{"gene":"MYCBP2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2010,"finding":"MYCBP2 (E3 ubiquitin ligase) regulates internalization of TRPV1 in peripheral sensory neurons through inhibition of p38 MAPK signaling; loss of MYCBP2 constitutively activates p38 MAPK, which in turn inhibits TRPV1 internalization and prevents desensitization of capsaicin-induced calcium increases, prolonging thermal hyperalgesia.","method":"Conditional knockout mouse model (MYCBP2 deficiency in peripheral sensory neurons), p38 MAPK inhibition rescue experiments, calcium imaging, behavioral assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, p38 MAPK inhibitor rescue, multiple orthogonal methods (calcium imaging, behavior, pharmacological rescue), replicated mechanistic linkage","pmids":["21098484"],"is_preprint":false},{"year":2010,"finding":"Crystal structures of both PHR domains (MmPHR1 and MmPHR2) of mouse Mycbp2/Phr1 were determined, revealing a novel beta-sandwich fold composed of 11 antiparallel beta-strands. MmPHR1 has conserved loops on its apical surface; the structure explains the loss-of-function mutation Gly1092→Glu in the C. elegans ortholog RPM-1.","method":"X-ray crystallography (structural determination of PHR domains from Mus musculus Mycbp2)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional variant interpretation, single study but rigorous structural method","pmids":["20156452"],"is_preprint":false},{"year":2013,"finding":"Mycbp2 genetically interacts with Robo2 to regulate axon guidance in the mouse olfactory system; double heterozygous (Mycbp2+/−; Robo2+/−) mice show severe olfactory projection defects, and loss of Mycbp2 causes aberrant expression of Robo2 in dorsal olfactory sensory neurons.","method":"Genetic epistasis (double heterozygous mouse mutants), immunohistochemistry, analysis of olfactory sensory neuron projection topography","journal":"Brain structure & function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double-mutant rescue/enhancement and defined anatomical phenotype, single lab","pmids":["23525682"],"is_preprint":false},{"year":2015,"finding":"MYCBP2 functions as a guanosine exchange factor (GEF) for the small GTPase Ran in DRG neurons via its RCC1-like domain, facilitating GDP/GTP exchange of Ran in the nucleus. SUMOylated RanGAP1 physically interacts with MYCBP2 and inhibits its E3 ubiquitin ligase activity. Loss of MYCBP2 causes increased nuclear localization of Ran.","method":"Co-immunoprecipitation (SUMOylated RanGAP1–MYCBP2 interaction), subcellular fractionation and immunofluorescence (nuclear Ran localization in MYCBP2-deficient DRGs), GDP/GTP exchange assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical GEF assay and Co-IP with defined cellular phenotype, single lab with multiple orthogonal methods","pmids":["26304119"],"is_preprint":false},{"year":2019,"finding":"MYCBP2 forms an E3 ubiquitin ligase complex with FBXO45; this complex ubiquitylates and promotes proteasomal degradation of the tumor suppressor FBXW7 during prolonged mitotic arrest, thereby promoting mitotic slippage and preventing mitotic cell death. FBXO45 binds to a conserved acidic N-terminal motif of FBXW7 specifically during extended mitotic delay.","method":"Co-immunoprecipitation, ubiquitylation assays, proteasome inhibitor rescue, cell fate assays (mitotic slippage vs. cell death), MYCBP2 and FBXO45 knockdown/overexpression","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitylation assay, rescue experiments, cell fate readout, multiple orthogonal methods in single focused study","pmids":["31285543"],"is_preprint":false},{"year":2024,"finding":"MYCBP2 forms a complex with EPHB2 receptor tyrosine kinase facilitated by FBXO45; this complex does not require EPHB2 tyrosine kinase activity and is destabilized by ephrin-B ligand binding. Paradoxically, loss of MYCBP2 increases ubiquitination and decreases protein levels of EPHB2, indicating MYCBP2 stabilizes EPHB2. MYCBP2 is required for efficient EPHB2 signaling responses in cell lines and primary neurons. In C. elegans, the ephrin receptor VAB-1 shows genetic interactions with known MYCBP2 binding proteins.","method":"Proteomics screen, biochemical Co-IP, ubiquitination assays, MYCBP2 knockdown in cell lines and primary neurons, C. elegans genetic epistasis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomics identification followed by reciprocal Co-IP, ubiquitination assay, cellular and in vivo genetic validation, multiple orthogonal methods","pmids":["38289221"],"is_preprint":false},{"year":2023,"finding":"MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor signaling; the MYCBP2-EPHB2 complex is facilitated by FBXO45, is independent of EPHB2 kinase activity, and is destabilized by ephrin-B ligands. Loss of MYCBP2 paradoxically increases EPHB2 ubiquitination and reduces its protein levels.","method":"Proteomics screen, Co-IP, ubiquitination assays, MYCBP2 knockdown, C. elegans genetics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint version of the peer-reviewed eLife study (PMID:38289221); evidence covered by the published version","pmids":["37693478"],"is_preprint":true},{"year":2022,"finding":"RGS12 associates with MYCBP2 and activates it (enhances phosphorylation of MYCBP2) to promote ubiquitination and degradation of KIF2A in synovial fibroblasts, thereby promoting cilia elongation and number; this pathway drives inflammatory arthritis pathogenesis.","method":"LC-MS/MS, co-immunoprecipitation, overexpression/knockdown experiments, cilia imaging, in vivo RGS12-deficient mouse model","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LC-MS interaction identification, Co-IP, ubiquitination assay, and in vivo rescue; single lab","pmids":["36700049"],"is_preprint":false},{"year":2022,"finding":"RGS12 associates with MYCBP2 in endothelial cells and enhances MYCBP2 phosphorylation to promote ciliogenesis and cilia elongation, driving angiogenesis in inflammatory arthritis.","method":"LC/MS and co-IP (RGS12-MYCBP2 interaction), overexpression/knockout experiments, cilia imaging","journal":"Cell insight","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — LC-MS/Co-IP interaction, phenotypic rescue, single lab; method depth is lower than full reconstitution","pmids":["37193553"],"is_preprint":false},{"year":2023,"finding":"RGS12 associates with and activates MYCBP2 to ubiquitinate and