II/H3K4me3 markers), and upregulates ~4,000 transcripts.\",\n      \"method\": \"siRNA microinjection into oocytes, BrUTP incorporation assay, immunofluorescence for phospho-RNA Pol II CTD and H3K4me3, microarray transcriptome analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with direct transcriptional activity readout in oocytes, single lab\",\n      \"pmids\": [\"22801551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"hnRNP E1 (PCBP1) binds pyrimidine-rich (C/CU-rich) elements in the 3' UTR of eNOS mRNA and stabilizes it; knockdown of hnRNP E1 decreases eNOS mRNA half-life, mRNA levels, and protein expression. Under hypoxia, increased Akt-mediated serine phosphorylation (including Ser43) of hnRNP E1 and increased nuclear localization disrupt hnRNP E1/eNOS 3'-UTR interactions, decreasing eNOS mRNA stability. The hnRNP E1/eNOS 3'-UTR complex also protects eNOS mRNA from inhibition by antisense RNA (sONE) and miR-765.\",\n      \"method\": \"RNA immunoprecipitation, EMSA, siRNA knockdown, mRNA half-life assay, phosphorylation analysis, nuclear/cytoplasmic fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, EMSA, mRNA stability assay, phosphorylation-localization link, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"23478261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PCBP1 and PCBP2 deliver iron to deoxyhypusine hydroxylase (DOHH), a dinuclear iron enzyme; cells depleted of PCBP1 or PCBP2 exhibit loss of DOHH activity and loss of the holo form of the enzyme. Lysates containing PCBP1/2 converted apo-DOHH to holo-DOHH in vitro more efficiently than lysates lacking them. PCBP1 bound to DOHH in iron-treated cells but not in iron-deficient cells. Depletion of PCBP1/2 also led to loss of cytosolic aconitase activity, suggesting a broader role in iron delivery to cytosolic non-heme iron enzymes.\",\n      \"method\": \"siRNA depletion, in vitro iron delivery assay with cell lysates, co-immunoprecipitation, enzyme activity assays (DOHH, aconitase)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of iron delivery, co-IP, multiple enzyme activity assays, single lab with multiple methods\",\n      \"pmids\": [\"24843120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pcbp1-null mouse embryos are non-viable at the peri-implantation stage, demonstrating that PCBP1 is individually essential for early mouse embryonic development and has evolved a non-redundant function distinct from its paralog PCBP2.\",\n      \"method\": \"Pcbp1 germline knockout mouse, embryonic lethality phenotyping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined developmental phenotype; independently replicated by a second paper (PMID 28381556)\",\n      \"pmids\": [\"26527618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PCBP1/hnRNP E1 translationally silences Cdc27 mRNA in normal mammary epithelial cells; shRNA-mediated knockdown of hnRNP E1 abrogates this silencing, causing constitutive CDC27 expression, premature activation of G2-M-APC/C-CDC20, aberrant degradation of FZR1/CDH1, loss of APC/C-CDH1 activity, mitotic aberrations, and aneuploidy.\",\n      \"method\": \"shRNA knockdown, polysome profiling, western blot, cell cycle analysis, mitotic aberration assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular and cellular phenotype, single lab\",\n      \"pmids\": [\"27102006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TGF-β directly regulates alternative splicing of CD44 through phosphorylated SMAD3 (pT179) interaction with PCBP1; SMAD3 and PCBP1 colocalize in SC35-positive nuclear speckles and interact at the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly, favoring expression of mesenchymal CD44s over epithelial CD44E isoform.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence/colocalization, splicing reporter assays, RIP, SMAD3 phospho-mutant analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, RIP, phospho-mutant epistasis, colocalization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27746021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"hnRNP E1 (PCBP1) KH domains mediate binding to a defined consensus motif in the 3' UTR of target mRNAs; phosphorylation at Ser43 (p-hnRNP E1 by Akt2) disrupts KH domain-RNA interaction, correlating with high p-hnRNP E1 levels in metastatic cells. An hnRNP E1 consensus binding motif was biochemically characterized for binding kinetics with KH domains.\",\n      \"method\": \"RNA-binding kinetics assays, KH domain deletion/mutation analysis, phospho-specific antibodies, western blot in cellular progression models\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding kinetics with defined domain mutations, single lab\",\n      \"pmids\": [\"27067543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PCBP1 stabilizes mu-opioid receptor (MOR) mRNA by binding a C-rich element (CRE) in the MOR 3' UTR; knockdown of PCBP1 decreases MOR mRNA half-life and protein expression. Phosphorylation of PCBP1 by PKA (via forskolin/cAMP) at serine residues promotes cytoplasmic localization and enhanced PCBP1/MOR 3'-UTR interaction. AUF1, also phosphorylated under these conditions, forms an increased interaction with PCBP1 and binds the CRE; PABP also increases its interaction with the CRE.