{"gene":"NSFL1C","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2018,"finding":"PINK1 physically interacts with VCP/p97 and its cofactor NSFL1C/p47 is required for PINK1-mediated increases in dendritic complexity. PINK1 binds and phosphorylates the catalytic subunit of PKA at T197, activating PKA, which in turn phosphorylates p47 at a novel site (S176) to regulate dendritic arborization. Neither VCP nor p47 interact directly with PKA, placing PINK1 as a scaffold in a PINK1-VCP-PKA-p47 signaling pathway.","method":"RNAi knockdown, unbiased proteomics (co-IP/MS), phosphorylation assays, dendritic morphology readout","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction identified by proteomics and functional RNAi, single lab, multiple orthogonal methods including phosphorylation site mapping","pmids":["30783609"],"is_preprint":false},{"year":2022,"finding":"In Pink1-/- cortical neurons and brain tissue, phosphorylation of NSFL1C/p47 is reduced. Transfection of a phosphomimetic p47 (mimicking PINK1-dependent phosphorylation) rescued dendritic branching and spine density defects in Pink1-/- neurons, establishing that PINK1-regulated p47 phosphorylation is functionally required for dendrite and spine development.","method":"Pink1-/- mouse knockout, Western blot for p47 phosphorylation, phosphomimetic p47 rescue transfection, Golgi-Cox staining, electrophysiology (mEPSC)","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with phosphomimetic rescue, single lab, multiple readouts","pmids":["36414008"],"is_preprint":false},{"year":2021,"finding":"NSFL1C/p47 acts as a negative regulator of the NF-κB signaling pathway. In ATLL cells, p47 is degraded via the autophagy-lysosomal pathway; inhibiting autophagy with chloroquine/hydroxychloroquine restores p47 levels and suppresses NF-κB activation, reducing tumor cell proliferation and inducing apoptosis.","method":"CQ/HCQ treatment of ATLL cell lines and primary cells, autophagy inhibition, NF-κB pathway activity assays, xenograft mouse model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with multiple cell models and in vivo xenograft, single lab","pmids":["34407152"],"is_preprint":false},{"year":2024,"finding":"NSFL1C/p47 suppresses HER2+ breast cancer metastasis by functioning in lysosomal damage repair for autophagy flux and in endosomal trafficking of NEMO (NF-κB essential modulator) for lysosomal degradation. p47 ablation specifically increases metastasis without promoting primary tumor growth.","method":"In vivo CRISPR knockout screen, mechanistic studies of NEMO trafficking and autophagy flux in HER2+ breast cancer cells, human patient database and tissue analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo CRISPR screen plus mechanistic follow-up on trafficking, single lab","pmids":["38363674"],"is_preprint":false},{"year":2024,"finding":"NSFL1C recruits USP9X to inhibit polyubiquitination of AURKB, thereby reducing VCP-mediated removal of AURKB from centromeres. This mechanism is essential for spindle assembly checkpoint (SAC) activation, and loss of NSFL1C suppresses SAC activation to promote survival of BRCA2-deficient cells.","method":"C. elegans genetic screen (Ceubxn-2/Cebrc-2 synthetic viability), mammalian NSFL1C loss-of-function, mechanistic dissection of USP9X recruitment and AURKB ubiquitination/centromere localization","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis in C. elegans plus mechanistic follow-up in mammalian cells, single lab, multiple orthogonal methods","pmids":["37934606"],"is_preprint":false},{"year":2022,"finding":"Engineered antibody fragments (via phage display) specifically targeting the p97-interacting domain of NSFL1C/p47 disrupt the intracellular p97/p47 protein-protein interaction and inhibit Golgi reassembly, demonstrating that the p97-p47 interaction is required for Golgi reassembly.","method":"Phage display, intracellular antibody fragment delivery, Golgi reassembly functional assay, selectivity profiling against other p97 adaptors","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered PPI inhibitor with functional cellular readout (Golgi reassembly), single lab, multiple orthogonal methods","pmids":["35819848"],"is_preprint":false},{"year":2025,"finding":"Reduction of NSFL1C/p47 (by genetic knockout or knockdown) decreased VCP-dependent tau seeding efficiency in HEK293T biosensor cells and human neurons, placing NSFL1C as a VCP cofactor that promotes tau seed amplification in a cytoplasmic processing complex.","method":"Genetic knockout/knockdown screen of 30 VCP cofactors in tau biosensor cells, proximity labeling (split-APEX2), tau seeding assays in HEK293T and human neurons","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic cofactor screen with proximity labeling and functional tau seeding readout, single lab","pmids":["39773263"],"is_preprint":false},{"year":2010,"finding":"In Saccharomyces cerevisiae, the p47 ortholog Shp1/Ubx1 (cofactor of Cdc48/p97) is required for autophagosome biogenesis. Shp1 physically interacts with the ubiquitin-like autophagy protein Atg8, and this interaction requires a FK motif within the non-ubiquitin-like N-terminal domain of Atg8. Ubiquitination and the proteasome are not required for this function.","method":"Yeast genetics (deletion mutants), in vitro interaction assays, domain mapping, autophagosome biogenesis assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast ortholog, genetic and in vitro binding data, single lab with multiple orthogonal methods","pmids":["20855502"],"is_preprint":false},{"year":2016,"finding":"In S. cerevisiae, Cdc48 and its cofactor Ubx1 (Shp1, the p47 ortholog) are required for turnover of the inner nuclear membrane protein Asi1. Asi1 degradation depends on ubiquitin, the E2 Ubc7, Cue1, and the Cdc48-Ubx1 complex, and occurs via nucleus-localized proteasomes, defining an inner nuclear membrane-associated protein quality control pathway.","method":"Yeast genetics (deletion mutants), protein stability/turnover assays, epistasis analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast ortholog, genetic epistasis with multiple deletion mutants and defined substrate, single lab","pmids":["27566164"],"is_preprint":false},{"year":2007,"finding":"NSFL1C undergoes differential tyrosine phosphorylation during breast cancer progression and was validated as a novel tyrosine kinase substrate and an authentic target of EGF signaling and the EGFR inhibitor gefitinib (Iressa).","method":"Phosphotyrosyl affinity enrichment, iTRAQ/LC-MS/MS proteomics, validation experiments with EGF stimulation and gefitinib treatment","journal":"Molecular & cellular proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mass spectrometry-based phosphoproteomics with EGF/gefitinib validation, single lab, no detailed mechanistic follow-up on NSFL1C specifically","pmids":["17855441"],"is_preprint":false},{"year":2025,"finding":"NMR backbone resonance assignments of full-length NSFL1C/p47 and a SIM-SEP fragment (residues 101-266) were obtained, revealing secondary structure propensities. p47 consists of three folded domains (UBA, SEP, UBX) connected by intrinsically disordered regions (IDRs), and the full-length protein and its complex with p97 are highly dynamic, hindering high-resolution crystallography/cryo-EM.","method":"NMR spectroscopy (1H, 13C, 15N backbone assignments), secondary structure propensity analysis","journal":"Biomolecular NMR assignments","confidence":"Low","confidence_rationale":"Tier 1 / Weak — NMR structural characterization (assignments only, no functional mutagenesis validation), single lab, partial structural data without full structure determination","pmids":["41188554"],"is_preprint":false}],"current_model":"NSFL1C/p47 is a cofactor of the AAA-ATPase VCP/p97 that directs p97 activity toward membrane remodeling (including Golgi reassembly and autophagosome biogenesis), NF-κB pathway regulation (as a negative regulator degraded by autophagy), tau seed amplification, and neuronal dendrite/spine development via a PINK1-PKA-p47 phosphorylation axis; it also regulates the spindle assembly checkpoint by recruiting USP9X to inhibit AURKB polyubiquitination, and is itself subject to tyrosine phosphorylation downstream of EGF receptor signaling."},"narrative":{"mechanistic_narrative":"NSFL1C/p47 is a cofactor of the AAA-ATPase VCP/p97 that directs p97 activity toward membrane remodeling and protein quality control, while also serving as a regulatory node in mitotic checkpoint control and neuronal development [PMID:35819848, PMID:37934606]. The direct p47–p97 interaction is required for Golgi reassembly, as engineered antibody fragments that disrupt this interface block reassembly without affecting other p97 adaptors [PMID:35819848]. In autophagy, p47 promotes autophagosome biogenesis—a function conserved in the yeast ortholog Shp1/Ubx1, which binds the ubiquitin-like protein Atg8 through a FK motif in a ubiquitin- and proteasome-independent manner [PMID:20855502]—and supports lysosomal damage repair and autophagic flux [PMID:38363674]. p47 acts as a negative regulator of NF-κB signaling: it is itself degraded by the autophagy-lysosomal pathway, such that autophagy inhibition restores p47 and suppresses NF-κB activation in ATLL cells [PMID:34407152], and it routes the NF-κB modulator NEMO through endosomal trafficking to lysosomal degradation to suppress HER2+ breast cancer metastasis [PMID:38363674]. In mitosis, p47 recruits the deubiquitinase USP9X to inhibit AURKB polyubiquitination, thereby limiting VCP-mediated extraction of AURKB from centromeres and enabling spindle assembly checkpoint activation [PMID:37934606]. p47 also functions as a VCP cofactor that promotes tau seed amplification in a cytoplasmic processing complex [PMID:39773263]. In neurons, p47 is phosphorylated downstream of a PINK1-VCP-PKA signaling axis at S176, and this phosphorylation is required for dendritic arborization and spine development [PMID:30783609, PMID:36414008]. The protein comprises UBA, SEP, and UBX domains connected by intrinsically disordered regions [PMID:41188554].","teleology":[{"year":2007,"claim":"Established that NSFL1C is a dynamically regulated signaling substrate, identifying it as a tyrosine kinase target downstream of EGFR rather than a static structural cofactor.","evidence":"Phosphotyrosyl affinity enrichment and iTRAQ/LC-MS/MS with EGF stimulation and gefitinib treatment in breast cancer","pmids":["17855441"],"confidence":"Low","gaps":["No mechanistic follow-up identifying the responsible kinase or the functional consequence of tyrosine phosphorylation on NSFL1C","Phosphosite not mapped to a domain or downstream effect"]},{"year":2010,"claim":"Defined a membrane-remodeling role for the p47 