degrade the cilia protein KIF2A in tumor-associated macrophages, thereby promoting M1 macrophage polarization and antitumor activity in oral squamous cell carcinoma.","method":"Co-IP, ubiquitination assays, RGS12 knockout macrophage model, MYCBP2 knockdown, in vitro and in vivo tumor models","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, KO rescue, single lab","pmids":["36797232"],"is_preprint":false},{"year":2024,"finding":"MYCBP2 promotes ubiquitination and proteasomal degradation of S100A9 in microglia, promoting M2 phenotype polarization and reducing oxidative stress; MYCBP2 knockdown counteracts these beneficial effects in vitro and in vivo.","method":"Proteomic profiling (MYCBP2 enrichment in extracellular vesicles), MYCBP2 knockdown with functional rescue assays, ubiquitination assays, in vivo spinal cord injury model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with defined phenotype, ubiquitination assay, and in vivo model; single lab","pmids":["38896802"],"is_preprint":false},{"year":2025,"finding":"MYCBP2 promotes ubiquitination and degradation of HNF4α via K33- and K48-linked polyubiquitin chains at lysines 300 and 307 of HNF4α, thereby modulating lipid metabolism gene expression in MASH-related hepatocellular carcinoma.","method":"In vitro ubiquitination assay, site-directed mutagenesis of HNF4α lysines, proteasome inhibitor treatment, co-IP, MYCBP2 knockdown/overexpression in cell lines and in vivo xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination assay, mutagenesis of specific ubiquitin acceptor lysines, linkage-type determination, single lab with multiple orthogonal methods","pmids":["40181155"],"is_preprint":false},{"year":2025,"finding":"MYCBP2 forms a novel E3 ligase complex with substrate specificity factor SPRYD3 (distinct from the FBXO45-MYCBP2 complex); SPRYD3-MYCBP2 promotes non-canonical ubiquitination on the deubiquitinase USP11 at cysteine 318, facilitating bipolar spindle formation and mitotic slippage during microtubule-targeting drug treatment.","method":"Co-IP (SPRYD3-MYCBP2 complex identification), ubiquitination assays, mutagenesis (USP11 C318), spindle assembly assays, cell fate assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — complex reconstitution, site-specific mutagenesis, non-canonical ubiquitination site identified, multiple orthogonal cellular assays; single lab","pmids":["41052634"],"is_preprint":false},{"year":2025,"finding":"TRIB2 acts as a scaffold that binds UCP1 through its pseudokinase domain and recruits MYCBP2 as the E3 ligase to promote UCP1 ubiquitination and proteasomal degradation, linking thermogenic adaptation to post-translational UCP1 regulation.","method":"Co-IP (TRIB2-UCP1-MYCBP2 complex), ubiquitination assay, Trib2 knockout mouse model, functional thermogenesis assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP complex identification, ubiquitination assay, in vivo KO phenotype; preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"MYCBP2 targets KIF14 for ubiquitin-mediated proteasomal degradation in AML cells; MYCBP2 knockdown increases KIF14 protein stability and partially reverses cell cycle arrest and apoptosis effects caused by MYCBP2 depletion.","method":"siRNA knockdown, co-IP, ubiquitination assay, flow cytometry (cell cycle), in vivo xenograft","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, rescue experiment with KIF14 OE; single lab","pmids":["42036047"],"is_preprint":false},{"year":2023,"finding":"Loss-of-function variants in MYCBP2 cause a neurodevelopmental disorder (MDCD) with corpus callosum defects, developmental delay, and epilepsy. CRISPR-introduced disease-associated variants in C. elegans rpm-1 produce axonal abnormalities, altered habituation behavior, and abnormal autophagy marker (LGG-1/LC3) accumulation in variants affecting ubiquitin ligase activity, establishing loss of MYCBP2 ubiquitin ligase function as the pathogenic mechanism.","method":"CRISPR/Cas9 gene editing in C. elegans, in vivo axon imaging, behavioral assays, autophagy marker analysis, human patient variant identification by exome sequencing","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR disease-variant knock-in in model organism, multiple phenotypic readouts (anatomy, behavior, cell biology), correlated with human patient cohort","pmids":["36200388"],"is_preprint":false},{"year":2002,"finding":"Ikaros (IKZF1) binds regulatory regions of MYCBP2 and transcriptionally activates its expression in ALL cells; CK2 inhibition (which activates Ikaros) increases MYCBP2 expression in an IKZF1-dependent manner, placing MYCBP2 downstream of the Ikaros/CK2 axis.","method":"ChIP (Ikaros binding to MYCBP2 regulatory regions), CK2 inhibitor treatment, IKZF1 deletion correlation analysis, qRT-PCR and Western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ChIP demonstrates Ikaros binding, pharmacologic rescue with CK2 inhibitor, multiple patient cohort correlations; single lab","pmids":["26517351"],"is_preprint":false},{"year":2024,"finding":"In a C. elegans model, introduction of the homologous HSAM-associated MYCBP2 missense variant results in reduced forgetting and increased membrane-bound glutamate receptor levels in relevant neurons, suggesting MYCBP2 normally promotes glutamate receptor removal/degradation to regulate memory.","method":"CRISPR knock-in of homologous variant in C. elegans, behavioral forgetting assays, glutamate receptor imaging","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, model organism only, single lab, mechanism inferred from gain-of-function variant","pmids":[],"is_preprint":true}],"current_model":"MYCBP2 is a large, atypical RING-domain E3 ubiquitin ligase and signaling hub that operates in multi-protein complexes (with FBXO45 or SPRYD3 as substrate-specificity factors) to ubiquitinate diverse substrates including FBXW7, HNF4α, KIF2A, KIF14, S100A9, UCP1, and USP11 (via non-canonical cysteine ubiquitination), thereby controlling mitotic cell fate, axon development and guidance, TRPV1 internalization via p38 MAPK, EPHB2 receptor stability and signaling, ciliogenesis, lipid metabolism, and neuronal plasticity; additionally, MYCBP2 acts as a cytoplasmic GEF for the Ran GTPase in neurons, and loss-of-function variants cause a human neurodevelopmental syndrome (MDCD) characterized by corpus callosum defects and intellectual disability."