\",\n      \"method\": \"RNA immunoprecipitation, RNA EMSA, siRNA knockdown, mRNA stability assay, phosphorylation analysis, subcellular fractionation\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, EMSA, mRNA stability assay, multiple binding partners, single lab\",\n      \"pmids\": [\"27836661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PCBP1 and NCOA4 are critical for iron trafficking through ferritin in developing erythroid cells; depletion of PCBP1 impairs iron loading into ferritin, reduces heme synthesis and hemoglobin formation. Pcbp1-knockout mice develop microcytic anemia with compensatory erythropoiesis. PCBP1 delivers iron to ferritin via a direct protein-protein interaction that is developmentally regulated and enhanced by iron deprivation; excess iron inhibits this interaction in vitro.\",\n      \"method\": \"Cell depletion experiments, Pcbp1 knockout mouse model, ex vivo erythroid differentiation, ferritin iron flux assays, heme/hemoglobin measurements, in vitro protein-protein interaction assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with multiple cellular phenotype readouts plus in vitro protein interaction validated; replicated with a second paper (PMID 29032941)\",\n      \"pmids\": [\"28375153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Pcbp1 is a component of the miRNA-processing pathway in skeletal muscle; it physically interacts with Argonaute 2 (AGO2) and other miRNA pathway components, modulating the processing of muscle-enriched miRNAs (miR-1, miR-133, miR-206). Hypomorphic Pcbp1 mutant mice show muscle growth defects due to impaired myoblast proliferation/differentiation and a slow-to-fast myofibril switch.\",\n      \"method\": \"siRNA knockdown in myoblasts, co-immunoprecipitation with AGO2, hypomorphic Pcbp1 mouse model, miRNA biogenesis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with AGO2, in vivo mouse model, miRNA processing assays; single lab\",\n      \"pmids\": [\"28381556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"During erythroid differentiation, PCBP1 directly delivers iron to ferritin via protein-protein interaction; this interaction is regulated by cellular iron levels (enhanced by iron deprivation, inhibited by iron excess) and is developmentally regulated. NCOA4 activity and HERC2-mediated lysosomal degradation of NCOA4 are also regulated by cellular iron levels.\",\n      \"method\": \"In vitro protein-protein interaction assay (iron-dependent), cellular iron manipulation, developmental stage analysis\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro protein-protein interaction with iron-dependence, single lab\",\n      \"pmids\": [\"29032941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIA1 and Pcbp1 bind a UUUUCCCCCC motif between the branch point and 3' splice site of protein 4.1R exon 16 in a collaborative manner to promote exon inclusion; they associate in a complex with RBM39, which interacts with U2AF65 and SF3b155 to promote U2 snRNP recruitment to the branch point and enhance spliceosome A complex formation.\",\n      \"method\": \"RNA binding assays with mutant motifs, co-immunoprecipitation of TIA1/Pcbp1/RBM39 complex, splicing reporter assays, spliceosome assembly assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of multiprotein complex, spliceosome assembly assay, splicing reporters with defined mutations; single lab\",\n      \"pmids\": [\"28193846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mutant HSPB1-P182L has a specifically increased interaction with PCBP1 compared to wild-type HSPB1, resulting in reduced translational repressive activity of PCBP1. RNA immunoprecipitation followed by RNA-seq in mouse brain identified PCBP1 mRNA targets enriched for a CTCCTCCTCCTCC consensus motif and neuronal transcripts including genes associated with hereditary neuropathies.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation followed by RNA-seq (RIP-seq), in vitro binding\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq provides broad target identification, co-IP demonstrates increased interaction, translational repression reduction assayed; single lab\",\n      \"pmids\": [\"28077174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"L-homocysteine triggers a dose-dependent high-affinity interaction between hnRNP E1 and a 25-nt cis-element in the 5' UTR of hnRNP-E1 mRNA itself, leading to auto-upregulation of hnRNP E1 translation (positive feedback loop); this interaction is disrupted by ferrous iron in a dose-dependent manner.\",\n      \"method\": \"In vitro RNA-protein binding assays, in vitro translation, antisense oligonucleotide and mutant cis-element perturbations, siRNA knockdown, cell transfection with mutant hnRNP E1\",\n      \"journal\": \"The Journal of nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution and mutagenesis, single lab\",\n      \"pmids\": [\"28250194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PCBP1 promotes mRNA stability of Csf2 (GM-CSF) and Il2 by recognizing UC-rich elements in their 3' UTRs; intracellular iron protects PCBP1 protein from caspase-mediated proteolysis, thereby linking iron levels to T cell cytokine production. Pcbp1 deficiency in T cells inhibits GM-CSF production and abolishes capacity to induce experimental autoimmune encephalomyelitis.