ortholog beyond ER-associated degradation by showing Shp1/Ubx1 is required for autophagosome biogenesis via a direct, ubiquitin-independent interaction with Atg8.","evidence":"Yeast genetics, in vitro interaction assays, and domain mapping in S. cerevisiae","pmids":["20855502"],"confidence":"Medium","gaps":["Conservation of the Atg8/LC3 interaction in mammalian p47 not directly tested","Whether p97 ATPase activity is required for the autophagy function not resolved here"]},{"year":2016,"claim":"Extended the Cdc48-Ubx1/p47 complex to inner nuclear membrane protein quality control, showing it mediates ubiquitin- and proteasome-dependent turnover of a defined substrate (Asi1).","evidence":"Yeast genetics and epistasis with deletion mutants and turnover assays in S. cerevisiae","pmids":["27566164"],"confidence":"Medium","gaps":["Substrate specificity determinants for Ubx1/p47 not defined","Mammalian counterpart of this INM pathway not addressed"]},{"year":2018,"claim":"Placed p47 in a neuronal signaling cascade, showing PINK1 scaffolds a PINK1-VCP-PKA pathway in which PKA phosphorylates p47 at a novel S176 site to control dendritic complexity.","evidence":"RNAi knockdown, co-IP/MS proteomics, phosphorylation site mapping, and dendritic morphology readouts","pmids":["30783609"],"confidence":"Medium","gaps":["How S176 phosphorylation alters p47-p97 activity mechanistically not resolved","Single-lab interaction network"]},{"year":2021,"claim":"Identified p47 as a negative regulator of NF-κB whose own abundance is set by autophagic degradation, providing a route by which autophagy modulation controls NF-κB-driven proliferation.","evidence":"Pharmacological autophagy inhibition (CQ/HCQ) in ATLL cell lines, primary cells, and xenografts with NF-κB activity assays","pmids":["34407152"],"confidence":"Medium","gaps":["Molecular mechanism by which p47 represses NF-κB not defined in this study","Autophagy receptor targeting p47 for degradation unknown"]},{"year":2022,"claim":"Demonstrated causally that the direct p47-p97 protein-protein interaction is required for Golgi reassembly using a selective intracellular PPI inhibitor.","evidence":"Phage-display-derived antibody fragments disrupting the p97-interacting domain, with Golgi reassembly readout and selectivity profiling against other adaptors","pmids":["35819848"],"confidence":"Medium","gaps":["Structural basis of the disrupted interface not resolved","Whether the same interface drives non-Golgi p47 functions not tested"]},{"year":2024,"claim":"Revealed a mitotic checkpoint function in which p47 recruits USP9X to protect AURKB from VCP-mediated centromere extraction, enabling SAC activation and explaining synthetic lethality with BRCA2 deficiency.","evidence":"C. elegans synthetic-viability screen plus mammalian loss-of-function and AURKB ubiquitination/centromere localization assays","pmids":["37934606"],"confidence":"Medium","gaps":["Direct USP9X-NSFL1C binding interface not mapped","How p47 switches between promoting and restraining VCP substrate processing unclear"]},{"year":2024,"claim":"Connected p47's membrane-trafficking and NF-κB activities to cancer metastasis, showing p47 supports lysosomal damage repair/autophagy flux and routes NEMO to lysosomal degradation to suppress HER2+ breast cancer metastasis.","evidence":"In vivo CRISPR knockout screen with mechanistic NEMO trafficking and autophagy-flux follow-up and patient tissue analysis","pmids":["38363674"],"confidence":"Medium","gaps":["Mechanism linking p47 to lysosomal membrane repair not fully resolved","Whether p97 ATPase activity drives NEMO trafficking not tested"]},{"year":2025,"claim":"Identified p47 from a systematic VCP-cofactor screen as a promoter of tau seed amplification, implicating the p97-p47 axis in a cytoplasmic proteopathic processing complex.","evidence":"Knockout/knockdown screen of 30 VCP cofactors with split-APEX2 proximity labeling and tau seeding assays in biosensor cells and human neurons","pmids":["39773263"],"confidence":"Medium","gaps":["Composition of the cytoplasmic processing complex not fully defined","Mechanism by which p47 enhances seed amplification not resolved"]},{"year":2025,"claim":"Provided the first backbone structural characterization of full-length p47, defining a UBA-SEP-UBX domain architecture linked by intrinsically disordered regions and a highly dynamic p97 complex.","evidence":"NMR backbone resonance assignments and secondary structure propensity analysis of full-length p47 and a SIM-SEP fragment","pmids":["41188554"],"confidence":"Low","gaps":["Assignments only; no high-resolution structure of p47 or the p47-p97 complex","No functional mutagenesis validating domain assignments"]},{"year":null,"claim":"It remains unresolved how p47's distinct functions—Golgi reassembly, autophagy, NF-κB regulation, SAC control, tau seeding, and dendrite development—are coordinated through a single p97-cofactor scaffold and switched between substrate-processing and substrate-protecting outcomes.","evidence":"No single study in the timeline integrates these activities mechanistically","pmids":[],"confidence":"Low","gaps":["No unifying model of how domain state or phosphorylation selects among p47 functions","No structure of the active p47-p97-substrate complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,7]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,3,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8]}],"complexes":["p97/p47 