{"gene":"MYCBP","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1998,"finding":"MYCBP (AMY-1) binds via its C-terminal region to the N-terminal transactivation domain (amino acids 58-148) of C-MYC, and stimulates E-box-dependent transcription by the MYC/Max complex without itself recognizing the E-box element.","method":"Co-immunoprecipitation, two-hybrid, transactivation reporter assay, FISH","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding mapped to specific domains, functional transcription assay, replicated in subsequent studies","pmids":["9797456"],"is_preprint":false},{"year":1998,"finding":"MYCBP (AMY-1) localizes in the cytoplasm at low c-myc expression levels but translocates to the nucleus during S phase when c-myc expression is elevated, linking its nuclear translocation to cell-cycle-dependent changes in C-MYC levels.","method":"Transfection with immunofluorescence microscopy, cell-cycle analysis","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional correlation, single lab","pmids":["9797456"],"is_preprint":false},{"year":2001,"finding":"MYCBP (AMY-1) binds in vitro and in vivo to the RII-binding region of AKAP149 and its testis-specific splicing variant S-AKAP84, and is localized to mitochondria in HeLa cells and sperm through this association.","method":"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, immunofluorescence/subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding + co-IP + localization, replicated in follow-up studies","pmids":["11483602"],"is_preprint":false},{"year":2002,"finding":"MYCBP (AMY-1) competitively binds to the RII-binding region of AKAP95 (nucleus) and AKAP84 (cytoplasm) in a concentration-dependent manner, forms a ternary complex with RII, and prevents the PKA catalytic subunit from binding to the AKAP complex, thereby suppressing PKA activity.","method":"Co-immunoprecipitation, in vitro binding assay, PKA activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding, co-IP, enzymatic activity assay; builds on prior study","pmids":["12414807"],"is_preprint":false},{"year":2002,"finding":"MYCBP (AMY-1) binds to the testis-specific protein AAT-1alpha, and together with S-AKAP84/AKAP149 and RII forms a quaternary complex in the mitochondria; AAT-1alpha is phosphorylated by PKA in vivo and in vitro within this complex.","method":"Yeast two-hybrid, co-immunoprecipitation, colocalization, in vivo and in vitro phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, in vitro phosphorylation confirmed","pmids":["12223483"],"is_preprint":false},{"year":2002,"finding":"MYCBP (AMY-1) binds to and colocalizes with the novel testis-specific protein AMAP-1, which is post-meiotically expressed in the testis, implicating MYCBP in spermatogenesis through this interaction.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, co-IP and colocalization without detailed functional dissection","pmids":["12151104"],"is_preprint":false},{"year":2000,"finding":"Overexpression of MYCBP (AMY-1) in K562 cells induces erythrocyte differentiation (elevated ε-globin mRNA, hemoglobin accumulation) and accelerates AraC-induced differentiation, demonstrating a role in cell differentiation independent of or distinct from c-MYC.","method":"Stable overexpression, RT-PCR for differentiation markers, hemoglobin assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with defined molecular readout, single lab","pmids":["10639579"],"is_preprint":false},{"year":2003,"finding":"The MYCBP promoter is synergistically activated by Sp1 (required in all cell types) and GATA-1 (required specifically in K562 cells), as shown by deletion reporter assays, mobility shift assay confirming protein binding, and co-immunoprecipitation of Sp1 and GATA-1 in K562 cells.","method":"Luciferase reporter assay, EMSA (mobility shift assay), co-immunoprecipitation","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods defining transcriptional regulation, single lab","pmids":["12620400"],"is_preprint":false},{"year":2006,"finding":"MYCBP (AMY-1) localizes to the trans-Golgi network (TGN) and nucleus; its TGN localization is mediated specifically through interaction with BIG2 (but not BIG1), a guanine-nucleotide exchange factor for ARFs, as demonstrated by RNAi knockdown of BIG2 displacing AMY-1 from the TGN.","method":"Co-immunoprecipitation, RNAi knockdown, immunofluorescence localization, in vitro binding","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP + RNAi rescue + localization with functional link, single lab but multiple orthogonal methods","pmids":["16866877"],"is_preprint":false},{"year":2014,"finding":"MYCBP forms a complex with Gli and Sufu in the absence of Hedgehog signaling but remains inactive; upon Hh pathway