\",\n      \"method\": \"T cell-specific Pcbp1 knockout, Csf2 3' UTR activity assays, mRNA stability assays, caspase cleavage assays, RNA binding assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific knockout with defined molecular (mRNA stability, caspase cleavage) and in vivo (EAE) phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"29958803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PCBP1 specifically binds heavily oxidized RNA containing two nearby 8-oxoguanine (8-oxoG) residues (but not RNA with a single 8-oxoG); PCBP1-deficient HeLa cells (CRISPR-Cas9) show higher survival, lower caspase-3 activation, and lower PARP-1 cleavage under hydrogen peroxide treatment. KH domain mutations that disrupt RNA binding abolish this pro-apoptotic function.\",\n      \"method\": \"CRISPR-Cas9 knockout, RNA binding assays with oxidized RNA substrates, KH domain mutagenesis, caspase-3/PARP-1 cleavage assays, cell survival assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — CRISPR KO with defined phenotype, in vitro RNA binding with mutagenesis, structure-function established; single lab\",\n      \"pmids\": [\"29891675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PCBP1 binds p27Kip1 3' UTR via its KH1 domain, primarily stabilizing p27 mRNA and also enhancing its translation; this increases p27 protein levels, inhibits cell proliferation and cell cycle progression, and reduces tumorigenesis in vivo.\",\n      \"method\": \"Transcriptome-wide RIP screen, point mutation/luciferase assay for binding site, mRNA stability assay, ribosome profiling, cell cycle and xenograft assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, mRNA stability, ribosome profiling with KH domain mutation; single lab\",\n      \"pmids\": [\"30086790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PCBP1 coordinates ferrous iron via conserved cysteine and glutamate residues and a noncovalently bound glutathione (GSH) molecule; the Fe-GSH-bound form of PCBP1 forms a complex with cytosolic BolA2 via a bridging Fe ligand. PCBP1-Fe-GSH-BolA2 serves as an intermediate complex required for assembly of [2Fe-2S] clusters on BolA2-Glrx3, linking the ferrous iron and Fe-S distribution systems in cells.\",\n      \"method\": \"Proteomics (PCBP1 interactome), in vitro biochemical reconstitution of iron-GSH-PCBP1-BolA2 complex, site-directed mutagenesis of Fe-coordinating residues, [2Fe-2S] cluster assembly assays in vitro and in cells\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis of coordinating residues, structural/biochemical characterization of complex; multiple orthogonal methods\",\n      \"pmids\": [\"31406370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PCBP1 inhibits alternative splicing of STAT3 exon 23 by binding an exonic splicing suppressor (ESS) in exon 23, thereby reducing the proportion of oncogenic STAT3α and increasing tumor-suppressive STAT3β.\",\n      \"method\": \"Overexpression/knockdown, RT-PCR splicing assay, luciferase/reporter assay for ESS, western blot for STAT3 isoforms\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined splicing phenotype and ESS mapping; single lab\",\n      \"pmids\": [\"31223278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PCBP1 facilitates binding of cGAS to cytosolic DNA; PCBP1 directly binds DNA and enhances cGAS-DNA interaction, promoting cGAS activation and innate immune signaling. PCBP1 is recruited to cGAS in a viral infection-dependent manner, and PCBP1 deficiency inhibits cGAS-mediated downstream gene transcription.\",\n      \"method\": \"Biochemical purification approach, co-immunoprecipitation (virus infection-dependent), DNA-binding assays, cGAS activation assays, PCBP1 knockdown with interferon-response readout\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, DNA binding assay, functional innate immune readout; single lab\",\n      \"pmids\": [\"32415261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TGF-β1 induces phosphorylation, poly-ubiquitination, and proteasomal degradation of PCBP1 in prostate cancer cells; loss of PCBP1 leads to increased CD44s (standard) isoform expression at the expense of CD44v, promoting EMT and cancer stem cell markers.\",\n      \"method\": \"Phosphorylation/ubiquitination assays, proteasome inhibitor experiments, RNAi knockdown, splicing assay (RT-PCR), in vitro and in vivo migration/invasion/tumor initiation assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM characterization (phospho/ubiquitin), gain- and loss-of-function with splicing and functional readouts; single lab\",\n      \"pmids\": [\"32440711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PCBP2, like PCBP1, selectively binds RNA carrying two nearby 8-oxoG residues; however, PCBP2 suppresses apoptosis under oxidative conditions while PCBP1 promotes it. PCBP2 mutations in conserved RNA-binding domains abolish 8-oxoG-RNA binding and the anti-apoptotic function. PCBP2-knockout cells show increased apoptosis, opposite to PCBP1-knockout cells.