complex","Cdc48-Ubx1 complex"],"partners":["VCP","PINK1","USP9X","AURKB","ATG8","NEMO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UNZ2","full_name":"NSFL1 cofactor p47","aliases":["UBX domain-containing protein 2C","p97 cofactor p47"],"length_aa":370,"mass_kda":40.6,"function":"Reduces the ATPase activity of VCP (By similarity). Necessary for the fragmentation of Golgi stacks during mitosis and for VCP-mediated reassembly of Golgi stacks after mitosis (By similarity). May play a role in VCP-mediated formation of transitional endoplasmic reticulum (tER) (By similarity). Inhibits the activity of CTSL (in vitro) (PubMed:15498563). Together with UBXN2B/p37, regulates the centrosomal levels of kinase AURKA/Aurora A during mitotic progression by promoting AURKA removal from centrosomes in prophase (PubMed:23649807). Also, regulates spindle orientation during mitosis (PubMed:23649807)","subcellular_location":"Nucleus; Golgi apparatus, Golgi stack; Chromosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q9UNZ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NSFL1C","classification":"Not Classified","n_dependent_lines":48,"n_total_lines":1208,"dependency_fraction":0.039735099337748346},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"VCP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NSFL1C","total_profiled":1310},"omim":[{"mim_id":"620965","title":"SMALL VCP-INTERACTING PROTEIN; SVIP","url":"https://www.omim.org/entry/620965"},{"mim_id":"611745","title":"VCP/p47 COMPLEX-INTERACTING PROTEIN 1;   VCPIP1","url":"https://www.omim.org/entry/611745"},{"mim_id":"610686","title":"UBX DOMAIN PROTEIN 2B; UBXN2B","url":"https://www.omim.org/entry/610686"},{"mim_id":"606610","title":"NSFL1 COFACTOR; NSFL1C","url":"https://www.omim.org/entry/606610"},{"mim_id":"601023","title":"VALOSIN-CONTAINING PROTEIN; VCP","url":"https://www.omim.org/entry/601023"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NSFL1C"},"hgnc":{"alias_symbol":["dJ776F14.1","p47","UBXD10","UBX1","UBXN2C"],"prev_symbol":[]},"alphafold":{"accession":"Q9UNZ2","domains":[{"cath_id":"1.10.8.10","chopping":"1-46","consensus_level":"medium","plddt":84.8163,"start":1,"end":46},{"cath_id":"3.30.420.210","chopping":"113-131_178-246","consensus_level":"medium","plddt":80.6414,"start":113,"end":246},{"cath_id":"3.10.20.90","chopping":"272-368","consensus_level":"high","plddt":85.6239,"start":272,"end":368}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNZ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNZ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UNZ2-F1-predicted_aligned_error_v6.png","plddt_mean":74.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NSFL1C","jax_strain_url":"https://www.jax.org/strain/search?query=NSFL1C"},"sequence":{"accession":"Q9UNZ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UNZ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UNZ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UNZ2"}},"corpus_meta":[{"pmid":"17855441","id":"PMC_17855441","title":"Differential expression of novel tyrosine kinase substrates during breast cancer development.","date":"2007","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/17855441","citation_count":116,"is_preprint":false},{"pmid":"20855502","id":"PMC_20855502","title":"Cdc48/p97 and Shp1/p47 regulate autophagosome biogenesis in concert with ubiquitin-like Atg8.","date":"2010","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20855502","citation_count":114,"is_preprint":false},{"pmid":"24642758","id":"PMC_24642758","title":"Metabolic changes associated with the long winter fast dominate the liver proteome in 13-lined ground squirrels.","date":"2014","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/24642758","citation_count":49,"is_preprint":false},{"pmid":"9383059","id":"PMC_9383059","title":"Is function of the Drosophila homeotic gene Ultrabithorax canalized?","date":"1997","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9383059","citation_count":44,"is_preprint":false},{"pmid":"30783609","id":"PMC_30783609","title":"PINK1 Interacts with VCP/p97 and Activates PKA to Promote NSFL1C/p47 Phosphorylation and Dendritic Arborization in Neurons.","date":"2018","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/30783609","citation_count":43,"is_preprint":false},{"pmid":"6790337","id":"PMC_6790337","title":"The role of dosage of the region 7D1-7D5-6 of the X chromosome in the production of homeotic transformations in Drosophila melanogaster.","date":"1980","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/6790337","citation_count":39,"is_preprint":false},{"pmid":"34407152","id":"PMC_34407152","title":"Antitumor effects of chloroquine/hydroxychloroquine mediated by inhibition of the NF-κB signaling pathway through abrogation of autophagic p47 degradation in adult T-cell leukemia/lymphoma cells.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34407152","citation_count":21,"is_preprint":false},{"pmid":"23555679","id":"PMC_23555679","title":"Promyelocytic leukemia (PML) protein plays important roles in regulating cell adhesion, morphology, proliferation and migration.