{"gene":"JMY","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2009,"finding":"JMY combines two actin nucleation activities: it activates the Arp2/3 complex via a WCA module and directly nucleates unbranched actin filaments via a Spire-like mechanism using tandem WH2 domains. Increased JMY expression enhances cell motility, loss of JMY slows migration, and upon differentiation of HL-60 cells into neutrophil-like cells, JMY translocates from the nucleus to the cytoplasm and concentrates at the leading edge.","method":"In vitro actin nucleation assays, Arp2/3 activation assays, RNAi knockdown, overexpression, live-cell imaging/immunofluorescence for localization","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical and cell biological methods in a highly-cited foundational paper","pmids":["19287377"],"is_preprint":false},{"year":2006,"finding":"Mdm2 targets JMY for ubiquitin-dependent proteasomal degradation via its RING finger domain, thereby suppressing p53 cofactor activity. This regulation is independent of the p53-binding domain in Mdm2 and of p53 activity itself. DNA damage increases JMY protein levels, and Mdm2 inhibitors induce JMY in unperturbed cells.","method":"Ubiquitination assays, small-molecule Mdm2 inhibitors, domain mutant analysis, immunoblotting","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ubiquitination assay, RING mutant, pharmacological inhibition) in a well-cited paper","pmids":["17170761"],"is_preprint":false},{"year":2012,"finding":"JMY's three WH2 domains overlap with an atypical bipartite nuclear localization sequence (NLS). Actin monomers bound to the WH2 domains block importin binding to the NLS and prevent nuclear import. Mutations impairing actin binding, or cellular conditions that reduce monomeric actin (e.g., actin polymerization), cause JMY nuclear accumulation. DNA damage induces cytoplasmic actin polymerization and nuclear import of JMY via importin β, requiring the WH2/NLS region.","method":"Mutagenesis of WH2 domains/NLS, importin binding assays, live-cell imaging, subcellular fractionation, pharmacological perturbation of actin dynamics","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution-level binding assays combined with mutagenesis and cell imaging with functional consequence","pmids":["22262458"],"is_preprint":false},{"year":2011,"finding":"JMY is required for spindle migration, asymmetric division, and cytokinesis during mouse oocyte meiotic maturation. JMY localizes at the spindle and cytoplasm; RNAi depletion or antibody injection leads to symmetric division, failure of spindle migration, disrupted actin cap and cortical granule-free domain formation, and arrest at telophase I.","method":"RNAi knockdown, antibody injection, immunostaining, fluorescence microscopy in mouse oocytes","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — two orthogonal loss-of-function approaches (RNAi and antibody injection) with specific phenotypic readouts","pmids":["21266449"],"is_preprint":false},{"year":2011,"finding":"Full-length JMY's actin nucleation activity is suppressed in cells compared to its isolated WWWCA domain, indicating intramolecular autoinhibition. The WWWCA domain is sufficient for actin-based bead motility in cytoplasmic extracts in an Arp2/3-dependent manner. Silencing JMY in neuronal cells enhances neurite formation, a function requiring JMY's actin nucleation activity, identifying JMY as a negative regulator of neuritogenesis.","method":"In vitro actin nucleation assays, bead motility assay in cytoplasmic extracts, RNAi knockdown, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution plus cellular loss-of-function with specific mechanistic readouts, replicated independently from the founding paper","pmids":["21965285"],"is_preprint":false},{"year":2011,"finding":"JMY is upregulated during hypoxia in a HIF-1α-dependent manner; HIF-1α is recruited to HIF-responsive elements in the JMY promoter and drives JMY transcription. JMY is required for enhanced cell motility and invasion under hypoxic conditions, as JMY depletion under hypoxia decreases migration.","method":"ChIP for HIF-1α at JMY promoter, luciferase reporter assays, siRNA knockdown, cell migration/invasion assays under hypoxia","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — ChIP, reporter assay, and functional knockdown provide multiple orthogonal lines of evidence","pmids":["21625218"],"is_preprint":false},{"year":2014,"finding":"JMY localizes to dynamic vesiculo-tubular structures decorated with actin and Arp2/3 complex, interacts with VAP-A (involved in vesicle-based transport), and overexpression of JMY causes Golgi dispersal and impairs VSV-G anterograde transport from the trans-Golgi network, indicating a role in vesicular trafficking at the trans-Golgi region and ER membrane contact sites.","method":"Mass spectrometry interactome, co-immunoprecipitation, immunofluorescence co-localization, VSV-G transport assay, overexpression","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — MS-identified interaction validated by co-IP and functional transport assay, single lab","pmids":["25015719"],"is_preprint":false},{"year":2018,"finding":"JMY activates MRTF-A transcriptional activity and promotes its nuclear translocation via a nucleation-independent mechanism: JMY's WH2/V domains compete with MRTF-A's RPEL motifs for G-actin binding in the cytoplasm, freeing MRTF-A for nuclear entry. The C-terminal CA region of JMY exerts an autoinhibitory effect on this activity. MRTF-A activation by JMY is independent of Arp2/3 complex activity and F-actin.","method":"Co-immunoprecipitation, luciferase reporter assays, immunofluorescence, Arp3 knockdown, Arp2/3 inhibitor, latrunculin treatment, nuclear-restricted JMY constructs, recombinant actin competition assay","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including biochemical competition assay, pharmacological inhibition, domain deletion mutants, and reporter assays","pmids":["30463620"],"is_preprint":false},{"year":2019,"finding":"During autophagy, LC3 recruits JMY to the phagophore membrane and promotes its actin nucleation activity; membrane-bound LC3 is sufficient to recruit JMY and stimulate JMY-mediated actin filament assembly in a reconstituted system. TTC5/STRAP acts as a negative regulator of autophagy by binding to JMY and antagonizing its activation at the phagophore.","method":"In vitro reconstitution with membrane-bound LC3, co-immunoprecipitation, cellular autophagy assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution system plus identified binding partner with opposing regulatory functions","pmids":["30593260"],"is_preprint":false},{"year":2018,"finding":"JMY is required for oligodendrocyte differentiation by modulating actin cytoskeleton dynamics; Jmy knockdown disrupts actin filament assembly and protrusion formation, preventing oligodendrocytes from acquiring an