\",\n      \"method\": \"CRISPR-Cas9 KO of PCBP1 and PCBP2, RNA binding assays, KH domain mutagenesis, caspase-3/PARP1 cleavage assays, rescue with WT vs. mutant proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — CRISPR KO of both paralogs with defined and opposing phenotypes, domain mutagenesis with rescue; rigorous comparison\",\n      \"pmids\": [\"32647012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Small molecule amplifiers bind directly to PCBP1 and require a PCBP1 consensus element within the CFTR open reading frame; amplifiers stabilize CFTR mRNA co-translationally and increase its association with polysomes, identifying PCBP1 as mediating CFTR mRNA stability and translational efficiency.\",\n      \"method\": \"Chemical proteomics (pulldown of amplifier-binding protein), polysome fractionation, PCBP1 consensus element mutation, mRNA stability assay\",\n      \"journal\": \"Journal of cystic fibrosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical proteomics pulldown, polysome profiling, consensus element mutagenesis; single lab\",\n      \"pmids\": [\"32067958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PCBP1 is an intracellular immune checkpoint in T cells; T cell-specific deletion of Pcbp1 favors regulatory T cell (Treg) differentiation over effector T cell (Teff) identity, upregulates inhibitory immune checkpoints (PD-1, TIGIT, VISTA) on tumor-infiltrating lymphocytes, and blunts antitumor immunity.\",\n      \"method\": \"T cell-specific Pcbp1 conditional knockout, flow cytometry for Treg/Teff markers and checkpoint molecules, tumor challenge models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype (Treg/Teff balance, checkpoint expression); single lab\",\n      \"pmids\": [\"32523987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PCBP1 deletion in mouse liver does not affect mitochondrial iron balance but impairs mitochondrial function: PCBP1 deletion reduces respiratory complexes II and IV, oxygen consumption, and ATP production, and depletes mitochondrial lipids cardiolipin and coenzyme Q; the dysfunction is caused by oxidative damage from unchaperoned (chemically reactive) iron.\",\n      \"method\": \"Liver-specific Pcbp1 knockout mouse, mitochondrial morphology analysis, respiratory complex quantification, oxygen consumption assay, mitochondrial lipid analysis, vitamin E and CoQ supplementation\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mitochondrial functional and biochemical readouts, dietary rescue experiments; single lab\",\n      \"pmids\": [\"34455040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PCBP1 and PCBP2 are jointly required for erythroid differentiation; combined inactivation of both loci in erythroid lineage leads to midgestational repression of erythroid/hematopoietic gene expression, loss of blood formation, and fetal demise, with overlapping and isoform-specific impacts on the erythroid transcriptome including mRNA representation and exon splicing.\",\n      \"method\": \"Lineage-specific conditional knockout of Pcbp1 and Pcbp2 in mouse embryo, RNA-seq (mRNA representation and splicing analysis), ex vivo erythroid progenitor depletion experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional double KO with defined transcriptomic and phenotypic readout; single lab\",\n      \"pmids\": [\"34180713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The E3 ubiquitin ligase ARIH1 interacts with hnRNP E1 (PCBP1) and promotes its ubiquitin-mediated degradation; ARIH1 silencing increases hnRNP E1 protein stability and reduces ubiquitination, while ARIH1 overexpression reduces hnRNP E1 levels. Loss of ARIH1 delays EMT induction and reduces invasion; overexpression promotes EMT and invasion in a manner dependent on hnRNP E1.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, ubiquitination assay, siRNA/overexpression with EMT phenotype readout, miniTurboID proximity labeling\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H, co-IP, ubiquitination assay, functional EMT phenotype; single lab\",\n      \"pmids\": [\"35102251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Dopamine D1 receptor signaling synergizes with ALK4/Smad3 pathway to activate PCBP1 in medium spiny neurons; PCBP1 and Smad3 interact, translocate to the nucleus, and bind to sequences in exon-4 and intron-4 of FosB pre-mRNA to promote alternative splicing and generation of ΔFosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impairs ΔFosB mRNA induction and behavioral sensitization to cocaine.