{"gene":"PFN1","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2021,"finding":"ALS-linked PFN1 variants G118V and M114T show differential binding to formin proteins compared to wild-type PFN1, and both augment formin-mediated actin assembly in vitro; molecular dynamics simulations revealed mutation-induced changes in internal dynamic couplings within an alpha helix that contacts both actin and polyproline. C71G variant showed severe destabilization resulting in loss-of-function in actin assembly.","method":"Unbiased proteomics (MS interactome), in vitro actin assembly assay, molecular dynamics simulations, mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (proteomics, in vitro actin assay, MD simulations) in single study with functional validation","pmids":["34074767"],"is_preprint":false},{"year":2019,"finding":"PFN1 interaction with VASP is required for efficient cell migration; this interaction is promoted by cell-substrate adhesion and requires downregulation of PKA activity. PKA-mediated phosphorylation of PFN1 at Ser137 negatively regulates the PFN1-VASP interaction.","method":"Mutagenesis in overexpression and knockdown-rescue settings, cell migration assays, PKA inhibitor/activator experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis with rescue experiments and multiple orthogonal functional readouts","pmids":["30814249"],"is_preprint":false},{"year":2016,"finding":"Mutant PFN1 (C71G) causes ALS by a gain of toxicity mechanism; transgenic mice expressing C71G mutant develop progressive motor neuron loss, form insoluble aggregates, disrupt cytoskeletal structure, and elevate ubiquitin and p62/SQSTM1 levels. Motor neuron degeneration precedes aggregate accumulation, indicating aggregation is not the trigger.","method":"Transgenic mouse model (C71G and WT), histopathology, immunostaining, behavioral assessment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean transgenic KO/KI model with defined cellular phenotype and multiple readouts","pmids":["27681617"],"is_preprint":false},{"year":2024,"finding":"ALS-linked mutant PFN1 shows enhanced binding affinity for PI3P (a critical signaling molecule in autophagic and endocytic processing), impairing autophagy and phagocytosis in iPSC-derived microglia; rapamycin rescued phagocytic dysfunction, implicating a gain-of-toxic function in autophagic and endo-lysosomal pathways.","method":"iPSC-derived microglia (iMGs), PI3P binding assay, phagocytosis assay, rapamycin rescue, lipid metabolism profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — human iPSC-derived cells with multiple orthogonal methods and pharmacological rescue","pmids":["38509062"],"is_preprint":false},{"year":2022,"finding":"The ALS-associated M114T PFN1 mutation destabilizes the protein and deregulates the RAB9-mediated alternative autophagy pathway involved in clearance of damaged mitochondria; motor neurons expressing M114T showed mitochondrial abnormalities.","method":"Patient lymphoblasts, transfected cell lines, lentiviral transgenic mice, autophagy pathway marker analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — patient cells and animal model with multiple readouts, single lab","pmids":["35628504"],"is_preprint":false},{"year":2021,"finding":"SH3BGRL promotes degradation of PFN1 by accelerating translation of the PFN1 E3 ubiquitin ligase STUB1 via interaction with ribosomal proteins, and by enhancing PFN1-STUB1 interaction; loss of PFN1 activates AKT, NF-kB, and WNT signaling pathways.","method":"Co-immunoprecipitation, western blot, overexpression/knockdown, in vivo xenograft, clinical tissue analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus functional rescue experiments, single lab with multiple orthogonal methods","pmids":["34331014"],"is_preprint":false},{"year":2022,"finding":"FBXL4 interacts with PFN1 and promotes its K48-linked ubiquitination at lysine 70, leading to proteasomal degradation of PFN1 and preservation of sarcomeric integrity in the heart.","method":"Co-immunoprecipitation, ubiquitination assay, site-specific mutagenesis, cardiac-specific KO and OE mouse models, AAV9 rescue","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 — specific ubiquitination site identified by mutagenesis, validated in vivo with KO/KI and rescue","pmids":["41589689"],"is_preprint":false},{"year":2022,"finding":"UCA1 lncRNA physically binds USP14, functions as a scaffold to recruit USP14 to PFN1, inhibiting ubiquitination-dependent degradation of PFN1 and prolonging its half-life; stabilized PFN1 activates the RhoA/ROCK pathway to induce ROS production in endothelial cells.","method":"Co-immunoprecipitation, exosome coculture, ubiquitination assay, RhoA/ROCK pathway analysis, endothelial dysfunction assay","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2-3 — protein-protein interaction and functional pathway data, single lab","pmids":["36160709"],"is_preprint":false},{"year":2020,"finding":"A frameshift mutation (D107Rfs*3) in PFN1 causing loss of the C-terminal domain leads to increased osteoclastogenesis with PDB-like features; PFN1 silencing in murine bone marrow-derived monocytes recapitulated the phenotype, implicating PFN1 loss-of-function in promoting enhanced osteoclast motility and actin ring formation.","method":"In vitro osteoclastogenesis from patient PBMCs, PFN1 silencing in murine bone marrow monocytes, whole exome sequencing","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — functional loss-of-function experiments in primary human and murine cells with defined phenotype","pmids":["32392277"],"is_preprint":false},{"year":2025,"finding":"PFN1 L112P mutation leads to enhanced actin ring-like structures at bone surfaces in osteoclast cultures without affecting NF-κB activation, causing early-onset Paget disease of bone phenotype in heterozygous knock-in mice.","method":"Heterozygous knock-in mouse model, osteoclast culture, actin ring staining, NF-κB activation assay","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse model with defined cellular mechanism, single lab","pmids":["40458045"],"is_preprint":false},{"year":2020,"finding":"Detergent-insoluble PFN1 inclusions are the first pathology in transgenic rats expressing mutant PFN1 C71G, preceding motor neuron loss and ALS-like symptoms, indicating protein aggregation is involved in neurodegeneration initiation.","method":"Genomic DNA transgenic rat model, detergent fractionation, histopathology, behavioral assessment","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean genomic transgenic model with temporal analysis of pathology, single lab","pmids":["32754913"],"is_preprint":false},{"year":2023,"finding":"Detergent-insoluble mutant PFN1 from paralyzed ALS rats seeds PFN1 inclusions and accelerates ALS-like phenotypes when administered to pre-symptomatic recipient mutant PFN1 rats; pathogenic PFN1 showed enhanced affinity for the molecular chaperone DNAJB6, sequestering it within inclusions.","method":"Intramuscular injection of spinal cord extracts, immunohistochemistry, co-immunoprecipitation for DNAJB6 interaction","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo seeding experiment with binding partner identification, single lab","pmids":["37817804"],"is_preprint":false},{"year":2022,"finding":"PFN1 binds Cdc42, activates it, and through Cdc42 increases phosphorylation of PAK, which further activates JNK phosphorylation, thereby inhibiting myogenic differentiation of bovine skeletal muscle satellite cells.","method":"Co-immunoprecipitation combined with mass spectrometry, phosphorylation assays, knockdown/overexpression, myogenic differentiation assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP/MS identification of binding partner with pathway validation, single lab","pmids":["36291059"],"is_preprint":false},{"year":2017,"finding":"In Drosophila motor neurons, wild-type human PFN1 