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23555679","citation_count":18,"is_preprint":false},{"pmid":"3123894","id":"PMC_3123894","title":"Studies on transvection at the bithorax complex in Drosophila melanogaster.","date":"1987","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/3123894","citation_count":16,"is_preprint":false},{"pmid":"39773263","id":"PMC_39773263","title":"VCP regulates early tau seed amplification via specific cofactors.","date":"2025","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/39773263","citation_count":14,"is_preprint":false},{"pmid":"10628847","id":"PMC_10628847","title":"Expression of the beta3 tubulin gene (beta Tub60D) in the visceral mesoderm of Drosophila is dependent on a complex enhancer that binds Tinman and UBX.","date":"1999","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/10628847","citation_count":14,"is_preprint":false},{"pmid":"27566164","id":"PMC_27566164","title":"Cdc48 and Ubx1 participate in a pathway associated with the inner nuclear membrane that governs Asi1 degradation.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/27566164","citation_count":13,"is_preprint":false},{"pmid":"36414008","id":"PMC_36414008","title":"Endogenous PTEN-Induced Kinase 1 Regulates Dendritic Architecture and Spinogenesis.","date":"2022","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36414008","citation_count":13,"is_preprint":false},{"pmid":"2123161","id":"PMC_2123161","title":"Genetic analysis of transvection effects involving cis-regulatory elements of the Drosophila Ultrabithorax gene.","date":"1990","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2123161","citation_count":12,"is_preprint":false},{"pmid":"35819848","id":"PMC_35819848","title":"Adaptor-Specific Antibody Fragment Inhibitors for the Intracellular Modulation of p97 (VCP) Protein-Protein Interactions.","date":"2022","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/35819848","citation_count":12,"is_preprint":false},{"pmid":"28807601","id":"PMC_28807601","title":"UBX domain-containing proteins are involved in lipid homeostasis and stress responses in Pichia pastoris.","date":"2017","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28807601","citation_count":10,"is_preprint":false},{"pmid":"38363674","id":"PMC_38363674","title":"In vivo CRISPR knockout screen identifies p47 as a suppressor of HER2+ breast cancer metastasis by regulating NEMO trafficking and autophagy flux.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38363674","citation_count":6,"is_preprint":false},{"pmid":"1677904","id":"PMC_1677904","title":"The Ultrabithorax gene of Drosophila and the specification of abdominal histoblasts.","date":"1991","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/1677904","citation_count":5,"is_preprint":false},{"pmid":"37934606","id":"PMC_37934606","title":"PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37934606","citation_count":4,"is_preprint":false},{"pmid":"37693404","id":"PMC_37693404","title":"VCP increases or decreases tau seeding using specific cofactors.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37693404","citation_count":4,"is_preprint":false},{"pmid":"27955744","id":"PMC_27955744","title":"Glycoproteomics analysis of plasma proteins associated with Opisthorchis viverrini infection-induced cholangiocarcinoma in hamster model.","date":"2016","source":"Asian Pacific journal of tropical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27955744","citation_count":3,"is_preprint":false},{"pmid":"38826306","id":"PMC_38826306","title":"VCP regulates early tau seed amplification via specific cofactors.","date":"2024","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/38826306","citation_count":2,"is_preprint":false},{"pmid":"40359616","id":"PMC_40359616","title":"Cdc48 plays a crucial role in redox homeostasis through dynamic reshaping of its interactome during early stationary phase.","date":"2025","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/40359616","citation_count":1,"is_preprint":false},{"pmid":"41301803","id":"PMC_41301803","title":"Proteomic Study of Diffuse Large B-Cell Lymphoma Identifying Proteins Associated with R-CHOP Response.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41301803","citation_count":0,"is_preprint":false},{"pmid":"41188554","id":"PMC_41188554","title":"1H, 13C, and 15N backbone resonance assignments of full-length and a SIM-SEP-containing fragment (101-266) of p47, a p97 adaptor protein.","date":"2025","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/41188554","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14950,"output_tokens":2872,"usd":0.043965,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10217,"output_tokens":3706,"usd":0.071868,"stage2_stop_reason":"end_turn"},"total_usd":0.115833,"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\": 2018,\n      \"finding\": \"PINK1 physically interacts with VCP/p97 and its cofactor NSFL1C/p47 is required for PINK1-mediated increases in dendritic complexity. PINK1 binds and phosphorylates the catalytic subunit of PKA at T197, activating PKA, which in turn phosphorylates p47 at a novel site (S176) to regulate dendritic arborization. Neither VCP nor p47 interact directly with PKA, placing PINK1 as a scaffold in a PINK1-VCP-PKA-p47 signaling pathway.