arborized morphology and reducing their ability to contact neurites and form myelin wraps in neuron co-cultures.","method":"RNAi knockdown, live-cell imaging, quantitative morphodynamics, neuron-oligodendrocyte co-culture myelination assay","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi with specific morphological and functional phenotypic readouts, single lab","pmids":["29732611"],"is_preprint":false},{"year":2021,"finding":"JMY and WHAMM are required for rapid DNA damage-induced intrinsic apoptosis in a p53-dependent pathway. JMY-mediated apoptosis requires Arp2/3-dependent actin nucleation; actin filaments assemble in cytoplasmic territories containing cytochrome c clusters and active caspase-3, and JMY loss reduces mitochondrial permeabilization and caspase cleavage. JMY loss also upregulates RhoD, which promotes cell survival.","method":"WASP-family gene inactivation (CRISPR/siRNA), caspase activation assays, cytochrome c release assay, immunofluorescence, gene expression analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic inactivation, organelle permeabilization assays, and localization studies establish pathway position","pmids":["33872315"],"is_preprint":false},{"year":2020,"finding":"JMY affects Sertoli cell blood-testis barrier (BTB) function through remodeling of junctional integrity and controls endocytic vesicle trafficking; Sertoli cell-specific Jmy knockout in mice causes impaired BTB integrity, spermatid adhesion defects, sperm structural deformity, and reduced fertility. JMY interacts with α-actinin1 and SORBS2 (sorbin and SH3 domain containing protein 2) to regulate actin cytoskeletal organization.","method":"Conditional knockout (Sertoli cell-specific), co-immunoprecipitation, immunofluorescence, sperm analysis","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with specific in vivo phenotype plus co-IP of binding partners, single lab","pmids":["32279424"],"is_preprint":false},{"year":2023,"finding":"Nuclear JMY, via its Arp2/3-dependent actin nucleation function, is required for effective p53-dependent regulation of DNA repair target genes (XPC, XRCC5/Ku80, TP53I3/PIG3). JMY depletion or knockout leads to increased DNA damage accumulation, and cells show reduced survival and increased sensitivity to DNA damage response kinase inhibitors.","method":"Transcriptomics, CRISPR knockout, siRNA knockdown, comet assay/DNA damage markers, domain mutant rescue experiments, cell survival assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (KO, KD, domain mutants, transcriptomics, DNA damage assays) establish mechanistic pathway position","pmids":["37142657"],"is_preprint":false},{"year":2020,"finding":"Ionizing radiation stabilizes HIF-1α in glioblastoma stem-like cells, which transcriptionally activates JMY; JMY then accumulates in the cytoplasm and promotes GSC migration via its actin nucleation-promoting activity, establishing a HIF1α→JMY→actin nucleation→motility pathway in irradiated GSCs.","method":"siRNA knockdown of JMY and HIF-1α, cell migration assays, immunofluorescence, irradiation experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional knockdown with pathway epistasis supported by localization data, single lab","pmids":["33128011"],"is_preprint":false},{"year":2025,"finding":"PCSK9 loss disrupts the cellular microfilament network via the LIN28A/HES5/JMY axis: PCSK9 promotes LIN28A degradation via the lysosomal pathway; LIN28A is an RNA-binding protein that regulates JMY expression through the transcription factor HES5. JMY overexpression in zebrafish worsens neural tube defects caused by PCSK9 loss, confirming JMY as a downstream effector.","method":"PCSK9 knockout ESC/neural organoid/NPC models, transcriptome sequencing, zebrafish overexpression, lysosomal inhibition assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — multi-model mechanistic epistasis with in vivo zebrafish validation, single lab","pmids":["40788992"],"is_preprint":false}],"current_model":"JMY is a multifunctional protein that nucleates actin filaments by two mechanisms — direct Spire-like nucleation via tandem WH2 domains and Arp2/3 complex activation via its WCA module — and its subcellular localization between cytoplasm and nucleus is regulated by actin monomer occupancy of its WH2/NLS region (blocking importin binding) and by LC3-mediated phagophore recruitment; in the cytoplasm JMY promotes cell migration, Golgi vesicle trafficking, apoptosis (via Arp2/3-dependent actin assembly near mitochondria), and MRTF-A activation by competing with RPEL motifs for G-actin, while in the nucleus JMY acts as a p53 cofactor (in a complex with p300/CBP, ASPP, and STRAP) to drive DNA repair gene transcription, and its protein level is controlled by Mdm2-mediated ubiquitin-dependent degradation and transcriptionally induced by HIF-1α."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing how JMY protein levels are controlled resolved a key regulatory question: Mdm2 directly targets JMY for ubiquitin-dependent degradation via its RING finger domain, independently of p53, explaining how DNA damage stabilizes JMY to augment p53 cofactor function.","evidence":"Ubiquitination assays, Mdm2 RING mutants, pharmacological Mdm2 inhibition, and immunoblotting in human cell lines","pmids":["17170761"],"confidence":"High","gaps":["Identity of deubiquitinases that counteract Mdm2-mediated JMY turnover unknown","No structural basis for Mdm2-JMY recognition"]},{"year":2009,"claim":"The discovery that JMY possesses dual actin nucleation activities — Arp2/3 activation via WCA and Spire-like nucleation via tandem WH2 domains — established it as the first protein combining both mechanisms, redefining JMY from a transcriptional cofactor to a cytoskeletal regulator of cell motility.","evidence":"In vitro pyrene-actin nucleation assays, Arp2/3 activation assays, RNAi and overexpression in HL-60 and adherent cells, live-cell migration imaging","pmids":["19287377"],"confidence":"High","gaps":["Mechanism of autoinhibition of full-length JMY not resolved in this study","Relative contributions of Arp2/3-dependent versus Spire-like nucleation in vivo unclear"]},{"year":2011,"claim":"Multiple studies collectively revealed JMY's functional breadth: autoinhibition suppresses full-length JMY's nucleation in cells, JMY is transcriptionally induced by HIF-1α to drive hypoxic migration, and JMY is required for asymmetric division in oocyte meiosis.","evidence":"In vitro nucleation and bead motility assays identifying autoinhibition (PMID:21965285); ChIP/reporter assays for HIF-1α at JMY promoter plus siRNA migration assays under hypoxia (PMID:21625218); RNAi and antibody injection in mouse oocytes with spindle migration phenotyping (PMID:21266449)","pmids":["21965285","21625218","21266449"],"confidence":"High","gaps":["Mechanism by which autoinhibition is relieved in vivo unresolved","Whether HIF-1α-driven JMY