},"narrative":{"mechanistic_narrative":"MYCBP2 is a large atypical RING-type E3 ubiquitin ligase that functions as a substrate-selective hub within multi-protein complexes to control mitotic cell fate, neuronal development and signaling, ciliogenesis, and metabolic regulation [PMID:31285543, PMID:41052634, PMID:36200388]. It partners with distinct specificity factors to direct ubiquitination: with FBXO45 it ubiquitinates and degrades the tumor suppressor FBXW7 during prolonged mitotic arrest to promote mitotic slippage [PMID:31285543], and with the alternative specificity factor SPRYD3 it carries out non-canonical cysteine ubiquitination of the deubiquitinase USP11 at Cys318 to support bipolar spindle formation and slippage under microtubule-targeting drug treatment [PMID:41052634]. Its catalytic activity is regulated: SUMOylated RanGAP1 binds MYCBP2 and inhibits its ligase activity, while RGS12 association enhances MYCBP2 phosphorylation to activate it [PMID:26304119, PMID:36700049]. Through targeted degradation MYCBP2 controls diverse substrates including KIF2A (promoting ciliogenesis and macrophage/synovial fibroblast phenotypes) [PMID:36700049, PMID:36797232], HNF4α via K33/K48 polyubiquitin chains in lipid metabolism [PMID:40181155], S100A9 in microglia [PMID:38896802], and KIF14 in leukemic cells [PMID:42036047]. In neurons it additionally acts independently of degradation, stabilizing the EPHB2 receptor to support ephrin signaling and functioning as a cytoplasmic GEF for the Ran GTPase via its RCC1-like domain [PMID:38289221, PMID:26304119]. Loss-of-function variants in MYCBP2 cause a neurodevelopmental disorder (MDCD) with corpus callosum defects, developmental delay, and epilepsy, with loss of ubiquitin ligase activity established as the pathogenic mechanism [PMID:36200388].","teleology":[{"year":2010,"claim":"Established that MYCBP2 acts in sensory neurons to restrain p38 MAPK signaling and thereby permit TRPV1 internalization, linking the ligase to nociceptor desensitization.","evidence":"Conditional knockout mouse, p38 MAPK inhibitor rescue, calcium imaging and behavioral assays","pmids":["21098484"],"confidence":"High","gaps":["Direct ubiquitination substrate in the p38/TRPV1 axis not identified","Whether MYCBP2 acts on p38 components directly or indirectly unresolved"]},{"year":2010,"claim":"Defined the structural fold of the MYCBP2 PHR domains and rationalized a conserved loss-of-function ortholog mutation, providing a structural basis for the protein's function.","evidence":"X-ray crystallography of mouse Mycbp2 PHR1 and PHR2 domains","pmids":["20156452"],"confidence":"High","gaps":["Functional partners bound by the PHR surface loops not defined","No structure of the catalytic ligase region"]},{"year":2013,"claim":"Placed MYCBP2 in an axon-guidance pathway through genetic interaction with Robo2, showing it regulates Robo2 expression in olfactory sensory neurons.","evidence":"Double-heterozygous mouse genetic epistasis and immunohistochemistry","pmids":["23525682"],"confidence":"Medium","gaps":["Whether Robo2 is a direct ubiquitination substrate not shown","Single-lab anatomical phenotype"]},{"year":2015,"claim":"Revealed a non-ligase enzymatic role: MYCBP2 acts as a Ran GEF via its RCC1-like domain, and its ligase activity is reciprocally inhibited by SUMOylated RanGAP1.","evidence":"Co-IP, GDP/GTP exchange assay, subcellular fractionation in DRG neurons","pmids":["26304119"],"confidence":"Medium","gaps":["Physiological consequences of Ran GEF activity in neurons incompletely defined","Single lab; GEF activity not structurally mapped"]},{"year":2019,"claim":"Identified the FBXO45-MYCBP2 ligase complex as a regulator of mitotic cell fate by degrading FBXW7 during mitotic arrest to promote slippage over death.","evidence":"Reciprocal Co-IP, ubiquitylation assays, proteasome rescue, cell fate readouts","pmids":["31285543"],"confidence":"High","gaps":["Upstream signal triggering FBXO45-FBXW7 recognition during arrest unclear","In vivo relevance not addressed"]},{"year":2022,"claim":"Showed RGS12 activates MYCBP2 by enhancing its phosphorylation, driving KIF2A degradation to control ciliogenesis across synovial fibroblasts and endothelial cells in inflammatory arthritis.","evidence":"LC-MS/MS, Co-IP, ubiquitination assays, cilia imaging, RGS12-deficient mouse models","pmids":["36700049","37193553"],"confidence":"Medium","gaps":["Kinase phosphorylating MYCBP2 downstream of RGS12 not identified","Single-lab findings"]},{"year":2023,"claim":"Extended the RGS12-MYCBP2-KIF2A axis to macrophage polarization, linking MYCBP2-mediated KIF2A degradation to M1 polarization and antitumor activity.","evidence":"Co-IP, ubiquitination assays, RGS12 knockout macrophages, in vivo tumor models","pmids":["36797232"],"confidence":"Medium","gaps":["Mechanistic link between KIF2A loss and polarization state incomplete","Single lab"]},{"year":2023,"claim":"Established a degradation-independent neuronal role: MYCBP2 stabilizes EPHB2 (via FBXO45, kinase-independent, ephrin-destabilized) and is required for efficient EPHB2 signaling.","evidence":"Proteomics screen, reciprocal Co-IP, ubiquitination assays, knockdown in cells and neurons, C. elegans genetics","pmids":["38289221","37693478"],"confidence":"High","gaps":["Molecular basis for paradoxical stabilization versus the ligase activity unresolved","Direct substrate whose degradation protects EPHB2 not identified"]},{"year":2023,"claim":"Defined MYCBP2 loss-of-function as the cause of a human neurodevelopmental syndrome (MDCD), with ligase-dead variants causing axon, behavioral, and autophagy defects in a model organism.","evidence":"Exome sequencing of patients, CRISPR variant knock-in in C. elegans, axon imaging, behavior, autophagy marker analysis","pmids":["36200388"],"confidence":"High","gaps":["Mammalian substrates underlying corpus callosum and epilepsy phenotypes not pinned down","Genotype-phenotype correlation across variant classes incomplete"]},{"year":2024,"claim":"Showed MYCBP2 promotes S100A9 degradation in microglia to favor an M2, low-oxidative-stress phenotype after injury.","evidence":"Proteomic profiling, knockdown with functional rescue, ubiquitination assays, spinal cord injury model","pmids":["38896802"],"confidence":"Medium","gaps":["Specificity factor directing S100A9 recognition not defined","Single lab"]},{"year":2025,"claim":"Identified the