activation, Sufu/p66β dissociate from Gli, enabling MYCBP to promote Gli protein activity and Hh target gene expression. MYCBP positively regulates Hh signaling downstream of Patched, Smoothened, and the primary cilium.","method":"Proteomic/co-IP identification of Sufu-interacting proteins, chromatin immunoprecipitation (ChIP), cell-based reporter assays, zebrafish genetic epistasis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (proteomics, ChIP, cell assays, in vivo zebrafish epistasis), moderate evidence","pmids":["25403183"],"is_preprint":false},{"year":2019,"finding":"EYA4 suppresses MYCBP expression by dephosphorylating β-catenin at Ser552, reducing its nuclear translocation and thereby inhibiting β-catenin/LEF1-driven transcription of MYCBP; siRNA rescue and MYCBP overexpression in EYA4-KO cells confirmed MYCBP acts downstream of EYA4 to control HCC cell proliferation and G2/M arrest.","method":"Phosphatase activity assay, western blot, siRNA knockdown/overexpression rescue, co-immunoprecipitation, luciferase reporter","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via rescue experiment + biochemical phosphatase assay, single lab","pmids":["31385398"],"is_preprint":false},{"year":2024,"finding":"The circular RNA circ_0002669 directly binds MYCBP protein (identified by biotin pulldown and mass spectrometry) and protects it from ubiquitin-mediated proteasomal degradation, thereby stabilizing MYCBP protein levels and promoting c-MYC target gene expression (CCND1, c-Jun, CDK4) in osteosarcoma cells.","method":"Biotin pulldown, mass spectrometry, luciferase reporter assay, RNA immunoprecipitation, ubiquitination assay","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein binding confirmed by pull-down/MS, ubiquitination assay, single lab","pmids":["38570856"],"is_preprint":false},{"year":2025,"finding":"Drosophila MYCBP physically associates with itself, Sakura, and Otu forming binary and ternary complexes; germline-specific depletion of mycbp disrupts Dpp/BMP signaling, causes aberrant bam expression, and leads to GSC loss and sterility; mycbp is also required for female-specific splicing of sex-lethal.","method":"Co-immunoprecipitation, null mutant analysis, germline-specific RNAi, signaling reporter assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP defining complexes + null mutant with multiple defined molecular phenotypes in Drosophila ortholog","pmids":["41325460"],"is_preprint":false}],"current_model":"MYCBP (AMY-1) is an 11-kDa protein that binds the N-terminal transactivation domain of C-MYC and stimulates E-box-dependent transcription; it also acts as a modulator of PKA signaling by associating with AKAPs (AKAP84/95/149) and the RII regulatory subunit to suppress PKA catalytic activity, localizes to mitochondria (via S-AKAP84), the trans-Golgi network (via BIG2), and nucleus in a context-dependent manner, and positively regulates Hedgehog signaling in the nucleus by enabling Gli activity upon Sufu/p66β dissociation—collectively placing MYCBP at the intersection of transcriptional regulation, cAMP/PKA signaling, membrane trafficking, and Hh pathway control."},"narrative":{"teleology":[{"year":1998,"claim":"Identifying MYCBP as a direct C-MYC-binding partner established that an 11-kDa protein could stimulate MYC/Max-dependent transcription without itself recognizing DNA, raising the question of how it modulates transcription mechanistically.","evidence":"Co-immunoprecipitation, yeast two-hybrid mapping of binding domains, and E-box reporter assays in mammalian cells","pmids":["9797456"],"confidence":"High","gaps":["No structural basis for how MYCBP enhances MYC transactivation","Whether MYCBP binds chromatin directly or solely through MYC is unresolved","Endogenous stoichiometry of the MYCBP-MYC complex unknown"]},{"year":1998,"claim":"Demonstrating cell-cycle-dependent nuclear translocation of MYCBP during S phase linked its subcellular localization to C-MYC expression dynamics, suggesting regulated compartmentalization as a functional control mechanism.","evidence":"Immunofluorescence with cell-cycle synchronization in transfected cells","pmids":["9797456"],"confidence":"Medium","gaps":["Nuclear import mechanism (NLS, carrier) not identified","Single overexpression system; endogenous protein not tracked","Functional consequence of nuclear translocation on specific MYC target genes not tested"]},{"year":2000,"claim":"Showing that MYCBP overexpression drives erythroid differentiation in K562 cells established a functional role beyond simple transcriptional coactivation, implicating it in lineage commitment.","evidence":"Stable overexpression with ε-globin RT-PCR and hemoglobin accumulation