\",\n      \"method\": \"RNAi knockdown, unbiased proteomics (co-IP/MS), phosphorylation assays, dendritic morphology readout\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction identified by proteomics and functional RNAi, single lab, multiple orthogonal methods including phosphorylation site mapping\",\n      \"pmids\": [\"30783609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Pink1-/- cortical neurons and brain tissue, phosphorylation of NSFL1C/p47 is reduced. Transfection of a phosphomimetic p47 (mimicking PINK1-dependent phosphorylation) rescued dendritic branching and spine density defects in Pink1-/- neurons, establishing that PINK1-regulated p47 phosphorylation is functionally required for dendrite and spine development.\",\n      \"method\": \"Pink1-/- mouse knockout, Western blot for p47 phosphorylation, phosphomimetic p47 rescue transfection, Golgi-Cox staining, electrophysiology (mEPSC)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with phosphomimetic rescue, single lab, multiple readouts\",\n      \"pmids\": [\"36414008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NSFL1C/p47 acts as a negative regulator of the NF-κB signaling pathway. In ATLL cells, p47 is degraded via the autophagy-lysosomal pathway; inhibiting autophagy with chloroquine/hydroxychloroquine restores p47 levels and suppresses NF-κB activation, reducing tumor cell proliferation and inducing apoptosis.\",\n      \"method\": \"CQ/HCQ treatment of ATLL cell lines and primary cells, autophagy inhibition, NF-κB pathway activity assays, xenograft mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with multiple cell models and in vivo xenograft, single lab\",\n      \"pmids\": [\"34407152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NSFL1C/p47 suppresses HER2+ breast cancer metastasis by functioning in lysosomal damage repair for autophagy flux and in endosomal trafficking of NEMO (NF-κB essential modulator) for lysosomal degradation. p47 ablation specifically increases metastasis without promoting primary tumor growth.\",\n      \"method\": \"In vivo CRISPR knockout screen, mechanistic studies of NEMO trafficking and autophagy flux in HER2+ breast cancer cells, human patient database and tissue analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CRISPR screen plus mechanistic follow-up on trafficking, single lab\",\n      \"pmids\": [\"38363674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NSFL1C recruits USP9X to inhibit polyubiquitination of AURKB, thereby reducing VCP-mediated removal of AURKB from centromeres. This mechanism is essential for spindle assembly checkpoint (SAC) activation, and loss of NSFL1C suppresses SAC activation to promote survival of BRCA2-deficient cells.\",\n      \"method\": \"C. elegans genetic screen (Ceubxn-2/Cebrc-2 synthetic viability), mammalian NSFL1C loss-of-function, mechanistic dissection of USP9X recruitment and AURKB ubiquitination/centromere localization\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis in C. elegans plus mechanistic follow-up in mammalian cells, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37934606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Engineered antibody fragments (via phage display) specifically targeting the p97-interacting domain of NSFL1C/p47 disrupt the intracellular p97/p47 protein-protein interaction and inhibit Golgi reassembly, demonstrating that the p97-p47 interaction is required for Golgi reassembly.\",\n      \"method\": \"Phage display, intracellular antibody fragment delivery, Golgi reassembly functional assay, selectivity profiling against other p97 adaptors\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered PPI inhibitor with functional cellular readout (Golgi reassembly), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35819848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Reduction of NSFL1C/p47 (by genetic knockout or knockdown) decreased VCP-dependent tau seeding efficiency in HEK293T biosensor cells and human neurons, placing NSFL1C as a VCP cofactor that promotes tau seed amplification in a cytoplasmic processing complex.\",\n      \"method\": \"Genetic knockout/knockdown screen of 30 VCP cofactors in tau biosensor cells, proximity labeling (split-APEX2), tau seeding assays in HEK293T and human neurons\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic cofactor screen with proximity labeling and functional tau seeding readout, single lab\",\n      \"pmids\": [\"39773263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Saccharomyces cerevisiae, the p47 ortholog Shp1/Ubx1 (cofactor of Cdc48/p97) is required for autophagosome biogenesis. Shp1 physically interacts with the ubiquitin-like autophagy protein Atg8, and this interaction requires a FK motif within the non-ubiquitin-like N-terminal domain of Atg8. Ubiquitination and the proteasome are not required for this function.\",\n      \"method\": \"Yeast genetics (deletion mutants), in vitro interaction assays, domain mapping, autophagosome biogenesis assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast ortholog, genetic and in vitro binding data, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20855502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In S. cerevisiae, Cdc48 and its cofactor Ubx1 (Shp1, the p47 ortholog) are required for turnover of the inner nuclear membrane protein Asi1. Asi1 degradation depends on ubiquitin, the E2 Ubc7, Cue1, and the Cdc48-Ubx1 complex, and occurs via nucleus-localized proteasomes, defining an inner nuclear membrane-associated protein quality control pathway.