SPRYD3-MYCBP2 complex as a distinct ligase assembly performing non-canonical cysteine ubiquitination of USP11 at Cys318 to control spindle formation and mitotic slippage.","evidence":"Co-IP, ubiquitination assays, USP11 C318 mutagenesis, spindle and cell fate assays","pmids":["41052634"],"confidence":"High","gaps":["How SPRYD3 versus FBXO45 specificity is selected unknown","Functional consequence of USP11 cysteine modification on its DUB activity not fully defined"]},{"year":2025,"claim":"Defined HNF4α as a degradation substrate, with MYCBP2 building K33/K48-linked chains at specific lysines to modulate lipid metabolism gene expression in liver cancer.","evidence":"In vitro ubiquitination, site-directed mutagenesis of HNF4α K300/K307, proteasome inhibition, Co-IP, in vivo xenograft","pmids":["40181155"],"confidence":"High","gaps":["Specificity factor recruiting HNF4α not identified","Role of K33 versus K48 chains mechanistically separated only partially"]},{"year":2025,"claim":"Added KIF14 as a MYCBP2 degradation target in leukemia, coupling MYCBP2 activity to cell cycle progression and apoptosis.","evidence":"siRNA knockdown, Co-IP, ubiquitination assay, flow cytometry, xenograft","pmids":["42036047"],"confidence":"Medium","gaps":["Specificity factor and direct binding interface unmapped","Single lab"]},{"year":2025,"claim":"Proposed that TRIB2 scaffolds UCP1 to recruit MYCBP2, linking the ligase to post-translational control of thermogenesis.","evidence":"Co-IP, ubiquitination assay, Trib2 knockout mouse, thermogenesis assays (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint; not peer-reviewed","Direct MYCBP2-UCP1 ubiquitination not separated from scaffold effect"]},{"year":null,"claim":"How MYCBP2 selects between substrate-specificity factors (FBXO45, SPRYD3, TRIB2 scaffolds) and switches between degradative ubiquitination, target stabilization, and Ran GEF activity in different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model for context-dependent partner selection","Structural basis of non-canonical cysteine ubiquitination undefined","Regulatory inputs (phosphorylation, SUMO) integration unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[4,11,12,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,11,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,12,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,5,15]}],"complexes":["MYCBP2-FBXO45 E3 ligase complex","MYCBP2-SPRYD3 E3 ligase complex"],"partners":["FBXO45","SPRYD3","EPHB2","RGS12","RANGAP1","FBXW7","USP11","HNF4A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75592","full_name":"E3 ubiquitin-protein ligase MYCBP2","aliases":["Myc-binding protein 2","Protein associated with Myc"],"length_aa":4678,"mass_kda":513.6,"function":"Atypical E3 ubiquitin-protein ligase which specifically mediates ubiquitination of threonine and serine residues on target proteins, instead of ubiquitinating lysine residues (PubMed:29643511). Shows esterification activity towards both threonine and serine, with a preference for threonine, and acts via two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates (PubMed:29643511). Interacts with the E2 enzymes UBE2D1, UBE2D3, UBE2E1 and UBE2L3 (PubMed:18308511, PubMed:29643511). Plays a key role in neural development, probably by mediating ubiquitination of threonine residues on target proteins (Probable). Involved in different processes such as regulation of neurite outgrowth, synaptic growth, synaptogenesis and axon degeneration (By similarity). Required for the formation of major central nervous system axon tracts (By similarity). Required for proper axon growth by regulating axon navigation and axon branching: acts by regulating the subcellular location and stability of MAP3K12/DLK (By similarity). Required for proper localization of retinogeniculate projections but not for eye-specific segregation (By similarity). Regulates axon guidance in the olfactory system (By similarity). Involved in Wallerian axon degeneration, an evolutionarily conserved process that drives the loss of damaged axons: acts by promoting destabilization of NMNAT2, probably via ubiquitination of NMNAT2 (By similarity). Catalyzes ubiquitination of threonine and/or serine residues on NMNAT2, consequences of threonine and/or serine ubiquitination are however unknown (PubMed:29643511). Regulates the internalization of TRPV1 in peripheral sensory neurons (By similarity). Mediates ubiquitination and subsequent proteasomal degradation of TSC2/tuberin (PubMed:18308511, PubMed:27278822). Independently of the E3 ubiquitin-protein ligase activity, also acts as a guanosine exchange factor (GEF) for RAN in neurons of dorsal root ganglia (PubMed:26304119). May function as a facilitator or regulator of transcriptional activation by MYC (PubMed:9689053). Acts in concert with HUWE1 to regulate the circadian clock gene expression by promoting the lithium-induced ubiquitination and degradation of NR1D1 (PubMed:20534529)","subcellular_location":"Nucleus; Cell projection, axon; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/O75592/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"PAM","url":"https://depmap.org/portal/gene/PAM","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CKAP2","stoichiometry":0.2},{"gene":"HSP90B1","stoichiometry":0.2},{"gene":"MAP4","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2},{"gene":"VCP","stoichiometry":0.2},{"gene":"VPS35","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MYCBP2","total_profiled":1310},"omim":[{"mim_id":"610392","title":"MYC-BINDING PROTEIN 2; MYCBP2","url":"https://www.omim.org/entry/610392"},{"mim_id":"609112","title":"F-BOX ONLY PROTEIN 45; FBXO45","url":"https://www.omim.org/entry/609112"},{"mim_id":"277000","title":"MAYER-ROKITANSKY-KUSTER-HAUSER SYNDROME; MRKH","url":"https://www.omim.org/entry/277000"},{"mim_id":"160700","title":"MYOPIA 2, AUTOSOMAL DOMINANT; MYP2","url":"https://www.omim.org/entry/160700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MYCBP2"},"hgnc":{"alias_symbol":["PAM","KIAA0916","FLJ10106","PHR1"],"prev_symbol":[]},"alphafold":{"accession":"O75592","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75592","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYCBP2","jax_strain_url":"https://www.jax.org/strain/search?query=MYCBP2"},"sequence":{"accession":"O75592","fasta_url":"https://rest.uniprot.org/uniprotkb/O75592.