induction uses the same nucleation mode as normoxic JMY unclear","Role of JMY's nuclear vs cytoplasmic pools in oocyte maturation not distinguished"]},{"year":2012,"claim":"A key question — how does JMY switch between cytoplasmic and nuclear pools? — was answered by demonstrating that the WH2 domains overlap with the NLS, so G-actin binding occludes importin recognition; DNA damage-induced actin polymerization frees the NLS for importin-β-mediated nuclear import.","evidence":"WH2/NLS mutagenesis, importin binding assays, subcellular fractionation, live-cell imaging, pharmacological actin perturbation","pmids":["22262458"],"confidence":"High","gaps":["Post-translational modifications that may further regulate nuclear import not identified","Kinetics of NLS exposure in living cells not quantified"]},{"year":2014,"claim":"Extending JMY's cytoplasmic roles beyond migration, JMY was shown to localize to vesiculo-tubular structures and interact with VAP-A, with overexpression dispersing the Golgi and impairing VSV-G anterograde transport, implicating JMY in actin-dependent vesicular trafficking at the trans-Golgi network.","evidence":"Mass spectrometry interactome, co-immunoprecipitation of VAP-A, immunofluorescence co-localization, VSV-G transport assay","pmids":["25015719"],"confidence":"Medium","gaps":["Overexpression-based phenotype; loss-of-function confirmation for trafficking role lacking","Whether JMY-VAP-A interaction is direct or mediated by a bridging factor not resolved"]},{"year":2018,"claim":"Two studies expanded JMY's functional repertoire: JMY activates MRTF-A by competing with RPEL motifs for G-actin in a nucleation-independent manner, and JMY is required for oligodendrocyte morphogenesis and myelination through actin-dependent protrusion dynamics.","evidence":"Recombinant actin competition assays, Arp2/3 inhibitor/knockdown confirming nucleation-independence, luciferase reporter for MRTF-A (PMID:30463620); RNAi in oligodendrocytes with live morphodynamics and neuron co-culture myelination assays (PMID:29732611)","pmids":["30463620","29732611"],"confidence":"High","gaps":["Physiological relevance of JMY-MRTF-A axis in vivo not tested","Whether JMY's role in myelination requires nuclear or cytoplasmic activity undetermined"]},{"year":2019,"claim":"JMY's role in autophagy was mechanistically defined: membrane-bound LC3 directly recruits JMY to phagophores and stimulates its actin nucleation activity, while TTC5/STRAP antagonizes this recruitment, establishing a regulated actin-dependent step in autophagosome formation.","evidence":"In vitro reconstitution with LC3-decorated membranes, co-immunoprecipitation, cellular autophagy flux assays","pmids":["30593260"],"confidence":"High","gaps":["Whether JMY's Spire-like or Arp2/3-dependent nucleation mode predominates at the phagophore unresolved","In vivo autophagy phenotype in JMY knockout animals not reported"]},{"year":2020,"claim":"Conditional knockout studies in mice demonstrated JMY's in vivo requirement: Sertoli cell-specific Jmy deletion impaired blood-testis barrier integrity, spermatid adhesion, and male fertility, with JMY interacting with α-actinin1 and SORBS2 to organize junctional actin; separately, irradiated glioblastoma stem cells use the HIF-1α→JMY pathway for radiation-induced migration.","evidence":"Sertoli cell-specific Jmy conditional knockout with sperm/BTB analysis and co-IP of partners (PMID:32279424); siRNA of JMY/HIF-1α in irradiated GSCs with migration and localization assays (PMID:33128011)","pmids":["32279424","33128011"],"confidence":"Medium","gaps":["Mechanism linking JMY to BTB tight junction proteins not fully delineated","Whether JMY drives invasion or only migration in GSCs in vivo unknown"]},{"year":2021,"claim":"A long-standing question about JMY's pro-apoptotic function was mechanistically resolved: JMY drives DNA damage-induced intrinsic apoptosis through Arp2/3-dependent actin assembly near mitochondria, promoting cytochrome c release and caspase activation, while JMY loss upregulates the survival factor RhoD.","evidence":"CRISPR and siRNA inactivation of WASP-family genes, caspase/cytochrome c assays, immunofluorescence of actin-cytochrome c co-territories, gene expression analysis","pmids":["33872315"],"confidence":"High","gaps":["How Arp2/3-nucleated actin physically promotes mitochondrial outer membrane permeabilization is mechanistically unresolved","Direct interaction between JMY-nucleated actin filaments and mitochondria not demonstrated"]},{"year":2023,"claim":"The nuclear function of JMY in DNA repair was mechanistically clarified: nuclear JMY uses Arp2/3-dependent actin nucleation to enable p53-dependent transcription of DNA repair genes (XPC, XRCC5, TP53I3), and JMY loss increases DNA damage accumulation and sensitizes cells to DDR kinase inhibitors.","evidence":"Transcriptomics, CRISPR knockout, siRNA, comet assay, domain mutant rescue, cell survival assays","pmids":["37142657"],"confidence":"High","gaps":["How nuclear actin nucleation by JMY facilitates p53-dependent transcription at the chromatin level is unknown","Whether JMY nucleates actin at specific genomic loci or broadly in the nucleoplasm unresolved"]},{"year":2025,"claim":"JMY was placed downstream of a PCSK9→LIN28A→HES5 axis controlling microfilament integrity in neural progenitors, with JMY overexpression worsening neural tube defects in zebrafish PCSK9-loss models.","evidence":"PCSK9 knockout ESC/neural organoid models, transcriptome sequencing, zebrafish JMY overexpression","pmids":["40788992"],"confidence":"Medium","gaps":["Whether endogenous JMY levels are rate-limiting for neural tube closure in mammals untested","Direct transcriptional regulation of JMY by HES5 not demonstrated at the promoter level"]},{"year":null,"claim":"Critical open questions remain: what relieves JMY's autoinhibition in specific cellular contexts, what is the structural basis for autoinhibition, and how does nuclear actin nucleated by JMY mechanistically facilitate p53-dependent transcription at target gene loci.