expression increases ghost boutons, active zone density, F-actin content, and filopodia formation at NMJ; ALS-causative PFN1 mutants display partial loss of these functions, indicating partial loss-of-function in promoting NMJ remodeling.","method":"Drosophila transgenic model expressing human PFN1, NMJ morphology analysis, locomotion and lifespan assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — ortholog model (Drosophila) with direct comparison of WT vs. mutant in defined cellular context","pmids":["28379367"],"is_preprint":false},{"year":2015,"finding":"Nicotine induces PFN1 overexpression in mouse testis (specifically in elongated spermatids) via Pfn1 promoter hypomethylation, which promotes actin polymerization and enhances sperm motility.","method":"2D gel electrophoresis, mass spectrometry, promoter methylation analysis, sperm motility measurement","journal":"Andrology","confidence":"Medium","confidence_rationale":"Tier 2-3 — epigenetic mechanism identified with functional readout, single lab","pmids":["26311342"],"is_preprint":false},{"year":2024,"finding":"OA increases while EPA decreases acetylation of PFN1, affecting its localization to the leading edge of prostate cancer cells, with OA promoting and EPA inhibiting lamellipodia/filopodia formation and cell migration.","method":"Global acetylome profiling, immunofluorescence, cell migration and invasion assays","journal":"Proteomics","confidence":"Low","confidence_rationale":"Tier 3 — acetylation identified by proteomics but specific site and writer not determined; single lab","pmids":["38430206"],"is_preprint":false},{"year":2019,"finding":"PFN1 knockdown in fibroblast limbal stem cells inhibits the integrin-β1/mTOR pathway and reduces NANOG expression, promoting epithelial lineage differentiation; resveratrol reduces PFN1 expression and similarly promotes differentiation.","method":"shRNA knockdown, western blot, gene expression analysis, resveratrol treatment","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — knockdown with pathway readout but mechanistic link between PFN1 and integrin-β1/mTOR not directly established","pmids":["31513338"],"is_preprint":false}],"current_model":"PFN1 (Profilin-1) is a small actin-binding protein that promotes actin polymerization by binding monomeric actin and polyproline-motif-containing proteins (including formins and VASP), with its interaction with VASP regulated by PKA-mediated phosphorylation at Ser137; ALS-linked mutations differentially affect PFN1 stability and function—severely destabilizing mutations (C71G) cause loss-of-function in actin assembly while other mutations (G118V, M114T) gain enhanced formin-mediated actin polymerization; mutant PFN1 forms detergent-insoluble aggregates with prion-like seeding properties, sequesters the chaperone DNAJB6, gains enhanced binding to PI3P to disrupt autophagy/endolysosomal pathways, and activates the RAB9-mediated alternative autophagy pathway; PFN1 protein stability is regulated by the E3 ligase FBXL4 through K48-linked ubiquitination at K70 and by STUB1, while USP14-mediated deubiquitination (scaffolded by UCA1) stabilizes PFN1 and activates RhoA/ROCK signaling; in osteoclasts, PFN1 loss-of-function enhances actin ring formation promoting Paget-like bone disease."},"narrative":{"teleology":[{"year":2015,"claim":"Establishing that PFN1 expression is epigenetically regulated and functionally linked to actin polymerization in vivo, nicotine-induced promoter hypomethylation increased PFN1 in spermatids and enhanced sperm motility through actin polymerization.","evidence":"2D gel electrophoresis, mass spectrometry, promoter methylation analysis, and sperm motility measurement in mouse testis","pmids":["26311342"],"confidence":"Medium","gaps":["Specific methylation sites on PFN1 promoter not mapped","Whether actin polymerization is the sole mediator of motility change not tested"]},{"year":2016,"claim":"Resolving whether ALS-linked PFN1 C71G causes disease through loss- or gain-of-function, transgenic mice showed that mutant PFN1 produces motor neuron degeneration preceding aggregate formation, establishing a gain-of-toxicity mechanism distinct from simple aggregation.","evidence":"Transgenic mouse model expressing C71G and WT PFN1 with histopathology, immunostaining, and behavioral assessment","pmids":["27681617"],"confidence":"High","gaps":["Precise toxic species (soluble oligomers vs. other conformers) not identified","Whether endogenous wild-type PFN1 contributes to or is sequestered by mutant unclear"]},{"year":2017,"claim":"Demonstrating PFN1's role at the neuromuscular junction, wild-type human PFN1 expression in Drosophila motor neurons increased active zone density, F-actin content, and filopodia, while ALS mutants showed partial loss of these functions.","evidence":"Drosophila transgenic model expressing human PFN1 variants with NMJ morphology analysis","pmids":["28379367"],"confidence":"Medium","gaps":["Cross-species differences between Drosophila chickadee and human PFN1 not fully controlled for","Whether NMJ remodeling defects are cell-autonomous not tested"]},{"year":2019,"claim":"Identifying how PFN1's interaction with VASP is regulated, PKA-mediated phosphorylation at Ser137 was shown to negatively regulate PFN1–VASP binding, and this interaction was required for efficient cell migration downstream of cell-substrate adhesion.","evidence":"Mutagenesis in knockdown-rescue settings with cell migration assays and PKA inhibitor/activator experiments","pmids":["30814249"],"confidence":"High","gaps":["Whether other kinases phosphorylate Ser137 in vivo not addressed","Structural basis of how pSer137 disrupts VASP binding not resolved"]},{"year":2020,"claim":"Establishing PFN1 loss-of-function in bone biology, a frameshift mutation truncating PFN1's C-terminus caused enhanced osteoclastogenesis with Paget-like features, and PFN1 silencing recapitulated the phenotype, linking PFN1 to osteoclast actin ring regulation.","evidence":"Patient PBMC-derived osteoclasts, murine bone marrow monocyte silencing, whole exome sequencing","pmids":["32392277"],"confidence":"Medium","gaps":["Whether PFN1 directly restrains actin ring formation or acts through intermediate effectors unknown","Penetrance and modifier genes in human disease not characterized"]},{"year":2020,"claim":"Clarifying the temporal sequence of ALS pathology, detergent-insoluble PFN1 C71G inclusions were shown to be the earliest pathological event in transgenic rats, preceding motor neuron loss—contrasting with the mouse model where degeneration preceded aggregation.","evidence":"Genomic DNA transgenic rat model with detergent fractionation, histopathology, and temporal analysis","pmids":["32754913"],"confidence":"Medium","gaps":["Discrepancy with mouse model regarding aggregation timing not reconciled","Whether inclusions are causative or correlative remains debated"]},{"year":2021,"claim":"Revealing that different ALS mutations alter PFN1 function through distinct mechanisms, G118V and M114T gained enhanced formin-mediated actin assembly through altered internal dynamic couplings, while C71G was severely destabilized causing loss-of-function in actin assembly.","evidence":"Unbiased proteomics, in vitro actin assembly assays, molecular dynamics simulations, and mutagenesis","pmids":["34074767"],"confidence":"High","gaps":["Whether enhanced formin-mediated polymerization is toxic in vivo not demonstrated","Which specific formins are most affected in motor neurons not determined"]},{"year":2021,"claim":"Identifying a ubiquitin-proteasome axis controlling PFN1 levels, SH3BGRL was found to promote PFN1 degradation by enhancing STUB1 translation and PFN1–STUB1 interaction, with PFN1 loss activating AKT, NF-κB, and WNT signaling.","evidence":"Co-immunoprecipitation, overexpression/knockdown, in vivo xenograft, and clinical tissue