\",\n      \"method\": \"Co-immunoprecipitation of PCBP1/Smad3, nuclear translocation imaging, RIP at FosB exon-4/intron-4, conditional neuronal knockout of ALK4 and PCBP1, behavioral sensitization assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, RIP, conditional KO with in vivo behavioral phenotype; single lab\",\n      \"pmids\": [\"35730718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PCBP1 acts as an adapter for the ac4C writer enzyme NAT10 in mammalian cells, tethering NAT10 to mRNA substrates for N4-acetylcytidine (ac4C) modification; knockdown of PCBP1 (or TDP43) decreases mRNA acetylation abundance and ablates cytidine-rich ac4C motifs in HEK293T cells. The NAT10/PCBP1/TDP43 complex was identified biochemically.\",\n      \"method\": \"Co-immunoprecipitation of NAT10/PCBP/TDP43 complex, siRNA knockdown, transcriptome-wide ac4C mapping, motif analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of complex, knockdown with ac4C profiling, single lab\",\n      \"pmids\": [\"39556689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PCBP1 regulates transcription by binding to poly(C) DNA tracts at transcription start sites; PCBP1 interacts with the G-quadruplex-specific RNA/DNA helicase DHX9 (RNA Helicase A) to modulate DHX9 accumulation and activity. PCBP1 depletion causes defects in R-loop processing and dysregulation of transcription of PCBP1 target genes.\",\n      \"method\": \"ChIP-seq (PCBP1 DNA-binding sites), co-immunoprecipitation with helicases including DHX9, R-loop assays, siRNA depletion with transcription readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, co-IP, R-loop assays with functional consequence; single lab\",\n      \"pmids\": [\"39342995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCBP1 binds directly to LACTB mRNA and promotes its degradation; PCBP1 knockdown increases LACTB expression, which promotes erastin-induced ferroptosis and mitochondrial dysfunction in bladder cancer cells. This binding was validated by RNA pull-down, RIP, and luciferase assays.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, luciferase reporter assay, PCBP1 knockdown/overexpression, ferroptosis assays, xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, RNA pulldown, luciferase, mRNA decay; single lab\",\n      \"pmids\": [\"37157950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCBP1 acts as a regulator of CCL2 expression in macrophages; RNA immunoprecipitation indicated PCBP1 interacts with Ccl2 mRNA. Conditional depletion of Pcbp1 in macrophages decreases CCL2 production by colonic CX3CR1+ macrophages, reduces inflammatory macrophage accumulation, and protects mice from DSS-induced colitis.\",\n      \"method\": \"Macrophage-specific Pcbp1 conditional knockout, RNA immunoprecipitation, colitis model, cytokine measurement\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with in vivo phenotype and RIP supporting mRNA interaction; single lab\",\n      \"pmids\": [\"36702545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCBP1 binds to and enhances the stability of TPM3 mRNA in esophageal squamous cell carcinoma by directly binding the 3' UTR, as validated by RIP; PCBP1 knockdown reduces TPM3 mRNA levels and increases its degradation rate, attenuating cell migration and invasion.\",\n      \"method\": \"RIP assay, actinomycin D mRNA stability assay, siRNA knockdown, migration/invasion assay\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP and mRNA stability assay, single lab, no reconstitution\",\n      \"pmids\": [\"35287546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCBP1 stabilizes DKK1 mRNA by direct binding (validated by RIP and RNA pulldown); PCBP1 knockdown decreases DKK1 mRNA stability and protein levels, relieving inhibition of the Wnt/β-catenin pathway and promoting lung adenocarcinoma progression.\",\n      \"method\": \"RNA-seq of PCBP1 knockdown cells, RIP, RNA pulldown, mRNA stability assay, western blot, in vivo xenograft\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP and pulldown with mRNA stability, single lab, no reconstitution\",\n      \"pmids\": [\"35907982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCBP1 KH3 domain mediates its interaction with the HTLV-1 Tax oncoprotein in the cytoplasm; PCBP1 facilitates assembly of the Tax/IKK complex, thereby potentiating Tax-mediated IKK-NF-κB signaling. PCBP1 knockdown attenuates Tax-dependent NF-κB activation and reduces proliferation of HTLV-1-transformed cells.\",\n      \"method\": \"Co-immunoprecipitation, colocalization assay, KH3 domain deletion/mutation analysis, knockdown with NF-κB reporter, IKK activity assay, cell proliferation assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain deletion, functional NF-κB assay, single lab\",\n      \"pmids\": [\"38690287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PCBP1 interacts with BCAT2 (branched-chain amino acid transaminase 2) at Leucine 239 of BCAT2; this interaction co-regulates the PI3K/AKT signaling pathway to inhibit autophagy, autophagy-related apoptosis, and ferroptosis in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, Leu239 point mutation, RNA sequencing, functional autophagy/apoptosis/ferroptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with site-specific mutation, MS, functional assays; single lab\",\n      \"pmids\": [\"40274762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PCBP1 undergoes O-GlcNAcylation at Threonine 99 in the cytoplasm (mediated by OGT in the presence of circPRELID2); this modification disrupts PCBP1 binding to the 3' UTR of ZEB2 mRNA, reversing ZEB2 translational silencing and promoting EMT and metastasis of gastric cancer cells.