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of full-length JMY available","Activating signals or co-factors that relieve autoinhibition in vivo not identified","Functional separation of JMY's Spire-like vs Arp2/3-dependent activities in specific biological contexts incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,4,9,10,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,10]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[6]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[6,8]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,5,13]}],"complexes":[],"partners":["ACTR2","ACTR3","VAPA","LC3","TTC5","ACTN1","SORBS2","MDM2"],"other_free_text":[]},"mechanistic_narrative":"JMY is a multifunctional actin nucleation factor that integrates cytoskeletal remodeling with transcriptional regulation, autophagy, and apoptosis. It nucleates actin filaments by two mechanisms — direct Spire-like nucleation via tandem WH2 domains and Arp2/3 complex activation via its C-terminal WCA module — and its nucleocytoplasmic distribution is governed by actin monomer occupancy of a WH2/NLS overlap region that blocks importin binding when G-actin is bound [PMID:19287377, PMID:22262458]. In the cytoplasm, JMY promotes cell migration, Golgi vesicular trafficking, oligodendrocyte morphogenesis, and LC3-mediated phagophore actin assembly during autophagy, while also driving Arp2/3-dependent mitochondrial permeabilization during DNA damage-induced apoptosis; additionally, JMY activates MRTF-A by competing with RPEL motifs for G-actin independently of its nucleation activity [PMID:30463620, PMID:33872315, PMID:30593260, PMID:25015719]. In the nucleus, JMY functions as a p53 cofactor whose Arp2/3-dependent actin nucleation is required for transcriptional activation of DNA repair genes such as XPC and XRCC5, and its protein levels are controlled by Mdm2-mediated ubiquitin-dependent degradation and transcriptionally induced by HIF-1α under hypoxia [PMID:37142657, PMID:17170761, PMID:21625218]."},"prefetch_data":{"uniprot":{"accession":"Q8N9B5","full_name":"Junction-mediating and -regulatory protein","aliases":[],"length_aa":988,"mass_kda":111.4,"function":"Acts both as a nuclear p53/TP53-cofactor and a cytoplasmic regulator of actin dynamics depending on conditions (PubMed:30420355). In nucleus, acts as a cofactor that increases p53/TP53 response via its interaction with p300/EP300. Increases p53/TP53-dependent transcription and apoptosis, suggesting an important role in p53/TP53 stress response such as DNA damage. In cytoplasm, acts as a nucleation-promoting factor for both branched and unbranched actin filaments (PubMed:30420355). Activates the Arp2/3 complex to induce branched actin filament networks. Also catalyzes actin polymerization in the absence of Arp2/3, creating unbranched filaments (PubMed:30420355). Contributes to cell motility by controlling actin dynamics. May promote the rapid formation of a branched actin network by first nucleating new mother filaments and then activating Arp2/3 to branch off these filaments. Upon nutrient stress, directly recruited by MAP1LC3B to the phagophore membrane surfaces to promote actin assembly during autophagy (PubMed:30420355). The p53/TP53-cofactor and actin activator activities are regulated via its subcellular location (By similarity)","subcellular_location":"Nucleus; Cytoplasmic vesicle; Cytoplasm, cytoskeleton; Endomembrane system; Cytoplasmic vesicle, autophagosome membrane","url":"https://www.uniprot.org/uniprotkb/Q8N9B5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JMY","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/JMY","total_profiled":1310},"omim":[{"mim_id":"619014","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 5; TTC5","url":"https://www.omim.org/entry/619014"},{"mim_id":"617075","title":"NASOPHARYNGEAL CARCINOMA, SUSCEPTIBILITY TO, 3; NPCA3","url":"https://www.omim.org/entry/617075"},{"mim_id":"613208","title":"XPC COMPLEX SUBUNIT, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPC","url":"https://www.omim.org/entry/613208"},{"mim_id":"612393","title":"WAS PROTEIN HOMOLOG ASSOCIATED WITH ACTIN, GOLGI MEMBRANES, AND MICROTUBULES; WHAMM","url":"https://www.omim.org/entry/612393"},{"mim_id":"605421","title":"A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 9; ADAMTS9","url":"https://www.omim.org/entry/605421"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/JMY"},"hgnc":{"alias_symbol":["FLJ37870","WHAMM2"],"prev_symbol":[]},"alphafold":{"accession":"Q8N9B5","domains":[{"cath_id":"3.30.1520.10","chopping":"27-61_227-265_274-321","consensus_level":"medium","plddt":76.8788,"start":27,"end":321},{"cath_id":"-","chopping":"323-488","consensus_level":"medium","plddt":93.615,"start":323,"end":488},{"cath_id":"1.10.287","chopping":"514-568_600-656","consensus_level":"medium","plddt":92.54,"start":514,"end":656}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N9B5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N9B5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N9B5-F1-predicted_aligned_error_v6.png","plddt_mean":65.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JMY","jax_strain_url":"https://www.jax.org/strain/search?query=JMY"},"sequence":{"accession":"Q8N9B5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N9B5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N9B5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N9B5"}},"corpus_meta":[{"pmid":"19287377","id":"PMC_19287377","title":"p53-cofactor JMY is a multifunctional actin nucleation factor.","date":"2009","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19287377","citation_count":209,"is_preprint":false},{"pmid":"20888769","id":"PMC_20888769","title":"WASH, WHAMM and JMY: regulation of Arp2/3 complex and beyond.","date":"2010","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20888769","citation_count":150,"is_preprint":false},{"pmid":"17170761","id":"PMC_17170761","title":"Mdm2 targets the p53 transcription cofactor JMY for degradation.","date":"2006","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/17170761","citation_count":64,"is_preprint":false},{"pmid":"22262458","id":"PMC_22262458","title":"Actin binding to WH2 domains regulates nuclear import of the multifunctional actin regulator JMY.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22262458","citation_count":50,"is_preprint":false},{"pmid":"21266449","id":"PMC_21266449","title":"JMY is required for asymmetric division and cytokinesis in mouse oocytes.","date":"2011","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/21266449","citation_count":49,"is_preprint":false},{"pmid":"34326916","id":"PMC_34326916","title":"Exosomal miR-218-5p/miR-363-3p from Endothelial Progenitor Cells Ameliorate Myocardial Infarction by Targeting the p53/JMY Signaling Pathway.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34326916","citation_count":49,"is_preprint":false},{"pmid":"21965285","id":"PMC_21965285","title":"The actin nucleation factor JMY is a negative regulator of neuritogenesis.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21965285","citation_count":35,"is_preprint":false},{"pmid":"25015719","id":"PMC_25015719","title":"JMY is involved in anterograde vesicle trafficking from the trans-Golgi network.","date":"2014","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25015719","citation_count":33,"is_preprint":false},{"pmid":"21625218","id":"PMC_21625218","title":"Hypoxia-driven cell motility reflects the interplay between JMY and HIF-1α.