analysis","pmids":["34331014"],"confidence":"Medium","gaps":["Specific ubiquitination sites by STUB1 on PFN1 not mapped","Whether STUB1-mediated degradation operates in neurons not tested"]},{"year":2022,"claim":"Defining a precise ubiquitination site governing PFN1 turnover, FBXL4 was shown to promote K48-linked ubiquitination of PFN1 at K70, and cardiac-specific FBXL4 knockout demonstrated that PFN1 accumulation disrupts sarcomeric integrity.","evidence":"Co-immunoprecipitation, ubiquitination assay, K70 mutagenesis, cardiac-specific KO/OE mouse models with AAV9 rescue","pmids":["41589689"],"confidence":"High","gaps":["Whether FBXL4 and STUB1 act redundantly or in distinct tissues not resolved","PFN1 interactome changes upon K70 ubiquitination not characterized"]},{"year":2022,"claim":"Identifying a deubiquitination mechanism that stabilizes PFN1, the lncRNA UCA1 was shown to scaffold USP14 recruitment to PFN1, inhibiting its ubiquitin-dependent degradation and activating RhoA/ROCK-mediated ROS production in endothelial cells.","evidence":"Co-immunoprecipitation, exosome coculture, ubiquitination assay, RhoA/ROCK pathway analysis","pmids":["36160709"],"confidence":"Medium","gaps":["Direct USP14 deubiquitination of PFN1 not shown with purified components","Whether UCA1-USP14-PFN1 axis operates outside endothelial cells unknown"]},{"year":2022,"claim":"Expanding PFN1's signaling repertoire beyond actin, PFN1 was found to bind and activate Cdc42, triggering PAK–JNK phosphorylation and inhibiting myogenic differentiation in skeletal muscle satellite cells.","evidence":"Co-immunoprecipitation with mass spectrometry, phosphorylation assays, knockdown/overexpression in bovine satellite cells","pmids":["36291059"],"confidence":"Medium","gaps":["Whether PFN1–Cdc42 binding is direct or bridged by actin not resolved","Relevance to human myogenesis not tested"]},{"year":2022,"claim":"Linking PFN1 mutations to alternative autophagy, M114T PFN1 was shown to deregulate the RAB9-mediated alternative autophagy pathway and cause mitochondrial abnormalities in motor neurons.","evidence":"Patient lymphoblasts, transfected cell lines, lentiviral transgenic mice, autophagy marker analysis","pmids":["35628504"],"confidence":"Medium","gaps":["Whether RAB9 pathway activation is a direct consequence of PFN1 destabilization or secondary not clear","Which mitochondrial clearance step is impaired not defined"]},{"year":2023,"claim":"Establishing prion-like properties of mutant PFN1, insoluble PFN1 from paralyzed ALS rats seeded inclusions and accelerated disease in recipient animals, while pathogenic PFN1 sequestered the chaperone DNAJB6 within inclusions.","evidence":"Intramuscular injection of spinal cord extracts in pre-symptomatic mutant PFN1 rats, co-immunoprecipitation for DNAJB6","pmids":["37817804"],"confidence":"Medium","gaps":["Whether seeding occurs in sporadic ALS without PFN1 mutations unknown","Whether DNAJB6 sequestration is causal for toxicity or a bystander effect not tested"]},{"year":2024,"claim":"Identifying a lipid-binding gain-of-function in ALS-mutant PFN1, enhanced PI3P binding was shown to impair autophagy and phagocytosis in iPSC-derived microglia, with rapamycin rescuing the phagocytic defect.","evidence":"iPSC-derived microglia, PI3P binding assay, phagocytosis assay, rapamycin rescue, lipid profiling","pmids":["38509062"],"confidence":"High","gaps":["Whether PI3P binding enhancement occurs in motor neurons not tested","Structural basis for enhanced PI3P affinity of mutant PFN1 not determined"]},{"year":2025,"claim":"Confirming PFN1 loss-of-function in bone disease with a knock-in model, heterozygous L112P mice developed early-onset Paget disease phenotype through enhanced osteoclast actin ring structures independent of NF-κB activation.","evidence":"Heterozygous knock-in mouse model, osteoclast culture, actin ring staining, NF-κB assay","pmids":["40458045"],"confidence":"Medium","gaps":["Whether L112P affects PFN1 stability or specifically actin-binding not characterized","Osteoblast contributions to the bone phenotype not assessed"]},{"year":null,"claim":"Major open questions include: how the same protein produces both gain- and loss-of-function disease phenotypes across cell types; the structural basis for enhanced PI3P binding by ALS mutants; whether FBXL4/STUB1 ubiquitination axes are relevant in motor neurons; and whether prion-like PFN1 seeding contributes to sporadic ALS.","evidence":"","pmids":[],"confidence":"Low","gaps":["Cell-type-specific determinants of PFN1 toxicity vs. loss-of-function not mapped","No high-resolution structure of disease-mutant PFN1 bound to PI3P","Whether therapeutic modulation of PFN1 stability would be beneficial or detrimental in ALS not known"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,2,13,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,8,9,13,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,10,11]}],"complexes":[],"partners":["VASP","FBXL4","STUB1","USP14","DNAJB6","CDC42"],"other_free_text":[]},"mechanistic_narrative":"PFN1 (Profilin-1) is a central regulator of actin dynamics that promotes actin polymerization through direct binding of monomeric actin and polyproline-motif-containing partners such as formins and VASP, with its interaction with VASP negatively regulated by PKA-mediated phosphorylation at Ser137 [PMID:30814249, PMID:34074767]. PFN1 protein stability is controlled by K48-linked ubiquitination at K70 mediated by the E3 ligase FBXL4 and by STUB1, while the deubiquitinase USP14 (scaffolded by lncRNA UCA1) stabilizes PFN1 to activate RhoA/ROCK signaling [PMID:41589689, PMID:34331014, PMID:36160709]. Mutations in PFN1 cause familial ALS through divergent mechanisms: severely destabilizing mutations (C71G) produce toxic aggregates with prion-like seeding properties that sequester the chaperone DNAJB6, while partially destabilizing mutations (G118V, M114T) gain enhanced formin-mediated actin assembly and disrupt autophagy/endolysosomal pathways through enhanced PI3P binding [PMID:27681617, PMID:37817804, PMID:34074767, PMID:38509062]. Loss-of-function PFN1 mutations also cause early-onset Paget disease of bone by enhancing osteoclast actin ring formation and motility [PMID:32392277, PMID:40458045]."},"prefetch_data":{"uniprot":{"accession":"P07737","full_name":"Profilin-1","aliases":["Epididymis tissue protein Li 184a","Profilin I"],"length_aa":140,"mass_kda":15.1,"function":"Binds to actin and affects the structure of the cytoskeleton. At high concentrations, profilin prevents the polymerization of actin, whereas it enhances it at low concentrations. By binding to PIP2, it inhibits the formation of IP3 and DG. Inhibits androgen receptor (AR) and HTT aggregation and binding of G-actin is essential for its inhibition of AR","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P07737/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PFN1","classification":"Common Essential","n_dependent_lines":975,"n_total_lines":1208,"dependency_fraction":0.8071192052980133},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000108518","cell_line_id":"CID000619","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"ACTB","stoichiometry":10.0},{"gene":"ACTG1","stoichiometry":10.0},{"gene":"RPS4X","stoichiometry":4.0},{"gene":"ACTR2","stoichiometry":0.2},{"gene":"FDPS","stoichiometry":0.2},{"gene":"INPPL1","stoichiometry":0.2},{"gene":"CYFIP1","stoichiometry":0.2},{"gene":"NHSL1","stoichiometry":0.2},{"gene":"BRK1","stoichiometry":0.2},{"gene":"SOWAHC","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000619","total_profiled":1310},"omim":[{"mim_id":"620475","title":"THROMBOCYTOPENIA 8, WITH DYSMORPHIC FEATURES AND DEVELOPMENTAL DELAY; THC8","url":"https://www.omim.org/entry/620475"},{"mim_id":"617861","title":"MYB-RELATED TRANSCRIPTION FACTOR, PARTNER OF PROFILIN; MYPOP","url":"https://www.omim.org/entry/617861"},{"mim_id":"616912","title":"ENAH/VASP-LIKE PROTEIN; EVL","url":"https://www.omim.org/entry/616912"},{"mim_id":"614808","title":"AMYOTROPHIC LATERAL SCLEROSIS 18; ALS18","url":"https://www.omim.org/entry/614808"},{"mim_id":"612812","title":"PROFILIN 3; PFN3","url":"https://www.omim.org/entry/612812"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PFN1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P07737","domains":[{"cath_id":"3.30.450.30","chopping":"1-140","consensus_level":"medium","plddt":95.7254,"start":1,"end":140}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07737","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07737-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07737-F1-predicted_aligned_error_v6.png","plddt_mean":95.