\",\n      \"method\": \"RIP for PCBP1/ZEB2 3'-UTR interaction, site-specific O-GlcNAc mutagenesis (T99), circPRELID2 knockdown/overexpression, OGT assay, polysome profiling, in vivo metastasis models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — PTM site mutagenesis, RIP, in vitro OGT modification, functional in vivo readout; single lab\",\n      \"pmids\": [\"41117067\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PCBP1 (hnRNP E1) is a multifunctional KH-domain RNA- and DNA-binding protein that acts as a cytosolic iron chaperone (binding Fe(II)-GSH and delivering it to ferritin, PHD/FIH hydroxylases, DOHH, aconitase, and the BolA2-Glrx3 [2Fe-2S] assembly pathway), a translational regulator (silencing LOX, Dab2, ILEI, PRL-3, CDC27, and ZEB2 mRNAs by blocking 80S assembly or elongation via binding to DICE/BAT/C-rich 3'- or 5'-UTR elements), an mRNA stabilizer (eNOS, MOR, p27, GM-CSF, DKK1), an alternative splicing factor (CD44, STAT3, FosB, protein 4.1R) that can interact with SMAD3 and spliceosomal components, and a transcriptional co-regulator that binds poly(C) DNA at promoters and recruits DHX9 helicase to resolve R-loops; its activity is controlled by phosphorylation at Ser43/Thr60/Thr127 (by Akt2/PAK1), covalent homocysteinylation, O-GlcNAcylation at Thr99, and ubiquitin-mediated degradation by ARIH1, with iron itself protecting PCBP1 from caspase-mediated cleavage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PCBP1 (hnRNP E1) is a multifunctional poly(C)-binding KH-domain protein that operates at the interface of post-transcriptional gene regulation and cytosolic iron homeostasis [#0, #7]. As a translational silencer, it binds C-rich cis-elements such as the dimeric DICE in the 15-lipoxygenase 3' UTR and blocks 80S ribosome assembly, an activity reconstituted from recombinant protein and requiring two PCBP1 molecules per dimeric element [#0, #1]; it extends this silencing to TGF-\\u03b2-regulated EMT transcripts (Dab2, ILEI), PRL-3, Cdc27, and ZEB2 through its KH domains binding to defined 3'- or 5'-UTR consensus motifs [#4, #5, #15, #17, #47]. The same RNA-binding activity is repurposed for mRNA stabilization, where PCBP1 binds C/U-rich elements to protect transcripts including eNOS, mu-opioid receptor, p27Kip1, and GM-CSF (Csf2) [#12, #18, #27, #25]. PCBP1 also functions as a nuclear alternative splicing regulator, negatively controlling CD44 variant exon inclusion and STAT3 exon 23 in concert with partners SMAD3, THAP11, TIA1/RBM39, and modulating FosB splicing in neurons [#16, #10, #22, #29, #38]. Independently of RNA, PCBP1 is a cytosolic iron chaperone that binds Fe(II) via cysteine/glutamate residues and a bound glutathione and delivers it to ferritin, PHD/FIH hydroxylases, deoxyhypusine hydroxylase, and the BolA2-Glrx3 [2Fe-2S] assembly pathway [#7, #13, #19, #28]. Its activities are gated by phosphorylation (Akt2 at Ser43; PAK1 at Thr60/Thr127) that releases it from target RNAs, by homocysteinylation that unmasks RNA binding during folate deficiency, by O-GlcNAcylation at Thr99, and by ARIH1-mediated ubiquitin degradation, while iron itself protects PCBP1 from caspase cleavage [#3, #4, #9, #47, #37, #25]. PCBP1 is essential for early mouse embryogenesis, erythroid iron loading and hemoglobinization, and T-cell cytokine programs that drive autoimmunity [#14, #19, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established PCBP1's founding mechanism: how a 3' UTR element can repress translation, by showing hnRNP E1 binds the LOX DICE and blocks 80S ribosome assembly.\",\n      \"evidence\": \"Protein purification from reticulocytes with reconstituted cell-free translation and DICE-reporter transfection\",\n      \"pmids\": [\"9160751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of 80S inhibition\", \"Generality beyond LOX not yet established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Refined the silencing mechanism by showing stoichiometry matters \\u2014 a dimeric DICE binding two PCBP1 molecules is required for repression, decoupling binding from inhibition.\",\n      \"evidence\": \"EMSA, sucrose gradients, and in vitro translation with DICE repeat-variant reporters\",\n      \"pmids\": [\"11827469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model of the dimeric complex not resolved\", \"single lab in vitro\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed PCBP1 silencing is recruited combinatorially via protein partners, being delivered to A2RE RNA through direct interaction with hnRNP A2.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, FCS, in vitro translation and microinjection\",\n      \"pmids\": [\"16775011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo target mRNAs of the A2/E1 complex not enumerated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the first switch controlling PCBP1 \\u2014 PAK1 phosphorylation at Thr60/Thr127 releases it from DICE to reverse silencing and redirect it to transcription and CD44 splicing.