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21625218","citation_count":31,"is_preprint":false},{"pmid":"29732611","id":"PMC_29732611","title":"Jmy regulates oligodendrocyte differentiation via modulation of actin cytoskeleton dynamics.","date":"2018","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/29732611","citation_count":27,"is_preprint":false},{"pmid":"37142657","id":"PMC_37142657","title":"p53-dependent DNA repair during the DNA damage response requires actin nucleation by JMY.","date":"2023","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/37142657","citation_count":22,"is_preprint":false},{"pmid":"29857553","id":"PMC_29857553","title":"The Role of JMY in p53 Regulation.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/29857553","citation_count":18,"is_preprint":false},{"pmid":"28133594","id":"PMC_28133594","title":"Online flow cytometry, an interesting investigation process for monitoring lipid accumulation, dimorphism, and cells' growth in the oleaginous yeast Yarrowia lipolytica JMY 775.","date":"2017","source":"Bioresources and bioprocessing","url":"https://pubmed.ncbi.nlm.nih.gov/28133594","citation_count":16,"is_preprint":false},{"pmid":"25279558","id":"PMC_25279558","title":"JMY functions as actin nucleation-promoting factor and mediator for p53-mediated DNA damage in porcine oocytes.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25279558","citation_count":12,"is_preprint":false},{"pmid":"33872315","id":"PMC_33872315","title":"The actin nucleation factors JMY and WHAMM enable a rapid Arp2/3 complex-mediated intrinsic pathway of apoptosis.","date":"2021","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33872315","citation_count":12,"is_preprint":false},{"pmid":"32279424","id":"PMC_32279424","title":"JMY expression by Sertoli cells contributes to mediating spermatogenesis in mice.","date":"2020","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/32279424","citation_count":11,"is_preprint":false},{"pmid":"30593260","id":"PMC_30593260","title":"Regulation of JMY's actin nucleation activity by TTC5/STRAP and LC3 during autophagy.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30593260","citation_count":10,"is_preprint":false},{"pmid":"25280461","id":"PMC_25280461","title":"JMY protein, a regulator of P53 and cytoplasmic actin filaments, is expressed in normal and neoplastic tissues.","date":"2014","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25280461","citation_count":10,"is_preprint":false},{"pmid":"19337319","id":"PMC_19337319","title":"Double JMY: making actin fast.","date":"2009","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19337319","citation_count":9,"is_preprint":false},{"pmid":"33128011","id":"PMC_33128011","title":"The HIF1α/JMY pathway promotes glioblastoma stem-like cell invasiveness after irradiation.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33128011","citation_count":7,"is_preprint":false},{"pmid":"26052154","id":"PMC_26052154","title":"Junction-mediating and regulatory protein (JMY) is essential for early porcine embryonic development.","date":"2015","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/26052154","citation_count":6,"is_preprint":false},{"pmid":"39736291","id":"PMC_39736291","title":"Mmu_circ_0001148 promotes endothlial-mesenchymal transition via regulating miR-218-5p/JMY axis and drives progression of atherosclerosis.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39736291","citation_count":5,"is_preprint":false},{"pmid":"40817234","id":"PMC_40817234","title":"m6A-modified circZNF548 regulates exosomal miR-7108-3p to activate CD3+CD8+ T cells and suppress NSCLC growth by JMY.","date":"2025","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/40817234","citation_count":4,"is_preprint":false},{"pmid":"38069185","id":"PMC_38069185","title":"Changes of Ex Vivo Cervical Epithelial Cells Due to Electroporation with JMY.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38069185","citation_count":4,"is_preprint":false},{"pmid":"30463620","id":"PMC_30463620","title":"Regulation of MRTF-A by JMY via a nucleation-independent mechanism.","date":"2018","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/30463620","citation_count":3,"is_preprint":false},{"pmid":"40788992","id":"PMC_40788992","title":"PCSK9 Loss-of-Function Disrupts Cellular Microfilament Network via LIN28A/HES5/JMY Axis in Neural Tube Defects.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40788992","citation_count":1,"is_preprint":false},{"pmid":"41748532","id":"PMC_41748532","title":"Junction-mediating and regulatory protein (JMY) is a promoting protein for radial migration of cortical neurons.","date":"2026","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41748532","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12414,"output_tokens":3966,"usd":0.048366},"stage2":{"model":"claude-opus-4-6","input_tokens":7418,"output_tokens":3544,"usd":0.188535},"total_usd":0.236901,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"JMY combines two actin nucleation activities: it activates the Arp2/3 complex via a WCA module and directly nucleates unbranched actin filaments via a Spire-like mechanism using tandem WH2 domains. Increased JMY expression enhances cell motility, loss of JMY slows migration, and upon differentiation of HL-60 cells into neutrophil-like cells, JMY translocates from the nucleus to the cytoplasm and concentrates at the leading edge.\",\n      \"method\": \"In vitro actin nucleation assays, Arp2/3 activation assays, RNAi knockdown, overexpression, live-cell imaging/immunofluorescence for localization\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical and cell biological methods in a highly-cited foundational paper\",\n      \"pmids\": [\"19287377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mdm2 targets JMY for ubiquitin-dependent proteasomal degradation via its RING finger domain, thereby suppressing p53 cofactor activity. This regulation is independent of the p53-binding domain in Mdm2 and of p53 activity itself. DNA damage increases JMY protein levels, and Mdm2 inhibitors induce JMY in unperturbed cells.\",\n      \"method\": \"Ubiquitination assays, small-molecule Mdm2 inhibitors, domain mutant analysis, immunoblotting\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ubiquitination assay, RING mutant, pharmacological inhibition) in a well-cited paper\",\n      \"pmids\": [\"17170761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JMY's three WH2 domains overlap with an atypical bipartite nuclear localization sequence (NLS). Actin monomers bound to the WH2 domains block importin binding to the NLS and prevent nuclear import. Mutations impairing actin binding, or cellular conditions that reduce monomeric actin (e.g., actin polymerization), cause JMY nuclear accumulation. DNA damage induces cytoplasmic actin polymerization and nuclear import of JMY via importin β, requiring the WH2/NLS region.