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PFN1","jax_strain_url":"https://www.jax.org/strain/search?query=PFN1"},"sequence":{"accession":"P07737","fasta_url":"https://rest.uniprot.org/uniprotkb/P07737.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07737/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07737"}},"corpus_meta":[{"pmid":"27681617","id":"PMC_27681617","title":"Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27681617","citation_count":88,"is_preprint":false},{"pmid":"15365097","id":"PMC_15365097","title":"The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene.","date":"2004","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15365097","citation_count":62,"is_preprint":false},{"pmid":"23428184","id":"PMC_23428184","title":"PFN1 mutations are rare in Han Chinese populations with amyotrophic lateral sclerosis.","date":"2013","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/23428184","citation_count":54,"is_preprint":false},{"pmid":"31863778","id":"PMC_31863778","title":"HLA-F-AS1/miR-330-3p/PFN1 axis promotes colorectal cancer progression.","date":"2019","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31863778","citation_count":50,"is_preprint":false},{"pmid":"34074767","id":"PMC_34074767","title":"ALS-linked PFN1 variants exhibit loss and gain of functions in the context of formin-induced actin polymerization.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34074767","citation_count":37,"is_preprint":false},{"pmid":"23312802","id":"PMC_23312802","title":"Explorative genetic study of UBQLN2 and PFN1 in an extended Flanders-Belgian cohort of frontotemporal lobar degeneration patients.","date":"2013","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/23312802","citation_count":34,"is_preprint":false},{"pmid":"23063648","id":"PMC_23063648","title":"Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia.","date":"2012","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/23063648","citation_count":33,"is_preprint":false},{"pmid":"33531647","id":"PMC_33531647","title":"LncRNA HLA-F-AS1 promotes colorectal cancer metastasis by inducing PFN1 in colorectal cancer-derived extracellular vesicles and mediating macrophage polarization.","date":"2021","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33531647","citation_count":33,"is_preprint":false},{"pmid":"23062600","id":"PMC_23062600","title":"Mutation analysis of PFN1 in familial amyotrophic lateral sclerosis patients.","date":"2012","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/23062600","citation_count":32,"is_preprint":false},{"pmid":"32606965","id":"PMC_32606965","title":"Knockdown of lncRNA HCP5 Suppresses the Progression of Colorectal Cancer by miR-299-3p/PFN1/AKT Axis.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32606965","citation_count":22,"is_preprint":false},{"pmid":"23182804","id":"PMC_23182804","title":"Mutations in the PFN1 gene are not a common cause in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration in France.","date":"2012","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/23182804","citation_count":22,"is_preprint":false},{"pmid":"26311342","id":"PMC_26311342","title":"Nicotine elevates sperm motility and induces Pfn1 promoter hypomethylation in mouse testis.","date":"2015","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/26311342","citation_count":20,"is_preprint":false},{"pmid":"38509062","id":"PMC_38509062","title":"Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38509062","citation_count":19,"is_preprint":false},{"pmid":"32392277","id":"PMC_32392277","title":"Mutation of PFN1 Gene in an Early Onset, Polyostotic Paget-like Disease.","date":"2020","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32392277","citation_count":19,"is_preprint":false},{"pmid":"30814249","id":"PMC_30814249","title":"The VASP-profilin1 (Pfn1) interaction is critical for efficient cell migration and is regulated by cell-substrate adhesion in a PKA-dependent manner.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30814249","citation_count":19,"is_preprint":false},{"pmid":"36160709","id":"PMC_36160709","title":"Trophoblast Exosomal UCA1 Induces Endothelial Injury through the PFN1-RhoA/ROCK Pathway in Preeclampsia: A Human-Specific Adaptive Pathogenic Mechanism.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36160709","citation_count":18,"is_preprint":false},{"pmid":"33942976","id":"PMC_33942976","title":"A novel lncRNA promotes myogenesis of bovine skeletal muscle satellite cells via PFN1-RhoA/Rac1.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33942976","citation_count":18,"is_preprint":false},{"pmid":"35628504","id":"PMC_35628504","title":"The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35628504","citation_count":17,"is_preprint":false},{"pmid":"23635659","id":"PMC_23635659","title":"Mutation analysis and immunopathological studies of PFN1 in familial and sporadic amyotrophic lateral sclerosis.","date":"2013","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/23635659","citation_count":17,"is_preprint":false},{"pmid":"36496032","id":"PMC_36496032","title":"LncRNA PEG11as aggravates cerebral ischemia/reperfusion injury after ischemic stroke through miR-342-5p/PFN1 axis.","date":"2022","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36496032","citation_count":15,"is_preprint":false},{"pmid":"34331014","id":"PMC_34331014","title":"Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34331014","citation_count":15,"is_preprint":false},{"pmid":"30203378","id":"PMC_30203378","title":"Changes in biophysical characteristics of PFN1 due to mutation causing amyotrophic lateral sclerosis.","date":"2018","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/30203378","citation_count":13,"is_preprint":false},{"pmid":"35148999","id":"PMC_35148999","title":"PFN1 Prevents Psoriasis Pathogenesis through IκBζ Regulation.","date":"2022","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/35148999","citation_count":13,"is_preprint":false},{"pmid":"31216283","id":"PMC_31216283","title":"In silico analysis of PFN1 related to amyotrophic lateral sclerosis.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31216283","citation_count":11,"is_preprint":false},{"pmid":"31611772","id":"PMC_31611772","title":"Developmental Expression of Mutant PFN1 in Motor Neurons Impacts Neuronal Growth and Motor Performance of Young and Adult Mice.","date":"2019","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31611772","citation_count":10,"is_preprint":false},{"pmid":"28379367","id":"PMC_28379367","title":"A Drosophila model of ALS reveals a partial loss of function of causative human PFN1 mutants.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28379367","citation_count":10,"is_preprint":false},{"pmid":"31513338","id":"PMC_31513338","title":"PFN1 and integrin-β1/mTOR axis involvement in cornea differentiation of fibroblast limbal stem cells.