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75592/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75592"}},"corpus_meta":[{"pmid":"25731699","id":"PMC_25731699","title":"MiR-1247-5p is overexpressed in castration resistant prostate cancer and targets MYCBP2.","date":"2015","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/25731699","citation_count":49,"is_preprint":false},{"pmid":"26517351","id":"PMC_26517351","title":"Clinical significance of high c-MYC and low MYCBP2 expression and their association with Ikaros dysfunction in adult acute lymphoblastic leukemia.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26517351","citation_count":46,"is_preprint":false},{"pmid":"21098484","id":"PMC_21098484","title":"The ubiquitin ligase MYCBP2 regulates transient receptor potential vanilloid receptor 1 (TRPV1) internalization through inhibition of p38 MAPK signaling.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21098484","citation_count":45,"is_preprint":false},{"pmid":"31285543","id":"PMC_31285543","title":"FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation.","date":"2019","source":"Cell death and 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immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27620505","citation_count":23,"is_preprint":false},{"pmid":"36797232","id":"PMC_36797232","title":"RGS12 represses oral squamous cell carcinoma by driving M1 polarization of tumor-associated macrophages via controlling ciliary MYCBP2/KIF2A signaling.","date":"2023","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/36797232","citation_count":19,"is_preprint":false},{"pmid":"30318507","id":"PMC_30318507","title":"Epigenetically regulated miR-1247 functions as a novel tumour suppressor via MYCBP2 in methylator colon cancers.","date":"2018","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30318507","citation_count":19,"is_preprint":false},{"pmid":"25634536","id":"PMC_25634536","title":"High myopia-excavated optic disc anomaly associated with a frameshift mutation in the MYC-binding protein 2 gene (MYCBP2).","date":"2015","source":"American journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/25634536","citation_count":11,"is_preprint":false},{"pmid":"23525682","id":"PMC_23525682","title":"The E3 ubiquitin ligase Mycbp2 genetically interacts with Robo2 to modulate axon guidance in the mouse olfactory system.","date":"2013","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/23525682","citation_count":10,"is_preprint":false},{"pmid":"22046451","id":"PMC_22046451","title":"Regulation of neuronal functions by the E3-ubiquitinligase protein associated with MYC (MYCBP2).","date":"2011","source":"Communicative & integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/22046451","citation_count":8,"is_preprint":false},{"pmid":"38289221","id":"PMC_38289221","title":"Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor 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loss of MYCBP2 constitutively activates p38 MAPK, which in turn inhibits TRPV1 internalization and prevents desensitization of capsaicin-induced calcium increases, prolonging thermal hyperalgesia.\",\n      \"method\": \"Conditional knockout mouse model (MYCBP2 deficiency in peripheral sensory neurons), p38 MAPK inhibition rescue experiments, calcium imaging, behavioral assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, p38 MAPK inhibitor rescue, multiple orthogonal methods (calcium imaging, behavior, pharmacological rescue), replicated mechanistic linkage\",\n      \"pmids\": [\"21098484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structures of both PHR domains (MmPHR1 and MmPHR2) of mouse Mycbp2/Phr1 were determined, revealing a novel beta-sandwich fold composed of 11 antiparallel beta-strands. MmPHR1 has conserved loops on its apical surface; the structure explains the loss-of-function mutation Gly1092→Glu in the C. elegans ortholog RPM-1.\",\n      \"method\": \"X-ray crystallography (structural determination of PHR domains from Mus musculus Mycbp2)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional variant interpretation, single study but rigorous structural method\",\n      \"pmids\": [\"20156452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mycbp2 genetically interacts with Robo2 to regulate axon guidance in the mouse olfactory system; double heterozygous (Mycbp2+/−; Robo2+/−) mice show severe olfactory projection defects, and loss of Mycbp2 causes aberrant expression of Robo2 in dorsal olfactory sensory neurons.\",\n      \"method\": \"Genetic epistasis (double heterozygous mouse mutants), immunohistochemistry, analysis of olfactory sensory neuron projection topography\",\n      \"journal\": \"Brain structure & function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double-mutant rescue/enhancement and defined anatomical phenotype, single lab\",\n      \"pmids\": [\"23525682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYCBP2 functions as a guanosine exchange factor (GEF) for the small GTPase Ran in DRG neurons via its RCC1-like domain, facilitating GDP/GTP exchange of Ran in the nucleus. SUMOylated RanGAP1 physically interacts with MYCBP2 and inhibits its E3 ubiquitin ligase activity. Loss of MYCBP2 causes increased nuclear localization of Ran.\",\n      \"method\": \"Co-immunoprecipitation (SUMOylated RanGAP1–MYCBP2 interaction), subcellular fractionation and immunofluorescence (nuclear Ran localization in MYCBP2-deficient DRGs), GDP/GTP exchange assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical GEF assay and Co-IP with defined cellular phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26304119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYCBP2 forms an E3 ubiquitin ligase complex with FBXO45; this complex ubiquitylates and promotes proteasomal degradation of the tumor suppressor FBXW7 during prolonged mitotic arrest, thereby promoting mitotic slippage and preventing mitotic cell death. FBXO45 binds to a conserved acidic N-terminal motif of FBXW7 specifically during extended mitotic delay.