\",\n      \"method\": \"Mutagenesis of WH2 domains/NLS, importin binding assays, live-cell imaging, subcellular fractionation, pharmacological perturbation of actin dynamics\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution-level binding assays combined with mutagenesis and cell imaging with functional consequence\",\n      \"pmids\": [\"22262458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JMY is required for spindle migration, asymmetric division, and cytokinesis during mouse oocyte meiotic maturation. JMY localizes at the spindle and cytoplasm; RNAi depletion or antibody injection leads to symmetric division, failure of spindle migration, disrupted actin cap and cortical granule-free domain formation, and arrest at telophase I.\",\n      \"method\": \"RNAi knockdown, antibody injection, immunostaining, fluorescence microscopy in mouse oocytes\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal loss-of-function approaches (RNAi and antibody injection) with specific phenotypic readouts\",\n      \"pmids\": [\"21266449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Full-length JMY's actin nucleation activity is suppressed in cells compared to its isolated WWWCA domain, indicating intramolecular autoinhibition. The WWWCA domain is sufficient for actin-based bead motility in cytoplasmic extracts in an Arp2/3-dependent manner. Silencing JMY in neuronal cells enhances neurite formation, a function requiring JMY's actin nucleation activity, identifying JMY as a negative regulator of neuritogenesis.\",\n      \"method\": \"In vitro actin nucleation assays, bead motility assay in cytoplasmic extracts, RNAi knockdown, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution plus cellular loss-of-function with specific mechanistic readouts, replicated independently from the founding paper\",\n      \"pmids\": [\"21965285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JMY is upregulated during hypoxia in a HIF-1α-dependent manner; HIF-1α is recruited to HIF-responsive elements in the JMY promoter and drives JMY transcription. JMY is required for enhanced cell motility and invasion under hypoxic conditions, as JMY depletion under hypoxia decreases migration.\",\n      \"method\": \"ChIP for HIF-1α at JMY promoter, luciferase reporter assays, siRNA knockdown, cell migration/invasion assays under hypoxia\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, reporter assay, and functional knockdown provide multiple orthogonal lines of evidence\",\n      \"pmids\": [\"21625218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JMY localizes to dynamic vesiculo-tubular structures decorated with actin and Arp2/3 complex, interacts with VAP-A (involved in vesicle-based transport), and overexpression of JMY causes Golgi dispersal and impairs VSV-G anterograde transport from the trans-Golgi network, indicating a role in vesicular trafficking at the trans-Golgi region and ER membrane contact sites.\",\n      \"method\": \"Mass spectrometry interactome, co-immunoprecipitation, immunofluorescence co-localization, VSV-G transport assay, overexpression\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — MS-identified interaction validated by co-IP and functional transport assay, single lab\",\n      \"pmids\": [\"25015719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMY activates MRTF-A transcriptional activity and promotes its nuclear translocation via a nucleation-independent mechanism: JMY's WH2/V domains compete with MRTF-A's RPEL motifs for G-actin binding in the cytoplasm, freeing MRTF-A for nuclear entry. The C-terminal CA region of JMY exerts an autoinhibitory effect on this activity. MRTF-A activation by JMY is independent of Arp2/3 complex activity and F-actin.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assays, immunofluorescence, Arp3 knockdown, Arp2/3 inhibitor, latrunculin treatment, nuclear-restricted JMY constructs, recombinant actin competition assay\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including biochemical competition assay, pharmacological inhibition, domain deletion mutants, and reporter assays\",\n      \"pmids\": [\"30463620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"During autophagy, LC3 recruits JMY to the phagophore membrane and promotes its actin nucleation activity; membrane-bound LC3 is sufficient to recruit JMY and stimulate JMY-mediated actin filament assembly in a reconstituted system. TTC5/STRAP acts as a negative regulator of autophagy by binding to JMY and antagonizing its activation at the phagophore.\",\n      \"method\": \"In vitro reconstitution with membrane-bound LC3, co-immunoprecipitation, cellular autophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution system plus identified binding partner with opposing regulatory functions\",\n      \"pmids\": [\"30593260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMY is required for oligodendrocyte differentiation by modulating actin cytoskeleton dynamics; Jmy knockdown disrupts actin filament assembly and protrusion formation, preventing oligodendrocytes from acquiring an arborized morphology and reducing their ability to contact neurites and form myelin wraps in neuron co-cultures.\",\n      \"method\": \"RNAi knockdown, live-cell imaging, quantitative morphodynamics, neuron-oligodendrocyte co-culture myelination assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with specific morphological and functional phenotypic readouts, single lab\",\n      \"pmids\": [\"29732611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JMY and WHAMM are required for rapid DNA damage-induced intrinsic apoptosis in a p53-dependent pathway. JMY-mediated apoptosis requires Arp2/3-dependent actin nucleation; actin filaments assemble in cytoplasmic territories containing cytochrome c clusters and active caspase-3, and JMY loss reduces mitochondrial permeabilization and caspase cleavage. JMY loss also upregulates RhoD, which promotes cell survival.\",\n      \"method\": \"WASP-family gene inactivation (CRISPR/siRNA), caspase activation assays, cytochrome c release assay, immunofluorescence, gene expression analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic inactivation, organelle permeabilization assays, and localization studies establish pathway position\",\n      \"pmids\": [\"33872315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMY affects Sertoli cell blood-testis barrier (BTB) function through remodeling of junctional integrity and controls endocytic vesicle trafficking; Sertoli cell-specific Jmy knockout in mice causes impaired BTB integrity, spermatid adhesion defects, sperm structural deformity, and reduced fertility. JMY interacts with α-actinin1 and SORBS2 (sorbin and SH3 domain containing protein 2) to regulate actin cytoskeletal organization.