assays","pmids":["10639579"],"confidence":"Medium","gaps":["Whether the differentiation effect is MYC-dependent or independent was not resolved","Loss-of-function experiment not performed","Single cell line tested"]},{"year":2001,"claim":"Discovery that MYCBP binds the RII-binding region of AKAPs (AKAP149/S-AKAP84) and localizes to mitochondria through this interaction revealed a second, non-transcriptional function linked to cAMP/PKA scaffolding.","evidence":"Yeast two-hybrid, in vitro binding, co-IP, and immunofluorescence/subcellular fractionation in HeLa cells and sperm","pmids":["11483602"],"confidence":"High","gaps":["Functional consequence of mitochondrial MYCBP on organelle biology not established","Whether MYCBP-AKAP and MYCBP-MYC interactions are mutually exclusive unknown"]},{"year":2002,"claim":"Establishing that MYCBP competitively excludes the PKA catalytic subunit from AKAP/RII complexes defined a biochemical mechanism by which it suppresses PKA signaling, placing it as a negative modulator of cAMP-dependent phosphorylation.","evidence":"Co-IP, in vitro binding competition assays, and PKA enzymatic activity measurements","pmids":["12414807"],"confidence":"High","gaps":["Physiological targets of PKA suppression by MYCBP not identified","In vivo consequences of MYCBP-mediated PKA inhibition not tested in animal models","Structural basis for competitive exclusion not resolved"]},{"year":2002,"claim":"Identification of a quaternary complex (MYCBP/S-AKAP84/RII/AAT-1α) at mitochondria with PKA-dependent phosphorylation of AAT-1α provided the first candidate downstream event of MYCBP-scaffolded signaling in the testis.","evidence":"Yeast two-hybrid, co-IP, colocalization, in vivo and in vitro phosphorylation assays","pmids":["12223483"],"confidence":"High","gaps":["Functional significance of AAT-1α phosphorylation unknown","Role of this complex in spermatogenesis not tested genetically"]},{"year":2006,"claim":"Demonstrating that BIG2 (but not BIG1) recruits MYCBP to the trans-Golgi network expanded its compartment-specific functions to membrane trafficking, with BIG2 knockdown displacing MYCBP from the TGN.","evidence":"Co-IP, RNAi knockdown of BIG2, immunofluorescence localization, in vitro binding","pmids":["16866877"],"confidence":"High","gaps":["What MYCBP does at the TGN functionally (e.g., vesicle budding, ARF regulation) is not known","Whether TGN and mitochondrial pools of MYCBP are independently regulated is unclear"]},{"year":2014,"claim":"Proteomic identification of MYCBP in the Sufu/Gli complex and demonstration that Hh-induced Sufu/p66β dissociation licenses MYCBP to promote Gli activity established MYCBP as a positive nuclear effector of Hedgehog signaling downstream of Smoothened.","evidence":"Sufu interactome by co-IP/proteomics, ChIP, cell-based Hh reporter assays, zebrafish epistasis experiments","pmids":["25403183"],"confidence":"High","gaps":["How MYCBP biochemically activates Gli (coactivator recruitment, chromatin remodeling) is unresolved","Whether MYCBP's MYC-coactivator and Hh-effector roles are coordinated or independent is unknown"]},{"year":2019,"claim":"Placing MYCBP transcription under β-catenin/LEF1 control, suppressed by EYA4-mediated dephosphorylation of β-catenin, connected Wnt signaling to MYCBP expression and revealed its role in hepatocellular carcinoma proliferation.","evidence":"Phosphatase assay, siRNA knockdown/overexpression rescue, co-IP, luciferase reporter in HCC cells","pmids":["31385398"],"confidence":"Medium","gaps":["Whether Wnt-driven MYCBP upregulation acts through MYC, Hh, or PKA pathways in HCC was not dissected","Single cancer type; generalizability not established"]},{"year":2024,"claim":"Showing that circ_0002669 binds MYCBP protein and shields it from ubiquitin-mediated proteasomal degradation revealed a post-translational stabilization mechanism that amplifies MYC target gene expression in osteosarcoma.","evidence":"Biotin pulldown, mass spectrometry, RNA immunoprecipitation, ubiquitination assay in osteosarcoma cells","pmids":["38570856"],"confidence":"Medium","gaps":["The E3 ubiquitin ligase targeting MYCBP is not identified","Whether circRNA-mediated stabilization operates in non-cancer contexts is unknown","Single study; independent confirmation needed"]},{"year":2025,"claim":"Genetic analysis in Drosophila revealed that MYCBP forms complexes with Sakura and Otu and is essential for germline stem cell maintenance via Dpp/BMP signaling, bam regulation, and sex-lethal splicing, establishing conserved roles in stem cell biology and RNA processing.","evidence":"Co-IP defining binary/ternary complexes, null mutant and germline-specific RNAi in Drosophila, signaling reporter