\",\n      \"evidence\": \"Y2H, kinase and luciferase assays, polysome fractionation, ChIP, and splicing minigene assays\",\n      \"pmids\": [\"17389360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physiological PAK1 substrate sites in vivo not fully mapped\", \"single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected PCBP1 to a signaling pathway and disease program: Akt2 phosphorylation at Ser43 releases it from the BAT element to derepress EMT transcripts, linking TGF-\\u03b2 to translational control.\",\n      \"evidence\": \"Polysome profiling, RNA-protein binding, Ser43Ala mutagenesis and translational reporters\",\n      \"pmids\": [\"20154680\", \"20609352\", \"20361869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of BAT-element targets incompletely defined\", \"relationship between translational and splicing roles unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed an entirely separate molecular role \\u2014 PCBP1 as a cytosolic iron chaperone metallating PHD/FIH hydroxylases, coupling iron availability to HIF1\\u03b1 regulation.\",\n      \"evidence\": \"siRNA depletion, reconstituted in vitro iron delivery with purified Fe-PCBP1, co-IP and hydroxylation/degradation assays\",\n      \"pmids\": [\"22055506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full client enzyme repertoire not yet defined\", \"structural basis of Fe handoff unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that covalent modification can switch on RNA binding \\u2014 homocysteinylation of KH-domain cysteines unmasks an RNA pocket, making PCBP1 a folate-deficiency sensor.\",\n      \"evidence\": \"In vitro RNA-protein binding with purified components, in vitro translation, covalent modification analysis\",\n      \"pmids\": [\"21930702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological extent of homocysteinylation not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the mRNA-stabilizing arm of PCBP1 and its phospho-regulation, showing it binds C/U-rich 3' UTRs to stabilize eNOS mRNA, an interaction disrupted by Akt/Ser43 phosphorylation under hypoxia.\",\n      \"evidence\": \"RIP, EMSA, mRNA half-life and phosphorylation/fractionation assays\",\n      \"pmids\": [\"23478261\", \"27836661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants distinguishing stabilizing vs silencing outcomes on C-rich elements unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Generalized the iron-chaperone function to multiple cytosolic non-heme iron enzymes (DOHH, aconitase) in an iron-dependent, interaction-based handoff.\",\n      \"evidence\": \"siRNA depletion, in vitro iron delivery with lysates, iron-dependent co-IP, and DOHH/aconitase activity assays\",\n      \"pmids\": [\"24843120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of client selectivity not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated PCBP1 is individually essential and non-redundant with PCBP2 through peri-implantation embryonic lethality of the null mouse.\",\n      \"evidence\": \"Pcbp1 germline knockout mouse phenotyping\",\n      \"pmids\": [\"26527618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which molecular function underlies lethality not isolated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped the splicing-regulatory mechanism: phospho-SMAD3 partners with PCBP1 in nuclear speckles to inhibit spliceosome assembly on CD44, and defined the KH-domain consensus disrupted by Ser43 phosphorylation.\",\n      \"evidence\": \"Reciprocal co-IP, RIP, colocalization, phospho-mutant epistasis, binding kinetics, and cell-cycle phenotyping\",\n      \"pmids\": [\"27746021\", \"27067543\", \"27102006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide splicing target set incomplete\", \"structural model of the PCBP1-spliceosome interface lacking\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined PCBP1's role in erythropoiesis as a ferritin iron donor whose iron-dependent protein interaction supports heme synthesis, with knockout mice showing microcytic anemia.\",\n      \"evidence\": \"Pcbp1 knockout mouse, ex vivo erythroid differentiation, ferritin iron-flux and in vitro protein-interaction assays\",\n      \"pmids\": [\"28375153\", \"29032941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination with NCOA4-mediated ferritinophagy not fully mechanistically integrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded the regulatory repertoire to miRNA processing, splicing co-factor complexes, and an autoregulatory loop, broadening PCBP1's reach across RNA metabolism.\",\n      \"evidence\": \"AGO2 co-IP and hypomorphic mouse (miRNA); TIA1/RBM39 complex co-IP and spliceosome assays; in vitro RNA binding for autoregulation\",\n      \"pmids\": [\"28381556\", \"28193846\", \"28250194\", \"28077174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical role within the miRNA machinery not reconstituted\", \"single-lab findings\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked iron status to immune and apoptotic outcomes: iron protects PCBP1 from caspase cleavage to sustain Csf2 mRNA stability, and oxidized-RNA sensing via two 8-oxoG residues drives apoptosis.