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31513338","citation_count":8,"is_preprint":false},{"pmid":"32754913","id":"PMC_32754913","title":"Detergent-insoluble inclusion constitutes the first pathology in PFN1 transgenic rats.","date":"2020","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32754913","citation_count":7,"is_preprint":false},{"pmid":"36291059","id":"PMC_36291059","title":"PFN1 Inhibits Myogenesis of Bovine Myoblast Cells via Cdc42-PAK/JNK.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36291059","citation_count":7,"is_preprint":false},{"pmid":"37820747","id":"PMC_37820747","title":"Long noncoding RNA RMRP ameliorates doxorubicin-induced apoptosis by interacting with PFN1 in a P53-Dependent manner.","date":"2023","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/37820747","citation_count":6,"is_preprint":false},{"pmid":"28541412","id":"PMC_28541412","title":"Association Study of Common Variants in PFN1 With Hypertension in a Han Chinese Population: A Case-Control Study and A Follow-up Study.","date":"2017","source":"American journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/28541412","citation_count":6,"is_preprint":false},{"pmid":"37728743","id":"PMC_37728743","title":"Genetic Screening of ZNF687 and PFN1 in a Paget's Disease of Bone Cohort Indicates an Important Role for the Nuclear Localization Signal of ZNF687.","date":"2023","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/37728743","citation_count":4,"is_preprint":false},{"pmid":"38430206","id":"PMC_38430206","title":"Global acetylome profiling indicates EPA impedes but OA promotes prostate cancer motility through altered acetylation of PFN1 and FLNA.","date":"2024","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/38430206","citation_count":4,"is_preprint":false},{"pmid":"30621420","id":"PMC_30621420","title":"Exploring the binding mechanism between human profilin (PFN1) and polyproline-10 through binding mode screening.","date":"2019","source":"The Journal of chemical physics","url":"https://pubmed.ncbi.nlm.nih.gov/30621420","citation_count":4,"is_preprint":false},{"pmid":"25249294","id":"PMC_25249294","title":"PFN1 mutations are also rare in the Catalan population with amyotrophic lateral sclerosis.","date":"2014","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25249294","citation_count":4,"is_preprint":false},{"pmid":"36176198","id":"PMC_36176198","title":"Comparison between PFN1 and SOD1 mutations in amyotrophic lateral sclerosis.","date":"2022","source":"European journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36176198","citation_count":2,"is_preprint":false},{"pmid":"39715971","id":"PMC_39715971","title":"Overexpression of miR-328-3p Inhibits Epithelial-Mesenchymal Transition in Prostate Cancer by Downregulating PFN1.","date":"2024","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39715971","citation_count":2,"is_preprint":false},{"pmid":"40948612","id":"PMC_40948612","title":"MAIT Cells with High PFN1 Expression Mediate Immune Activation and Metabolic Reprogramming in Psoriasis.","date":"2025","source":"Clinical, cosmetic and investigational dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/40948612","citation_count":1,"is_preprint":false},{"pmid":"37401976","id":"PMC_37401976","title":"Association of PFN1 Gene Polymorphisms with Bone Mineral Density, Bone Turnover Markers, and Osteoporotic Fractures in Chinese Population.","date":"2023","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/37401976","citation_count":1,"is_preprint":false},{"pmid":"40413526","id":"PMC_40413526","title":"Viral-mediated knockdown of Atxn2 attenuates TDP-43 pathology and muscle dysfunction in the PFN1C71G ALS mouse model.","date":"2025","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/40413526","citation_count":1,"is_preprint":false},{"pmid":"37398081","id":"PMC_37398081","title":"Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37398081","citation_count":1,"is_preprint":false},{"pmid":"40458045","id":"PMC_40458045","title":"A Missense Mutation in Close Proximity of ALS-linked PFN1 Mutations Causes Only Early-onset Paget Disease of Bone.","date":"2025","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40458045","citation_count":1,"is_preprint":false},{"pmid":"34992429","id":"PMC_34992429","title":"PFN1 Gene Polymorphisms and the Bone Mineral Density Response to Alendronate Therapy in Postmenopausal Chinese Women with Low Bone Mass.","date":"2021","source":"Pharmacogenomics and personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34992429","citation_count":1,"is_preprint":false},{"pmid":"37895866","id":"PMC_37895866","title":"Osteolytic Bone Loss and Skeletal Deformities in a Mouse Model for Early-Onset Paget's Disease of Bone with PFN1 Mutation Are Treatable by Alendronate.","date":"2023","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37895866","citation_count":1,"is_preprint":false},{"pmid":"39120820","id":"PMC_39120820","title":"PFN1 Knockdown Aggravates Mitophagy to Retard Lung Adenocarcinoma Initiation and M2 Macrophage Polarization.","date":"2024","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39120820","citation_count":1,"is_preprint":false},{"pmid":"37817804","id":"PMC_37817804","title":"Detergent-insoluble PFN1 inoculation expedites disease onset and progression in PFN1 transgenic rats.","date":"2023","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37817804","citation_count":0,"is_preprint":false},{"pmid":"39621144","id":"PMC_39621144","title":"Circ_0000972 Inhibits Hepatocellular Carcinoma Cell Stemness by Targeting miR-96-5p/PFN1.","date":"2024","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39621144","citation_count":0,"is_preprint":false},{"pmid":"40587522","id":"PMC_40587522","title":"Metal Ion Nanodepots Orchestrate Neuronal Axon and Dendrite Growth via the Actin-PFN1 Pathway.","date":"2025","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/40587522","citation_count":0,"is_preprint":false},{"pmid":"36846111","id":"PMC_36846111","title":"Novel variant c.92T > G (p.Val31Gly) in the PFN1 gene (ALS18) responsible for a specific phenotype in a large Bulgarian amyotrophic lateral sclerosis pedigree.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36846111","citation_count":0,"is_preprint":false},{"pmid":"41589689","id":"PMC_41589689","title":"F-Box and Leucine-Rich Repeat Protein 4 (FBXL4) Maintains Sarcomere Integrity and Cardiac Function by Enhancing K48-Linked Ubiquitinated Degradation of Profilin-1 (PFN1).","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41589689","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.18.665115","title":"Small molecule intervention of actin-binding protein profilin1 reduces tumor angiogenesis in renal cell carcinoma","date":"2025-07-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.18.665115","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.29.668156","title":"Benchmarking of proximity-dependent biotinylation enzymes across cellular compartments and time windows","date":"2025-08-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.29.668156","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.14.676084","title":"Cell type specific analysis of ALS-associated proteins reveals immune-regulated targets","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.14.676084","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.09.612156","title":"Identification of novel myokines and putative protein targets that mediate functional adaptations in response to chronic contractile activity induced skeletal muscle-extracellular vesicle treatment","date":"2024-09-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.09.612156","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.17.24315623","title":"Identification of Shared and Unique Key Biomarkers of Alcohol Liver Cirrhosis and Non-Alcoholic Steatohepatitis Through Machine Learning Network-Based Algorithms","date":"2024-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.17.24315623","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.08.602491","title":"Aberrant remodelling of astrocytic architecture in acute hepatic encephalopathy: complexity of oedematic atrophic astrocytes","date":"2024-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.08.602491","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":29819,"output_tokens":3905,"usd":0.074016},"stage2":{"model":"claude-opus-4-6","input_tokens":7353,"output_tokens":3760,"usd":0.196148},"total_usd":0.270164,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"ALS-linked PFN1 variants G118V and M114T show differential binding to formin proteins compared to wild-type PFN1, and both augment formin-mediated actin assembly in vitro; molecular dynamics simulations revealed mutation-induced changes in internal dynamic couplings within an alpha helix that contacts both actin and polyproline. C71G variant showed severe destabilization resulting in loss-of-function in actin assembly.