\",\n      \"method\": \"Conditional knockout (Sertoli cell-specific), co-immunoprecipitation, immunofluorescence, sperm analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with specific in vivo phenotype plus co-IP of binding partners, single lab\",\n      \"pmids\": [\"32279424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear JMY, via its Arp2/3-dependent actin nucleation function, is required for effective p53-dependent regulation of DNA repair target genes (XPC, XRCC5/Ku80, TP53I3/PIG3). JMY depletion or knockout leads to increased DNA damage accumulation, and cells show reduced survival and increased sensitivity to DNA damage response kinase inhibitors.\",\n      \"method\": \"Transcriptomics, CRISPR knockout, siRNA knockdown, comet assay/DNA damage markers, domain mutant rescue experiments, cell survival assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (KO, KD, domain mutants, transcriptomics, DNA damage assays) establish mechanistic pathway position\",\n      \"pmids\": [\"37142657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ionizing radiation stabilizes HIF-1α in glioblastoma stem-like cells, which transcriptionally activates JMY; JMY then accumulates in the cytoplasm and promotes GSC migration via its actin nucleation-promoting activity, establishing a HIF1α→JMY→actin nucleation→motility pathway in irradiated GSCs.\",\n      \"method\": \"siRNA knockdown of JMY and HIF-1α, cell migration assays, immunofluorescence, irradiation experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional knockdown with pathway epistasis supported by localization data, single lab\",\n      \"pmids\": [\"33128011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PCSK9 loss disrupts the cellular microfilament network via the LIN28A/HES5/JMY axis: PCSK9 promotes LIN28A degradation via the lysosomal pathway; LIN28A is an RNA-binding protein that regulates JMY expression through the transcription factor HES5. JMY overexpression in zebrafish worsens neural tube defects caused by PCSK9 loss, confirming JMY as a downstream effector.\",\n      \"method\": \"PCSK9 knockout ESC/neural organoid/NPC models, transcriptome sequencing, zebrafish overexpression, lysosomal inhibition assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-model mechanistic epistasis with in vivo zebrafish validation, single lab\",\n      \"pmids\": [\"40788992\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JMY is a multifunctional protein that nucleates actin filaments by two mechanisms — direct Spire-like nucleation via tandem WH2 domains and Arp2/3 complex activation via its WCA module — and its subcellular localization between cytoplasm and nucleus is regulated by actin monomer occupancy of its WH2/NLS region (blocking importin binding) and by LC3-mediated phagophore recruitment; in the cytoplasm JMY promotes cell migration, Golgi vesicle trafficking, apoptosis (via Arp2/3-dependent actin assembly near mitochondria), and MRTF-A activation by competing with RPEL motifs for G-actin, while in the nucleus JMY acts as a p53 cofactor (in a complex with p300/CBP, ASPP, and STRAP) to drive DNA repair gene transcription, and its protein level is controlled by Mdm2-mediated ubiquitin-dependent degradation and transcriptionally induced by HIF-1α.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"JMY is a multifunctional actin nucleation factor that integrates cytoskeletal remodeling with transcriptional regulation, autophagy, and apoptosis. It nucleates actin filaments by two mechanisms — direct Spire-like nucleation via tandem WH2 domains and Arp2/3 complex activation via its C-terminal WCA module — and its nucleocytoplasmic distribution is governed by actin monomer occupancy of a WH2/NLS overlap region that blocks importin binding when G-actin is bound [PMID:19287377, PMID:22262458]. In the cytoplasm, JMY promotes cell migration, Golgi vesicular trafficking, oligodendrocyte morphogenesis, and LC3-mediated phagophore actin assembly during autophagy, while also driving Arp2/3-dependent mitochondrial permeabilization during DNA damage-induced apoptosis; additionally, JMY activates MRTF-A by competing with RPEL motifs for G-actin independently of its nucleation activity [PMID:30463620, PMID:33872315, PMID:30593260, PMID:25015719]. In the nucleus, JMY functions as a p53 cofactor whose Arp2/3-dependent actin nucleation is required for transcriptional activation of DNA repair genes such as XPC and XRCC5, and its protein levels are controlled by Mdm2-mediated ubiquitin-dependent degradation and transcriptionally induced by HIF-1α under hypoxia [PMID:37142657, PMID:17170761, PMID:21625218].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing how JMY protein levels are controlled resolved a key regulatory question: Mdm2 directly targets JMY for ubiquitin-dependent degradation via its RING finger domain, independently of p53, explaining how DNA damage stabilizes JMY to augment p53 cofactor function.\",\n      \"evidence\": \"Ubiquitination assays, Mdm2 RING mutants, pharmacological Mdm2 inhibition, and immunoblotting in human cell lines\",\n      \"pmids\": [\"17170761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of deubiquitinases that counteract Mdm2-mediated JMY turnover unknown\", \"No structural basis for Mdm2-JMY recognition\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The discovery that JMY possesses dual actin nucleation activities — Arp2/3 activation via WCA and Spire-like nucleation via tandem WH2 domains — established it as the first protein combining both mechanisms, redefining JMY from a transcriptional cofactor to a cytoskeletal regulator of cell motility.\",\n      \"evidence\": \"In vitro pyrene-actin nucleation assays, Arp2/3 activation assays, RNAi and overexpression in HL-60 and adherent cells, live-cell migration imaging\",\n      \"pmids\": [\"19287377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of autoinhibition of full-length JMY not resolved in this study\", \"Relative contributions of Arp2/3-dependent versus Spire-like nucleation in vivo unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Multiple studies collectively revealed JMY's functional breadth: autoinhibition suppresses full-length JMY's nucleation in cells, JMY is transcriptionally induced by HIF-1α to drive hypoxic migration, and JMY is required for asymmetric division in oocyte meiosis.\",\n      \"evidence\": \"In vitro nucleation and bead motility assays identifying autoinhibition (PMID:21965285); ChIP/reporter assays for HIF-1α at JMY promoter plus siRNA migration assays under hypoxia (PMID:21625218); RNAi and antibody injection in mouse oocytes with spindle migration phenotyping (PMID:21266449)\",\n      \"pmids\": [\"21965285\", \"21625218\", \"21266449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which autoinhibition is relieved in vivo unresolved\", \"Whether HIF-1α-driven JMY induction uses the same nucleation mode as normoxic JMY unclear\", \"Role of JMY's nuclear vs cytoplasmic pools in oocyte maturation not distinguished\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A key question — how does JMY switch between cytoplasmic and nuclear pools? — was answered by demonstrating that the WH2 domains overlap with the NLS, so G-actin binding occludes importin recognition; DNA damage-induced actin polymerization frees the NLS for importin-β-mediated nuclear import.