\",\n      \"evidence\": \"T-cell-specific knockout with EAE, mRNA stability and caspase assays; CRISPR KO with oxidized-RNA binding and caspase/PARP readouts\",\n      \"pmids\": [\"29958803\", \"29891675\", \"30086790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single protein integrates iron, RNA oxidation and apoptosis mechanistically not unified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural-biochemical basis of iron chaperoning, showing Fe(II) coordination by Cys/Glu plus glutathione and handoff to BolA2 for [2Fe-2S] assembly, linking ferrous-iron and Fe-S systems.\",\n      \"evidence\": \"Interactome proteomics, in vitro reconstitution of Fe-GSH-PCBP1-BolA2 complex, mutagenesis of coordinating residues, cluster-assembly assays\",\n      \"pmids\": [\"31406370\", \"31223278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the metallated complex not resolved\", \"in-cell flux through the pathway not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed paralog-specific and innate-immune functions \\u2014 PCBP1 vs PCBP2 produce opposing apoptotic outcomes on 8-oxoG-RNA, and PCBP1 directly binds DNA to promote cGAS activation.\",\n      \"evidence\": \"CRISPR KO of both paralogs with rescue; biochemical purification, DNA-binding and cGAS activation assays; checkpoint/Treg phenotyping\",\n      \"pmids\": [\"32647012\", \"32415261\", \"32523987\", \"32440711\", \"32067958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for opposite PCBP1/PCBP2 effects unknown\", \"mechanism of DNA-dependent cGAS enhancement undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified upstream control and new effector roles: ARIH1 ubiquitinates PCBP1 to drive EMT, PCBP1 adapts NAT10 for mRNA ac4C modification, and binds poly(C) DNA recruiting DHX9 to resolve R-loops.\",\n      \"evidence\": \"Y2H/co-IP/ubiquitination (ARIH1); complex co-IP and ac4C mapping (NAT10/TDP43); ChIP-seq, helicase co-IP and R-loop assays; FosB splicing conditional KO\",\n      \"pmids\": [\"35102251\", \"39556689\", \"39342995\", \"35730718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DHX9-binding interface unmapped\", \"physiological scope of ac4C adapter role unclear\", \"single-lab studies\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended PCBP1 mRNA-stability control across cancer contexts (LACTB, TPM3, DKK1, CCL2), tying it to ferroptosis, Wnt signaling, and inflammation.\",\n      \"evidence\": \"RIP, RNA pulldown, luciferase, and mRNA-stability assays with conditional knockout for CCL2/colitis\",\n      \"pmids\": [\"37157950\", \"36702545\", \"35287546\", \"35907982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding-site consensus across these targets not unified\", \"several are low-confidence single-assay studies\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a metabolic PTM switch \\u2014 OGT-mediated O-GlcNAcylation at Thr99 disrupts PCBP1 binding to ZEB2 mRNA to derepress translation and drive metastasis.\",\n      \"evidence\": \"T99 site mutagenesis, RIP, in vitro OGT modification, polysome profiling, and in vivo metastasis models\",\n      \"pmids\": [\"41117067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between O-GlcNAcylation and phosphorylation switches not resolved\", \"single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PCBP1 partitions among its iron-chaperone, translational-silencing, mRNA-stabilizing, splicing, and DNA-binding activities within a single cell, and what structural states underlie each, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of how one KH-domain protein switches between RNA, DNA and iron-binding modes\", \"Quantitative apportionment of cellular PCBP1 among functions unknown\", \"Cross-talk among phosphorylation, homocysteinylation, O-GlcNAcylation and ubiquitination not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 12, 17, 25, 26, 27]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [30, 40]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [7, 13, 19, 28]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 4, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 16, 22, 39]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [9, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 13, 28, 45]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 16, 38, 40]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [16, 40]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 16, 22, 39]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 13, 19, 28, 35]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 25, 30, 34, 42]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 40]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 19, 36]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [25, 26, 46]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PCBP2\", \"SMAD3\", \"DHX9\", \"NAT10\", \"AGO2\", \"BolA2\", \"ARIH1\", \"TIA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}