\",\n      \"method\": \"Unbiased proteomics (MS interactome), in vitro actin assembly assay, molecular dynamics simulations, mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (proteomics, in vitro actin assay, MD simulations) in single study with functional validation\",\n      \"pmids\": [\"34074767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PFN1 interaction with VASP is required for efficient cell migration; this interaction is promoted by cell-substrate adhesion and requires downregulation of PKA activity. PKA-mediated phosphorylation of PFN1 at Ser137 negatively regulates the PFN1-VASP interaction.\",\n      \"method\": \"Mutagenesis in overexpression and knockdown-rescue settings, cell migration assays, PKA inhibitor/activator experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with rescue experiments and multiple orthogonal functional readouts\",\n      \"pmids\": [\"30814249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutant PFN1 (C71G) causes ALS by a gain of toxicity mechanism; transgenic mice expressing C71G mutant develop progressive motor neuron loss, form insoluble aggregates, disrupt cytoskeletal structure, and elevate ubiquitin and p62/SQSTM1 levels. Motor neuron degeneration precedes aggregate accumulation, indicating aggregation is not the trigger.\",\n      \"method\": \"Transgenic mouse model (C71G and WT), histopathology, immunostaining, behavioral assessment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean transgenic KO/KI model with defined cellular phenotype and multiple readouts\",\n      \"pmids\": [\"27681617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALS-linked mutant PFN1 shows enhanced binding affinity for PI3P (a critical signaling molecule in autophagic and endocytic processing), impairing autophagy and phagocytosis in iPSC-derived microglia; rapamycin rescued phagocytic dysfunction, implicating a gain-of-toxic function in autophagic and endo-lysosomal pathways.\",\n      \"method\": \"iPSC-derived microglia (iMGs), PI3P binding assay, phagocytosis assay, rapamycin rescue, lipid metabolism profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human iPSC-derived cells with multiple orthogonal methods and pharmacological rescue\",\n      \"pmids\": [\"38509062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The ALS-associated M114T PFN1 mutation destabilizes the protein and deregulates the RAB9-mediated alternative autophagy pathway involved in clearance of damaged mitochondria; motor neurons expressing M114T showed mitochondrial abnormalities.\",\n      \"method\": \"Patient lymphoblasts, transfected cell lines, lentiviral transgenic mice, autophagy pathway marker analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient cells and animal model with multiple readouts, single lab\",\n      \"pmids\": [\"35628504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SH3BGRL promotes degradation of PFN1 by accelerating translation of the PFN1 E3 ubiquitin ligase STUB1 via interaction with ribosomal proteins, and by enhancing PFN1-STUB1 interaction; loss of PFN1 activates AKT, NF-kB, and WNT signaling pathways.\",\n      \"method\": \"Co-immunoprecipitation, western blot, overexpression/knockdown, in vivo xenograft, clinical tissue analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional rescue experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34331014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXL4 interacts with PFN1 and promotes its K48-linked ubiquitination at lysine 70, leading to proteasomal degradation of PFN1 and preservation of sarcomeric integrity in the heart.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-specific mutagenesis, cardiac-specific KO and OE mouse models, AAV9 rescue\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — specific ubiquitination site identified by mutagenesis, validated in vivo with KO/KI and rescue\",\n      \"pmids\": [\"41589689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UCA1 lncRNA physically binds USP14, functions as a scaffold to recruit USP14 to PFN1, inhibiting ubiquitination-dependent degradation of PFN1 and prolonging its half-life; stabilized PFN1 activates the RhoA/ROCK pathway to induce ROS production in endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation, exosome coculture, ubiquitination assay, RhoA/ROCK pathway analysis, endothelial dysfunction assay\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — protein-protein interaction and functional pathway data, single lab\",\n      \"pmids\": [\"36160709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A frameshift mutation (D107Rfs*3) in PFN1 causing loss of the C-terminal domain leads to increased osteoclastogenesis with PDB-like features; PFN1 silencing in murine bone marrow-derived monocytes recapitulated the phenotype, implicating PFN1 loss-of-function in promoting enhanced osteoclast motility and actin ring formation.\",\n      \"method\": \"In vitro osteoclastogenesis from patient PBMCs, PFN1 silencing in murine bone marrow monocytes, whole exome sequencing\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional loss-of-function experiments in primary human and murine cells with defined phenotype\",\n      \"pmids\": [\"32392277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PFN1 L112P mutation leads to enhanced actin ring-like structures at bone surfaces in osteoclast cultures without affecting NF-κB activation, causing early-onset Paget disease of bone phenotype in heterozygous knock-in mice.\",\n      \"method\": \"Heterozygous knock-in mouse model, osteoclast culture, actin ring staining, NF-κB activation assay\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with defined cellular mechanism, single lab\",\n      \"pmids\": [\"40458045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Detergent-insoluble PFN1 inclusions are the first pathology in transgenic rats expressing mutant PFN1 C71G, preceding motor neuron loss and ALS-like symptoms, indicating protein aggregation is involved in neurodegeneration initiation.\",\n      \"method\": \"Genomic DNA transgenic rat model, detergent fractionation, histopathology, behavioral assessment\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genomic transgenic model with temporal analysis of pathology, single lab\",\n      \"pmids\": [\"32754913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Detergent-insoluble mutant PFN1 from paralyzed ALS rats seeds PFN1 inclusions and accelerates ALS-like phenotypes when administered to pre-symptomatic recipient mutant PFN1 rats; pathogenic PFN1 showed enhanced affinity for the molecular chaperone DNAJB6, sequestering it within inclusions.\",\n      \"method\": \"Intramuscular injection of spinal cord extracts, immunohistochemistry, co-immunoprecipitation for DNAJB6 interaction\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo seeding experiment with binding partner identification, single lab\",\n      \"pmids\": [\"37817804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PFN1 binds Cdc42, activates it, and through Cdc42 increases phosphorylation of PAK, which further activates JNK phosphorylation, thereby inhibiting myogenic differentiation of bovine skeletal muscle satellite cells.