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, proteasome inhibitor rescue, cell fate assays (mitotic slippage vs. cell death), MYCBP2 and FBXO45 knockdown/overexpression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitylation assay, rescue experiments, cell fate readout, multiple orthogonal methods in single focused study\",\n      \"pmids\": [\"31285543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYCBP2 forms a complex with EPHB2 receptor tyrosine kinase facilitated by FBXO45; this complex does not require EPHB2 tyrosine kinase activity and is destabilized by ephrin-B ligand binding. Paradoxically, loss of MYCBP2 increases ubiquitination and decreases protein levels of EPHB2, indicating MYCBP2 stabilizes EPHB2. MYCBP2 is required for efficient EPHB2 signaling responses in cell lines and primary neurons. In C. elegans, the ephrin receptor VAB-1 shows genetic interactions with known MYCBP2 binding proteins.\",\n      \"method\": \"Proteomics screen, biochemical Co-IP, ubiquitination assays, MYCBP2 knockdown in cell lines and primary neurons, C. elegans genetic epistasis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomics identification followed by reciprocal Co-IP, ubiquitination assay, cellular and in vivo genetic validation, multiple orthogonal methods\",\n      \"pmids\": [\"38289221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor signaling; the MYCBP2-EPHB2 complex is facilitated by FBXO45, is independent of EPHB2 kinase activity, and is destabilized by ephrin-B ligands. Loss of MYCBP2 paradoxically increases EPHB2 ubiquitination and reduces its protein levels.\",\n      \"method\": \"Proteomics screen, Co-IP, ubiquitination assays, MYCBP2 knockdown, C. elegans genetics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint version of the peer-reviewed eLife study (PMID:38289221); evidence covered by the published version\",\n      \"pmids\": [\"37693478\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RGS12 associates with MYCBP2 and activates it (enhances phosphorylation of MYCBP2) to promote ubiquitination and degradation of KIF2A in synovial fibroblasts, thereby promoting cilia elongation and number; this pathway drives inflammatory arthritis pathogenesis.\",\n      \"method\": \"LC-MS/MS, co-immunoprecipitation, overexpression/knockdown experiments, cilia imaging, in vivo RGS12-deficient mouse model\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LC-MS interaction identification, Co-IP, ubiquitination assay, and in vivo rescue; single lab\",\n      \"pmids\": [\"36700049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RGS12 associates with MYCBP2 in endothelial cells and enhances MYCBP2 phosphorylation to promote ciliogenesis and cilia elongation, driving angiogenesis in inflammatory arthritis.\",\n      \"method\": \"LC/MS and co-IP (RGS12-MYCBP2 interaction), overexpression/knockout experiments, cilia imaging\",\n      \"journal\": \"Cell insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — LC-MS/Co-IP interaction, phenotypic rescue, single lab; method depth is lower than full reconstitution\",\n      \"pmids\": [\"37193553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RGS12 associates with and activates MYCBP2 to ubiquitinate and degrade the cilia protein KIF2A in tumor-associated macrophages, thereby promoting M1 macrophage polarization and antitumor activity in oral squamous cell carcinoma.\",\n      \"method\": \"Co-IP, ubiquitination assays, RGS12 knockout macrophage model, MYCBP2 knockdown, in vitro and in vivo tumor models\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, KO rescue, single lab\",\n      \"pmids\": [\"36797232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYCBP2 promotes ubiquitination and proteasomal degradation of S100A9 in microglia, promoting M2 phenotype polarization and reducing oxidative stress; MYCBP2 knockdown counteracts these beneficial effects in vitro and in vivo.\",\n      \"method\": \"Proteomic profiling (MYCBP2 enrichment in extracellular vesicles), MYCBP2 knockdown with functional rescue assays, ubiquitination assays, in vivo spinal cord injury model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with defined phenotype, ubiquitination assay, and in vivo model; single lab\",\n      \"pmids\": [\"38896802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYCBP2 promotes ubiquitination and degradation of HNF4α via K33- and K48-linked polyubiquitin chains at lysines 300 and 307 of HNF4α, thereby modulating lipid metabolism gene expression in MASH-related hepatocellular carcinoma.\",\n      \"method\": \"In vitro ubiquitination assay, site-directed mutagenesis of HNF4α lysines, proteasome inhibitor treatment, co-IP, MYCBP2 knockdown/overexpression in cell lines and in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination assay, mutagenesis of specific ubiquitin acceptor lysines, linkage-type determination, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40181155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYCBP2 forms a novel E3 ligase complex with substrate specificity factor SPRYD3 (distinct from the FBXO45-MYCBP2 complex); SPRYD3-MYCBP2 promotes non-canonical ubiquitination on the deubiquitinase USP11 at cysteine 318, facilitating bipolar spindle formation and mitotic slippage during microtubule-targeting drug treatment.\",\n      \"method\": \"Co-IP (SPRYD3-MYCBP2 complex identification), ubiquitination assays, mutagenesis (USP11 C318), spindle assembly assays, cell fate assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — complex reconstitution, site-specific mutagenesis, non-canonical ubiquitination site identified, multiple orthogonal cellular assays; single lab\",\n      \"pmids\": [\"41052634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIB2 acts as a scaffold that binds UCP1 through its pseudokinase domain and recruits MYCBP2 as the E3 ligase to promote UCP1 ubiquitination and proteasomal degradation, linking thermogenic adaptation to post-translational UCP1 regulation.\",\n      \"method\": \"Co-IP (TRIB2-UCP1-MYCBP2 complex), ubiquitination assay, Trib2 knockout mouse model, functional thermogenesis assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP complex identification, ubiquitination assay, in vivo KO phenotype; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYCBP2 targets KIF14 for ubiquitin-mediated proteasomal degradation in AML cells; MYCBP2 knockdown increases KIF14 protein stability and partially reverses cell cycle arrest and apoptosis effects caused by MYCBP2 depletion.