\",\n      \"evidence\": \"WH2/NLS mutagenesis, importin binding assays, subcellular fractionation, live-cell imaging, pharmacological actin perturbation\",\n      \"pmids\": [\"22262458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-translational modifications that may further regulate nuclear import not identified\", \"Kinetics of NLS exposure in living cells not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extending JMY's cytoplasmic roles beyond migration, JMY was shown to localize to vesiculo-tubular structures and interact with VAP-A, with overexpression dispersing the Golgi and impairing VSV-G anterograde transport, implicating JMY in actin-dependent vesicular trafficking at the trans-Golgi network.\",\n      \"evidence\": \"Mass spectrometry interactome, co-immunoprecipitation of VAP-A, immunofluorescence co-localization, VSV-G transport assay\",\n      \"pmids\": [\"25015719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based phenotype; loss-of-function confirmation for trafficking role lacking\", \"Whether JMY-VAP-A interaction is direct or mediated by a bridging factor not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two studies expanded JMY's functional repertoire: JMY activates MRTF-A by competing with RPEL motifs for G-actin in a nucleation-independent manner, and JMY is required for oligodendrocyte morphogenesis and myelination through actin-dependent protrusion dynamics.\",\n      \"evidence\": \"Recombinant actin competition assays, Arp2/3 inhibitor/knockdown confirming nucleation-independence, luciferase reporter for MRTF-A (PMID:30463620); RNAi in oligodendrocytes with live morphodynamics and neuron co-culture myelination assays (PMID:29732611)\",\n      \"pmids\": [\"30463620\", \"29732611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of JMY-MRTF-A axis in vivo not tested\", \"Whether JMY's role in myelination requires nuclear or cytoplasmic activity undetermined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"JMY's role in autophagy was mechanistically defined: membrane-bound LC3 directly recruits JMY to phagophores and stimulates its actin nucleation activity, while TTC5/STRAP antagonizes this recruitment, establishing a regulated actin-dependent step in autophagosome formation.\",\n      \"evidence\": \"In vitro reconstitution with LC3-decorated membranes, co-immunoprecipitation, cellular autophagy flux assays\",\n      \"pmids\": [\"30593260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether JMY's Spire-like or Arp2/3-dependent nucleation mode predominates at the phagophore unresolved\", \"In vivo autophagy phenotype in JMY knockout animals not reported\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conditional knockout studies in mice demonstrated JMY's in vivo requirement: Sertoli cell-specific Jmy deletion impaired blood-testis barrier integrity, spermatid adhesion, and male fertility, with JMY interacting with α-actinin1 and SORBS2 to organize junctional actin; separately, irradiated glioblastoma stem cells use the HIF-1α→JMY pathway for radiation-induced migration.\",\n      \"evidence\": \"Sertoli cell-specific Jmy conditional knockout with sperm/BTB analysis and co-IP of partners (PMID:32279424); siRNA of JMY/HIF-1α in irradiated GSCs with migration and localization assays (PMID:33128011)\",\n      \"pmids\": [\"32279424\", \"33128011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking JMY to BTB tight junction proteins not fully delineated\", \"Whether JMY drives invasion or only migration in GSCs in vivo unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A long-standing question about JMY's pro-apoptotic function was mechanistically resolved: JMY drives DNA damage-induced intrinsic apoptosis through Arp2/3-dependent actin assembly near mitochondria, promoting cytochrome c release and caspase activation, while JMY loss upregulates the survival factor RhoD.\",\n      \"evidence\": \"CRISPR and siRNA inactivation of WASP-family genes, caspase/cytochrome c assays, immunofluorescence of actin-cytochrome c co-territories, gene expression analysis\",\n      \"pmids\": [\"33872315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Arp2/3-nucleated actin physically promotes mitochondrial outer membrane permeabilization is mechanistically unresolved\", \"Direct interaction between JMY-nucleated actin filaments and mitochondria not demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The nuclear function of JMY in DNA repair was mechanistically clarified: nuclear JMY uses Arp2/3-dependent actin nucleation to enable p53-dependent transcription of DNA repair genes (XPC, XRCC5, TP53I3), and JMY loss increases DNA damage accumulation and sensitizes cells to DDR kinase inhibitors.\",\n      \"evidence\": \"Transcriptomics, CRISPR knockout, siRNA, comet assay, domain mutant rescue, cell survival assays\",\n      \"pmids\": [\"37142657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear actin nucleation by JMY facilitates p53-dependent transcription at the chromatin level is unknown\", \"Whether JMY nucleates actin at specific genomic loci or broadly in the nucleoplasm unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"JMY was placed downstream of a PCSK9→LIN28A→HES5 axis controlling microfilament integrity in neural progenitors, with JMY overexpression worsening neural tube defects in zebrafish PCSK9-loss models.\",\n      \"evidence\": \"PCSK9 knockout ESC/neural organoid models, transcriptome sequencing, zebrafish JMY overexpression\",\n      \"pmids\": [\"40788992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether endogenous JMY levels are rate-limiting for neural tube closure in mammals untested\", \"Direct transcriptional regulation of JMY by HES5 not demonstrated at the promoter level\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Critical open questions remain: what relieves JMY's autoinhibition in specific cellular contexts, what is the structural basis for autoinhibition, and how does nuclear actin nucleated by JMY mechanistically facilitate p53-dependent transcription at target gene loci.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of full-length JMY available\", \"Activating signals or co-factors that relieve autoinhibition in vivo not identified\", \"Functional separation of JMY's Spire-like vs Arp2/3-dependent activities in specific biological contexts incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 4, 9, 10, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 5, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACTR2\",\n      \"ACTR3\",\n      \"VAPA\",\n      \"LC3\",\n      \"TTC5\",\n      \"ACTN1\",\n      \"SORBS2\",\n      \"MDM2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}