\",\n      \"method\": \"Co-immunoprecipitation combined with mass spectrometry, phosphorylation assays, knockdown/overexpression, myogenic differentiation assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP/MS identification of binding partner with pathway validation, single lab\",\n      \"pmids\": [\"36291059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Drosophila motor neurons, wild-type human PFN1 expression increases ghost boutons, active zone density, F-actin content, and filopodia formation at NMJ; ALS-causative PFN1 mutants display partial loss of these functions, indicating partial loss-of-function in promoting NMJ remodeling.\",\n      \"method\": \"Drosophila transgenic model expressing human PFN1, NMJ morphology analysis, locomotion and lifespan assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ortholog model (Drosophila) with direct comparison of WT vs. mutant in defined cellular context\",\n      \"pmids\": [\"28379367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nicotine induces PFN1 overexpression in mouse testis (specifically in elongated spermatids) via Pfn1 promoter hypomethylation, which promotes actin polymerization and enhances sperm motility.\",\n      \"method\": \"2D gel electrophoresis, mass spectrometry, promoter methylation analysis, sperm motility measurement\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — epigenetic mechanism identified with functional readout, single lab\",\n      \"pmids\": [\"26311342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OA increases while EPA decreases acetylation of PFN1, affecting its localization to the leading edge of prostate cancer cells, with OA promoting and EPA inhibiting lamellipodia/filopodia formation and cell migration.\",\n      \"method\": \"Global acetylome profiling, immunofluorescence, cell migration and invasion assays\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — acetylation identified by proteomics but specific site and writer not determined; single lab\",\n      \"pmids\": [\"38430206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PFN1 knockdown in fibroblast limbal stem cells inhibits the integrin-β1/mTOR pathway and reduces NANOG expression, promoting epithelial lineage differentiation; resveratrol reduces PFN1 expression and similarly promotes differentiation.\",\n      \"method\": \"shRNA knockdown, western blot, gene expression analysis, resveratrol treatment\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — knockdown with pathway readout but mechanistic link between PFN1 and integrin-β1/mTOR not directly established\",\n      \"pmids\": [\"31513338\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PFN1 (Profilin-1) is a small actin-binding protein that promotes actin polymerization by binding monomeric actin and polyproline-motif-containing proteins (including formins and VASP), with its interaction with VASP regulated by PKA-mediated phosphorylation at Ser137; ALS-linked mutations differentially affect PFN1 stability and function—severely destabilizing mutations (C71G) cause loss-of-function in actin assembly while other mutations (G118V, M114T) gain enhanced formin-mediated actin polymerization; mutant PFN1 forms detergent-insoluble aggregates with prion-like seeding properties, sequesters the chaperone DNAJB6, gains enhanced binding to PI3P to disrupt autophagy/endolysosomal pathways, and activates the RAB9-mediated alternative autophagy pathway; PFN1 protein stability is regulated by the E3 ligase FBXL4 through K48-linked ubiquitination at K70 and by STUB1, while USP14-mediated deubiquitination (scaffolded by UCA1) stabilizes PFN1 and activates RhoA/ROCK signaling; in osteoclasts, PFN1 loss-of-function enhances actin ring formation promoting Paget-like bone disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PFN1 (Profilin-1) is a central regulator of actin dynamics that promotes actin polymerization through direct binding of monomeric actin and polyproline-motif-containing partners such as formins and VASP, with its interaction with VASP negatively regulated by PKA-mediated phosphorylation at Ser137 [PMID:30814249, PMID:34074767]. PFN1 protein stability is controlled by K48-linked ubiquitination at K70 mediated by the E3 ligase FBXL4 and by STUB1, while the deubiquitinase USP14 (scaffolded by lncRNA UCA1) stabilizes PFN1 to activate RhoA/ROCK signaling [PMID:41589689, PMID:34331014, PMID:36160709]. Mutations in PFN1 cause familial ALS through divergent mechanisms: severely destabilizing mutations (C71G) produce toxic aggregates with prion-like seeding properties that sequester the chaperone DNAJB6, while partially destabilizing mutations (G118V, M114T) gain enhanced formin-mediated actin assembly and disrupt autophagy/endolysosomal pathways through enhanced PI3P binding [PMID:27681617, PMID:37817804, PMID:34074767, PMID:38509062]. Loss-of-function PFN1 mutations also cause early-onset Paget disease of bone by enhancing osteoclast actin ring formation and motility [PMID:32392277, PMID:40458045].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that PFN1 expression is epigenetically regulated and functionally linked to actin polymerization in vivo, nicotine-induced promoter hypomethylation increased PFN1 in spermatids and enhanced sperm motility through actin polymerization.\",\n      \"evidence\": \"2D gel electrophoresis, mass spectrometry, promoter methylation analysis, and sperm motility measurement in mouse testis\",\n      \"pmids\": [\"26311342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific methylation sites on PFN1 promoter not mapped\", \"Whether actin polymerization is the sole mediator of motility change not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolving whether ALS-linked PFN1 C71G causes disease through loss- or gain-of-function, transgenic mice showed that mutant PFN1 produces motor neuron degeneration preceding aggregate formation, establishing a gain-of-toxicity mechanism distinct from simple aggregation.\",\n      \"evidence\": \"Transgenic mouse model expressing C71G and WT PFN1 with histopathology, immunostaining, and behavioral assessment\",\n      \"pmids\": [\"27681617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise toxic species (soluble oligomers vs. other conformers) not identified\", \"Whether endogenous wild-type PFN1 contributes to or is sequestered by mutant unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating PFN1's role at the neuromuscular junction, wild-type human PFN1 expression in Drosophila motor neurons increased active zone density, F-actin content, and filopodia, while ALS mutants showed partial loss of these functions.\",\n      \"evidence\": \"Drosophila transgenic model expressing human PFN1 variants with NMJ morphology analysis\",\n      \"pmids\": [\"28379367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cross-species differences between Drosophila chickadee and human PFN1 not fully controlled for\", \"Whether NMJ remodeling defects are cell-autonomous not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying how PFN1's interaction with VASP is regulated, PKA-mediated phosphorylation at Ser137 was shown to negatively regulate PFN1–VASP binding, and this interaction was required for efficient cell migration downstream of cell-substrate adhesion.