\",\n      \"method\": \"Yeast genetics (deletion mutants), protein stability/turnover assays, epistasis analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast ortholog, genetic epistasis with multiple deletion mutants and defined substrate, single lab\",\n      \"pmids\": [\"27566164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NSFL1C undergoes differential tyrosine phosphorylation during breast cancer progression and was validated as a novel tyrosine kinase substrate and an authentic target of EGF signaling and the EGFR inhibitor gefitinib (Iressa).\",\n      \"method\": \"Phosphotyrosyl affinity enrichment, iTRAQ/LC-MS/MS proteomics, validation experiments with EGF stimulation and gefitinib treatment\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mass spectrometry-based phosphoproteomics with EGF/gefitinib validation, single lab, no detailed mechanistic follow-up on NSFL1C specifically\",\n      \"pmids\": [\"17855441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NMR backbone resonance assignments of full-length NSFL1C/p47 and a SIM-SEP fragment (residues 101-266) were obtained, revealing secondary structure propensities. p47 consists of three folded domains (UBA, SEP, UBX) connected by intrinsically disordered regions (IDRs), and the full-length protein and its complex with p97 are highly dynamic, hindering high-resolution crystallography/cryo-EM.\",\n      \"method\": \"NMR spectroscopy (1H, 13C, 15N backbone assignments), secondary structure propensity analysis\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structural characterization (assignments only, no functional mutagenesis validation), single lab, partial structural data without full structure determination\",\n      \"pmids\": [\"41188554\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NSFL1C/p47 is a cofactor of the AAA-ATPase VCP/p97 that directs p97 activity toward membrane remodeling (including Golgi reassembly and autophagosome biogenesis), NF-κB pathway regulation (as a negative regulator degraded by autophagy), tau seed amplification, and neuronal dendrite/spine development via a PINK1-PKA-p47 phosphorylation axis; it also regulates the spindle assembly checkpoint by recruiting USP9X to inhibit AURKB polyubiquitination, and is itself subject to tyrosine phosphorylation downstream of EGF receptor signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NSFL1C/p47 is a cofactor of the AAA-ATPase VCP/p97 that directs p97 activity toward membrane remodeling and protein quality control, while also serving as a regulatory node in mitotic checkpoint control and neuronal development [#5, #4]. The direct p47–p97 interaction is required for Golgi reassembly, as engineered antibody fragments that disrupt this interface block reassembly without affecting other p97 adaptors [#5]. In autophagy, p47 promotes autophagosome biogenesis—a function conserved in the yeast ortholog Shp1/Ubx1, which binds the ubiquitin-like protein Atg8 through a FK motif in a ubiquitin- and proteasome-independent manner [#7]—and supports lysosomal damage repair and autophagic flux [#3]. p47 acts as a negative regulator of NF-κB signaling: it is itself degraded by the autophagy-lysosomal pathway, such that autophagy inhibition restores p47 and suppresses NF-κB activation in ATLL cells [#2], and it routes the NF-κB modulator NEMO through endosomal trafficking to lysosomal degradation to suppress HER2+ breast cancer metastasis [#3]. In mitosis, p47 recruits the deubiquitinase USP9X to inhibit AURKB polyubiquitination, thereby limiting VCP-mediated extraction of AURKB from centromeres and enabling spindle assembly checkpoint activation [#4]. p47 also functions as a VCP cofactor that promotes tau seed amplification in a cytoplasmic processing complex [#6]. In neurons, p47 is phosphorylated downstream of a PINK1-VCP-PKA signaling axis at S176, and this phosphorylation is required for dendritic arborization and spine development [#0, #1]. The protein comprises UBA, SEP, and UBX domains connected by intrinsically disordered regions [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that NSFL1C is a dynamically regulated signaling substrate, identifying it as a tyrosine kinase target downstream of EGFR rather than a static structural cofactor.\",\n      \"evidence\": \"Phosphotyrosyl affinity enrichment and iTRAQ/LC-MS/MS with EGF stimulation and gefitinib treatment in breast cancer\",\n      \"pmids\": [\"17855441\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic follow-up identifying the responsible kinase or the functional consequence of tyrosine phosphorylation on NSFL1C\", \"Phosphosite not mapped to a domain or downstream effect\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a membrane-remodeling role for the p47 ortholog beyond ER-associated degradation by showing Shp1/Ubx1 is required for autophagosome biogenesis via a direct, ubiquitin-independent interaction with Atg8.\",\n      \"evidence\": \"Yeast genetics, in vitro interaction assays, and domain mapping in S. cerevisiae\",\n      \"pmids\": [\"20855502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of the Atg8/LC3 interaction in mammalian p47 not directly tested\", \"Whether p97 ATPase activity is required for the autophagy function not resolved here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the Cdc48-Ubx1/p47 complex to inner nuclear membrane protein quality control, showing it mediates ubiquitin- and proteasome-dependent turnover of a defined substrate (Asi1).