\",\n      \"method\": \"siRNA knockdown, co-IP, ubiquitination assay, flow cytometry (cell cycle), in vivo xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, rescue experiment with KIF14 OE; single lab\",\n      \"pmids\": [\"42036047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss-of-function variants in MYCBP2 cause a neurodevelopmental disorder (MDCD) with corpus callosum defects, developmental delay, and epilepsy. CRISPR-introduced disease-associated variants in C. elegans rpm-1 produce axonal abnormalities, altered habituation behavior, and abnormal autophagy marker (LGG-1/LC3) accumulation in variants affecting ubiquitin ligase activity, establishing loss of MYCBP2 ubiquitin ligase function as the pathogenic mechanism.\",\n      \"method\": \"CRISPR/Cas9 gene editing in C. elegans, in vivo axon imaging, behavioral assays, autophagy marker analysis, human patient variant identification by exome sequencing\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR disease-variant knock-in in model organism, multiple phenotypic readouts (anatomy, behavior, cell biology), correlated with human patient cohort\",\n      \"pmids\": [\"36200388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ikaros (IKZF1) binds regulatory regions of MYCBP2 and transcriptionally activates its expression in ALL cells; CK2 inhibition (which activates Ikaros) increases MYCBP2 expression in an IKZF1-dependent manner, placing MYCBP2 downstream of the Ikaros/CK2 axis.\",\n      \"method\": \"ChIP (Ikaros binding to MYCBP2 regulatory regions), CK2 inhibitor treatment, IKZF1 deletion correlation analysis, qRT-PCR and Western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ChIP demonstrates Ikaros binding, pharmacologic rescue with CK2 inhibitor, multiple patient cohort correlations; single lab\",\n      \"pmids\": [\"26517351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a C. elegans model, introduction of the homologous HSAM-associated MYCBP2 missense variant results in reduced forgetting and increased membrane-bound glutamate receptor levels in relevant neurons, suggesting MYCBP2 normally promotes glutamate receptor removal/degradation to regulate memory.\",\n      \"method\": \"CRISPR knock-in of homologous variant in C. elegans, behavioral forgetting assays, glutamate receptor imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, model organism only, single lab, mechanism inferred from gain-of-function variant\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MYCBP2 is a large, atypical RING-domain E3 ubiquitin ligase and signaling hub that operates in multi-protein complexes (with FBXO45 or SPRYD3 as substrate-specificity factors) to ubiquitinate diverse substrates including FBXW7, HNF4α, KIF2A, KIF14, S100A9, UCP1, and USP11 (via non-canonical cysteine ubiquitination), thereby controlling mitotic cell fate, axon development and guidance, TRPV1 internalization via p38 MAPK, EPHB2 receptor stability and signaling, ciliogenesis, lipid metabolism, and neuronal plasticity; additionally, MYCBP2 acts as a cytoplasmic GEF for the Ran GTPase in neurons, and loss-of-function variants cause a human neurodevelopmental syndrome (MDCD) characterized by corpus callosum defects and intellectual disability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYCBP2 is a large atypical RING-type E3 ubiquitin ligase that functions as a substrate-selective hub within multi-protein complexes to control mitotic cell fate, neuronal development and signaling, ciliogenesis, and metabolic regulation [#4, #12, #15]. It partners with distinct specificity factors to direct ubiquitination: with FBXO45 it ubiquitinates and degrades the tumor suppressor FBXW7 during prolonged mitotic arrest to promote mitotic slippage [#4], and with the alternative specificity factor SPRYD3 it carries out non-canonical cysteine ubiquitination of the deubiquitinase USP11 at Cys318 to support bipolar spindle formation and slippage under microtubule-targeting drug treatment [#12]. Its catalytic activity is regulated: SUMOylated RanGAP1 binds MYCBP2 and inhibits its ligase activity, while RGS12 association enhances MYCBP2 phosphorylation to activate it [#3, #7]. Through targeted degradation MYCBP2 controls diverse substrates including KIF2A (promoting ciliogenesis and macrophage/synovial fibroblast phenotypes) [#7, #9], HNF4\\u03b1 via K33/K48 polyubiquitin chains in lipid metabolism [#11], S100A9 in microglia [#10], and KIF14 in leukemic cells [#14]. In neurons it additionally acts independently of degradation, stabilizing the EPHB2 receptor to support ephrin signaling and functioning as a cytoplasmic GEF for the Ran GTPase via its RCC1-like domain [#5, #3]. Loss-of-function variants in MYCBP2 cause a neurodevelopmental disorder (MDCD) with corpus callosum defects, developmental delay, and epilepsy, with loss of ubiquitin ligase activity established as the pathogenic mechanism [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that MYCBP2 acts in sensory neurons to restrain p38 MAPK signaling and thereby permit TRPV1 internalization, linking the ligase to nociceptor desensitization.\",\n      \"evidence\": \"Conditional knockout mouse, p38 MAPK inhibitor rescue, calcium imaging and behavioral assays\",\n      \"pmids\": [\"21098484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination substrate in the p38/TRPV1 axis not identified\", \"Whether MYCBP2 acts on p38 components directly or indirectly unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the structural fold of the MYCBP2 PHR domains and rationalized a conserved loss-of-function ortholog mutation, providing a structural basis for the protein's function.\",\n      \"evidence\": \"X-ray crystallography of mouse Mycbp2 PHR1 and PHR2 domains\",\n      \"pmids\": [\"20156452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional partners bound by the PHR surface loops not defined\", \"No structure of the catalytic ligase region\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed MYCBP2 in an axon-guidance pathway through genetic interaction with Robo2, showing it regulates Robo2 expression in olfactory sensory neurons.\",\n      \"evidence\": \"Double-heterozygous mouse genetic epistasis and immunohistochemistry\",\n      \"pmids\": [\"23525682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Robo2 is a direct ubiquitination substrate not shown\", \"Single-lab anatomical phenotype\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a non-ligase enzymatic role: MYCBP2 acts as a Ran GEF via its RCC1-like domain, and its ligase activity is reciprocally inhibited by SUMOylated RanGAP1.