\",\n      \"evidence\": \"Mutagenesis in knockdown-rescue settings with cell migration assays and PKA inhibitor/activator experiments\",\n      \"pmids\": [\"30814249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other kinases phosphorylate Ser137 in vivo not addressed\", \"Structural basis of how pSer137 disrupts VASP binding not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing PFN1 loss-of-function in bone biology, a frameshift mutation truncating PFN1's C-terminus caused enhanced osteoclastogenesis with Paget-like features, and PFN1 silencing recapitulated the phenotype, linking PFN1 to osteoclast actin ring regulation.\",\n      \"evidence\": \"Patient PBMC-derived osteoclasts, murine bone marrow monocyte silencing, whole exome sequencing\",\n      \"pmids\": [\"32392277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PFN1 directly restrains actin ring formation or acts through intermediate effectors unknown\", \"Penetrance and modifier genes in human disease not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Clarifying the temporal sequence of ALS pathology, detergent-insoluble PFN1 C71G inclusions were shown to be the earliest pathological event in transgenic rats, preceding motor neuron loss—contrasting with the mouse model where degeneration preceded aggregation.\",\n      \"evidence\": \"Genomic DNA transgenic rat model with detergent fractionation, histopathology, and temporal analysis\",\n      \"pmids\": [\"32754913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepancy with mouse model regarding aggregation timing not reconciled\", \"Whether inclusions are causative or correlative remains debated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealing that different ALS mutations alter PFN1 function through distinct mechanisms, G118V and M114T gained enhanced formin-mediated actin assembly through altered internal dynamic couplings, while C71G was severely destabilized causing loss-of-function in actin assembly.\",\n      \"evidence\": \"Unbiased proteomics, in vitro actin assembly assays, molecular dynamics simulations, and mutagenesis\",\n      \"pmids\": [\"34074767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether enhanced formin-mediated polymerization is toxic in vivo not demonstrated\", \"Which specific formins are most affected in motor neurons not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying a ubiquitin-proteasome axis controlling PFN1 levels, SH3BGRL was found to promote PFN1 degradation by enhancing STUB1 translation and PFN1–STUB1 interaction, with PFN1 loss activating AKT, NF-κB, and WNT signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression/knockdown, in vivo xenograft, and clinical tissue analysis\",\n      \"pmids\": [\"34331014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ubiquitination sites by STUB1 on PFN1 not mapped\", \"Whether STUB1-mediated degradation operates in neurons not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining a precise ubiquitination site governing PFN1 turnover, FBXL4 was shown to promote K48-linked ubiquitination of PFN1 at K70, and cardiac-specific FBXL4 knockout demonstrated that PFN1 accumulation disrupts sarcomeric integrity.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, K70 mutagenesis, cardiac-specific KO/OE mouse models with AAV9 rescue\",\n      \"pmids\": [\"41589689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FBXL4 and STUB1 act redundantly or in distinct tissues not resolved\", \"PFN1 interactome changes upon K70 ubiquitination not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying a deubiquitination mechanism that stabilizes PFN1, the lncRNA UCA1 was shown to scaffold USP14 recruitment to PFN1, inhibiting its ubiquitin-dependent degradation and activating RhoA/ROCK-mediated ROS production in endothelial cells.\",\n      \"evidence\": \"Co-immunoprecipitation, exosome coculture, ubiquitination assay, RhoA/ROCK pathway analysis\",\n      \"pmids\": [\"36160709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct USP14 deubiquitination of PFN1 not shown with purified components\", \"Whether UCA1-USP14-PFN1 axis operates outside endothelial cells unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanding PFN1's signaling repertoire beyond actin, PFN1 was found to bind and activate Cdc42, triggering PAK–JNK phosphorylation and inhibiting myogenic differentiation in skeletal muscle satellite cells.\",\n      \"evidence\": \"Co-immunoprecipitation with mass spectrometry, phosphorylation assays, knockdown/overexpression in bovine satellite cells\",\n      \"pmids\": [\"36291059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PFN1–Cdc42 binding is direct or bridged by actin not resolved\", \"Relevance to human myogenesis not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking PFN1 mutations to alternative autophagy, M114T PFN1 was shown to deregulate the RAB9-mediated alternative autophagy pathway and cause mitochondrial abnormalities in motor neurons.\",\n      \"evidence\": \"Patient lymphoblasts, transfected cell lines, lentiviral transgenic mice, autophagy marker analysis\",\n      \"pmids\": [\"35628504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RAB9 pathway activation is a direct consequence of PFN1 destabilization or secondary not clear\", \"Which mitochondrial clearance step is impaired not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing prion-like properties of mutant PFN1, insoluble PFN1 from paralyzed ALS rats seeded inclusions and accelerated disease in recipient animals, while pathogenic PFN1 sequestered the chaperone DNAJB6 within inclusions.\",\n      \"evidence\": \"Intramuscular injection of spinal cord extracts in pre-symptomatic mutant PFN1 rats, co-immunoprecipitation for DNAJB6\",\n      \"pmids\": [\"37817804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether seeding occurs in sporadic ALS without PFN1 mutations unknown\", \"Whether DNAJB6 sequestration is causal for toxicity or a bystander effect not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying a lipid-binding gain-of-function in ALS-mutant PFN1, enhanced PI3P binding was shown to impair autophagy and phagocytosis in iPSC-derived microglia, with rapamycin rescuing the phagocytic defect.\",\n      \"evidence\": \"iPSC-derived microglia, PI3P binding assay, phagocytosis assay, rapamycin rescue, lipid profiling\",\n      \"pmids\": [\"38509062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PI3P binding enhancement occurs in motor neurons not tested\", \"Structural basis for enhanced PI3P affinity of mutant PFN1 not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirming PFN1 loss-of-function in bone disease with a knock-in model, heterozygous L112P mice developed early-onset Paget disease phenotype through enhanced osteoclast actin ring structures independent of NF-κB activation.\",\n      \"evidence\": \"Heterozygous knock-in mouse model, osteoclast culture, actin ring staining, NF-κB assay\",\n      \"pmids\": [\"40458045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether L112P affects PFN1 stability or specifically actin-binding not characterized\", \"Osteoblast contributions to the bone phenotype not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: how the same protein produces both gain- and loss-of-function disease phenotypes across cell types; the structural basis for enhanced PI3P binding by ALS mutants; whether FBXL4/STUB1 ubiquitination axes are relevant in motor neurons; and whether prion-like PFN1 seeding contributes to sporadic ALS.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Cell-type-specific determinants of PFN1 toxicity vs. loss-of-function not mapped\", \"No high-resolution structure of disease-mutant PFN1 bound to PI3P\", \"Whether therapeutic modulation of PFN1 stability would be beneficial or detrimental in ALS not known\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 2, 13, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 8, 9, 13, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"VASP\",\n      \"FBXL4\",\n      \"STUB1\",\n      \"USP14\",\n      \"DNAJB6\",\n      \"CDC42\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}