\",\n      \"evidence\": \"Yeast genetics and epistasis with deletion mutants and turnover assays in S. cerevisiae\",\n      \"pmids\": [\"27566164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate specificity determinants for Ubx1/p47 not defined\", \"Mammalian counterpart of this INM pathway not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed p47 in a neuronal signaling cascade, showing PINK1 scaffolds a PINK1-VCP-PKA pathway in which PKA phosphorylates p47 at a novel S176 site to control dendritic complexity.\",\n      \"evidence\": \"RNAi knockdown, co-IP/MS proteomics, phosphorylation site mapping, and dendritic morphology readouts\",\n      \"pmids\": [\"30783609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How S176 phosphorylation alters p47-p97 activity mechanistically not resolved\", \"Single-lab interaction network\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified p47 as a negative regulator of NF-κB whose own abundance is set by autophagic degradation, providing a route by which autophagy modulation controls NF-κB-driven proliferation.\",\n      \"evidence\": \"Pharmacological autophagy inhibition (CQ/HCQ) in ATLL cell lines, primary cells, and xenografts with NF-κB activity assays\",\n      \"pmids\": [\"34407152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which p47 represses NF-κB not defined in this study\", \"Autophagy receptor targeting p47 for degradation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated causally that the direct p47-p97 protein-protein interaction is required for Golgi reassembly using a selective intracellular PPI inhibitor.\",\n      \"evidence\": \"Phage-display-derived antibody fragments disrupting the p97-interacting domain, with Golgi reassembly readout and selectivity profiling against other adaptors\",\n      \"pmids\": [\"35819848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the disrupted interface not resolved\", \"Whether the same interface drives non-Golgi p47 functions not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a mitotic checkpoint function in which p47 recruits USP9X to protect AURKB from VCP-mediated centromere extraction, enabling SAC activation and explaining synthetic lethality with BRCA2 deficiency.\",\n      \"evidence\": \"C. elegans synthetic-viability screen plus mammalian loss-of-function and AURKB ubiquitination/centromere localization assays\",\n      \"pmids\": [\"37934606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct USP9X-NSFL1C binding interface not mapped\", \"How p47 switches between promoting and restraining VCP substrate processing unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected p47's membrane-trafficking and NF-κB activities to cancer metastasis, showing p47 supports lysosomal damage repair/autophagy flux and routes NEMO to lysosomal degradation to suppress HER2+ breast cancer metastasis.\",\n      \"evidence\": \"In vivo CRISPR knockout screen with mechanistic NEMO trafficking and autophagy-flux follow-up and patient tissue analysis\",\n      \"pmids\": [\"38363674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking p47 to lysosomal membrane repair not fully resolved\", \"Whether p97 ATPase activity drives NEMO trafficking not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified p47 from a systematic VCP-cofactor screen as a promoter of tau seed amplification, implicating the p97-p47 axis in a cytoplasmic proteopathic processing complex.\",\n      \"evidence\": \"Knockout/knockdown screen of 30 VCP cofactors with split-APEX2 proximity labeling and tau seeding assays in biosensor cells and human neurons\",\n      \"pmids\": [\"39773263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Composition of the cytoplasmic processing complex not fully defined\", \"Mechanism by which p47 enhances seed amplification not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the first backbone structural characterization of full-length p47, defining a UBA-SEP-UBX domain architecture linked by intrinsically disordered regions and a highly dynamic p97 complex.\",\n      \"evidence\": \"NMR backbone resonance assignments and secondary structure propensity analysis of full-length p47 and a SIM-SEP fragment\",\n      \"pmids\": [\"41188554\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Assignments only; no high-resolution structure of p47 or the p47-p97 complex\", \"No functional mutagenesis validating domain assignments\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how p47's distinct functions—Golgi reassembly, autophagy, NF-κB regulation, SAC control, tau seeding, and dendrite development—are coordinated through a single p97-cofactor scaffold and switched between substrate-processing and substrate-protecting outcomes.\",\n      \"evidence\": \"No single study in the timeline integrates these activities mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model of how domain state or phosphorylation selects among p47 functions\", \"No structure of the active p47-p97-substrate complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"p97/p47 complex\", \"Cdc48-Ubx1 complex\"],\n    \"partners\": [\"VCP\", \"PINK1\", \"USP9X\", \"AURKB\", \"Atg8\", \"NEMO\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}