assays","pmids":["41325460"],"confidence":"High","gaps":["Whether the Sakura/Otu complex is conserved in mammals is unknown","Mechanism by which MYCBP influences sex-lethal splicing not defined","Whether BMP-pathway role in Drosophila GSCs reflects a mammalian Hedgehog or TGFβ function is unresolved"]},{"year":null,"claim":"How MYCBP's distinct interaction modalities — MYC coactivation, AKAP/PKA scaffolding, BIG2-mediated TGN targeting, and Gli activation — are coordinated within a single cell, and which E3 ligase targets MYCBP for degradation, remain open mechanistic questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of MYCBP alone or in any complex","Conditional knockout phenotype in mammalian systems not reported","Integration of multiple signaling roles into a unified model lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,4,8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,8,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,9,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,9,11]}],"complexes":["AKAP/RII/MYCBP ternary complex","Sufu/Gli/MYCBP complex","Sakura/Otu/MYCBP complex"],"partners":["MYC","AKAP1","AKAP2","PRKAR2A","ARFGEF2","SUFU","GLI1"],"other_free_text":[]},"mechanistic_narrative":"MYCBP is a small adaptor protein that operates at the intersection of transcriptional regulation, cAMP/PKA signaling, membrane trafficking, and Hedgehog pathway control. It binds the N-terminal transactivation domain of C-MYC and stimulates E-box-dependent transcription without directly recognizing DNA, and its protein levels are stabilized by circ_0002669 through protection from ubiquitin-mediated degradation [PMID:9797456, PMID:38570856]. MYCBP associates with AKAPs (AKAP84, AKAP95, AKAP149) and the RII regulatory subunit of PKA, competitively excluding the PKA catalytic subunit to suppress PKA activity, and is directed to mitochondria via S-AKAP84 or to the trans-Golgi network via the ARF-GEF BIG2 [PMID:12414807, PMID:11483602, PMID:16866877]. In Hedgehog signaling, MYCBP resides in a nuclear complex with Gli and Sufu; upon pathway activation and Sufu/p66β dissociation, MYCBP promotes Gli-dependent target gene expression, and its Drosophila ortholog is required for germline stem cell maintenance and Dpp/BMP signaling [PMID:25403183, PMID:41325460]."},"prefetch_data":{"uniprot":{"accession":"Q99417","full_name":"c-Myc-binding protein","aliases":["Associate of Myc 1","AMY-1"],"length_aa":103,"mass_kda":12.0,"function":"May control the transcriptional activity of MYC. Stimulates the activation of E box-dependent transcription by MYC","subcellular_location":"Cytoplasm; Nucleus; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q99417/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYCBP","classification":"Not Classified","n_dependent_lines":87,"n_total_lines":1208,"dependency_fraction":0.07201986754966887},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARFGEF1","stoichiometry":0.2},{"gene":"ARFGEF2","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MYCBP","total_profiled":1310},"omim":[{"mim_id":"609910","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 91; CFAP91","url":"https://www.omim.org/entry/609910"},{"mim_id":"609835","title":"MYCBP-ASSOCIATED PROTEIN; MYCBPAP","url":"https://www.omim.org/entry/609835"},{"mim_id":"606535","title":"MYC-BINDING PROTEIN; MYCBP","url":"https://www.omim.org/entry/606535"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MYCBP"},"hgnc":{"alias_symbol":["AMY-1"],"prev_symbol":[]},"alphafold":{"accession":"Q99417","domains":[{"cath_id":"-","chopping":"1-56","consensus_level":"medium","plddt":87.4966,"start":1,"end":56},{"cath_id":"1.20.5","chopping":"59-95","consensus_level":"medium","plddt":91.9443,"start":59,"end":95}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99417","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99417-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99417-F1-predicted_aligned_error_v6.png","plddt_mean":86.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYCBP","jax_strain_url":"https://www.jax.org/strain/search?query=MYCBP"},"sequence":{"accession":"Q99417","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99417.