\",\n      \"evidence\": \"Co-IP, GDP/GTP exchange assay, subcellular fractionation in DRG neurons\",\n      \"pmids\": [\"26304119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequences of Ran GEF activity in neurons incompletely defined\", \"Single lab; GEF activity not structurally mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the FBXO45-MYCBP2 ligase complex as a regulator of mitotic cell fate by degrading FBXW7 during mitotic arrest to promote slippage over death.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitylation assays, proteasome rescue, cell fate readouts\",\n      \"pmids\": [\"31285543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal triggering FBXO45-FBXW7 recognition during arrest unclear\", \"In vivo relevance not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RGS12 activates MYCBP2 by enhancing its phosphorylation, driving KIF2A degradation to control ciliogenesis across synovial fibroblasts and endothelial cells in inflammatory arthritis.\",\n      \"evidence\": \"LC-MS/MS, Co-IP, ubiquitination assays, cilia imaging, RGS12-deficient mouse models\",\n      \"pmids\": [\"36700049\", \"37193553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase phosphorylating MYCBP2 downstream of RGS12 not identified\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the RGS12-MYCBP2-KIF2A axis to macrophage polarization, linking MYCBP2-mediated KIF2A degradation to M1 polarization and antitumor activity.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, RGS12 knockout macrophages, in vivo tumor models\",\n      \"pmids\": [\"36797232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between KIF2A loss and polarization state incomplete\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a degradation-independent neuronal role: MYCBP2 stabilizes EPHB2 (via FBXO45, kinase-independent, ephrin-destabilized) and is required for efficient EPHB2 signaling.\",\n      \"evidence\": \"Proteomics screen, reciprocal Co-IP, ubiquitination assays, knockdown in cells and neurons, C. elegans genetics\",\n      \"pmids\": [\"38289221\", \"37693478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for paradoxical stabilization versus the ligase activity unresolved\", \"Direct substrate whose degradation protects EPHB2 not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined MYCBP2 loss-of-function as the cause of a human neurodevelopmental syndrome (MDCD), with ligase-dead variants causing axon, behavioral, and autophagy defects in a model organism.\",\n      \"evidence\": \"Exome sequencing of patients, CRISPR variant knock-in in C. elegans, axon imaging, behavior, autophagy marker analysis\",\n      \"pmids\": [\"36200388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian substrates underlying corpus callosum and epilepsy phenotypes not pinned down\", \"Genotype-phenotype correlation across variant classes incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed MYCBP2 promotes S100A9 degradation in microglia to favor an M2, low-oxidative-stress phenotype after injury.\",\n      \"evidence\": \"Proteomic profiling, knockdown with functional rescue, ubiquitination assays, spinal cord injury model\",\n      \"pmids\": [\"38896802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity factor directing S100A9 recognition not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the SPRYD3-MYCBP2 complex as a distinct ligase assembly performing non-canonical cysteine ubiquitination of USP11 at Cys318 to control spindle formation and mitotic slippage.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, USP11 C318 mutagenesis, spindle and cell fate assays\",\n      \"pmids\": [\"41052634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SPRYD3 versus FBXO45 specificity is selected unknown\", \"Functional consequence of USP11 cysteine modification on its DUB activity not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined HNF4\\u03b1 as a degradation substrate, with MYCBP2 building K33/K48-linked chains at specific lysines to modulate lipid metabolism gene expression in liver cancer.\",\n      \"evidence\": \"In vitro ubiquitination, site-directed mutagenesis of HNF4\\u03b1 K300/K307, proteasome inhibition, Co-IP, in vivo xenograft\",\n      \"pmids\": [\"40181155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity factor recruiting HNF4\\u03b1 not identified\", \"Role of K33 versus K48 chains mechanistically separated only partially\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added KIF14 as a MYCBP2 degradation target in leukemia, coupling MYCBP2 activity to cell cycle progression and apoptosis.\",\n      \"evidence\": \"siRNA knockdown, Co-IP, ubiquitination assay, flow cytometry, xenograft\",\n      \"pmids\": [\"42036047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity factor and direct binding interface unmapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed that TRIB2 scaffolds UCP1 to recruit MYCBP2, linking the ligase to post-translational control of thermogenesis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, Trib2 knockout mouse, thermogenesis assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not peer-reviewed\", \"Direct MYCBP2-UCP1 ubiquitination not separated from scaffold effect\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYCBP2 selects between substrate-specificity factors (FBXO45, SPRYD3, TRIB2 scaffolds) and switches between degradative ubiquitination, target stabilization, and Ran GEF activity in different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model for context-dependent partner selection\", \"Structural basis of non-canonical cysteine ubiquitination undefined\", \"Regulatory inputs (phosphorylation, SUMO) integration unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [4, 11, 12, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 11, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 12, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 5, 15]}\n    ],\n    \"complexes\": [\n      \"MYCBP2-FBXO45 E3 ligase complex\",\n      \"MYCBP2-SPRYD3 E3 ligase complex\"\n    ],\n    \"partners\": [\n      \"FBXO45\",\n      \"SPRYD3\",\n      \"EPHB2\",\n      \"RGS12\",\n      \"RanGAP1\",\n      \"FBXW7\",\n      \"USP11\",\n      \"HNF4A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}