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99417/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99417"}},"corpus_meta":[{"pmid":"9797456","id":"PMC_9797456","title":"AMY-1, a novel C-MYC binding protein that stimulates transcription activity of C-MYC.","date":"1998","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/9797456","citation_count":74,"is_preprint":false},{"pmid":"31094023","id":"PMC_31094023","title":"Non-coding RNA MFI2-AS1 promotes colorectal cancer cell proliferation, migration and invasion through miR-574-5p/MYCBP axis.","date":"2019","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/31094023","citation_count":52,"is_preprint":false},{"pmid":"25403183","id":"PMC_25403183","title":"Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling.","date":"2014","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/25403183","citation_count":39,"is_preprint":false},{"pmid":"93520","id":"PMC_93520","title":"[Genetic analysis of interspecific crosses Mus musculus L. x Mus spretus Lataste: linkage of Adh-1 with Amy-1 on chromosome 3 and Es-14 with Mod-1 on chromosome 9].","date":"1979","source":"Comptes rendus des seances de l'Academie des sciences. 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/40379626","citation_count":0,"is_preprint":false},{"pmid":"38994720","id":"PMC_38994720","title":"Upregulation of the long noncoding RNA GJA9-MYCBP and PVT1 is a potential diagnostic biomarker for acute lymphoblastic leukemia.","date":"2024","source":"Cancer reports (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/38994720","citation_count":0,"is_preprint":false},{"pmid":"41724729","id":"PMC_41724729","title":"Domain-Level Interaction of FAP174 (MYCBP-1) and FAP147 (MYCBPAP) Proteins of the C2a Projection of Chlamydomonas Cilia.","date":"2026","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/41724729","citation_count":0,"is_preprint":false},{"pmid":"41325460","id":"PMC_41325460","title":"MYCBP interacts with Sakura and Otu and is essential for germline stem cell renewal and differentiation and oogenesis.","date":"2025","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41325460","citation_count":0,"is_preprint":false},{"pmid":"40631179","id":"PMC_40631179","title":"MYCBP interacts with Sakura and Otu and is essential for germline stem cell renewal and differentiation and oogenesis.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40631179","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16590,"output_tokens":2956,"usd":0.047055},"stage2":{"model":"claude-opus-4-6","input_tokens":6341,"output_tokens":3178,"usd":0.166733},"total_usd":0.213788,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"MYCBP (AMY-1) binds via its C-terminal region to the N-terminal transactivation domain (amino acids 58-148) of C-MYC, and stimulates E-box-dependent transcription by the MYC/Max complex without itself recognizing the E-box element.\",\n      \"method\": \"Co-immunoprecipitation, two-hybrid, transactivation reporter assay, FISH\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding mapped to specific domains, functional transcription assay, replicated in subsequent studies\",\n      \"pmids\": [\"9797456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MYCBP (AMY-1) localizes in the cytoplasm at low c-myc expression levels but translocates to the nucleus during S phase when c-myc expression is elevated, linking its nuclear translocation to cell-cycle-dependent changes in C-MYC levels.\",\n      \"method\": \"Transfection with immunofluorescence microscopy, cell-cycle analysis\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional correlation, single lab\",\n      \"pmids\": [\"9797456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MYCBP (AMY-1) binds in vitro and in vivo to the RII-binding region of AKAP149 and its testis-specific splicing variant S-AKAP84, and is localized to mitochondria in HeLa cells and sperm through this association.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, immunofluorescence/subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding + co-IP + localization, replicated in follow-up studies\",\n      \"pmids\": [\"11483602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MYCBP (AMY-1) competitively binds to the RII-binding region of AKAP95 (nucleus) and AKAP84 (cytoplasm) in a concentration-dependent manner, forms a ternary complex with RII, and prevents the PKA catalytic subunit from binding to the AKAP complex, thereby suppressing PKA activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, PKA activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding, co-IP, enzymatic activity assay; builds on prior study\",\n      \"pmids\": [\"12414807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MYCBP (AMY-1) binds to the testis-specific protein AAT-1alpha, and together with S-AKAP84/AKAP149 and RII forms a quaternary complex in the mitochondria; AAT-1alpha is phosphorylated by PKA in vivo and in vitro within this complex.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, colocalization, in vivo and in vitro phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, in vitro phosphorylation confirmed\",\n      \"pmids\": [\"12223483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MYCBP (AMY-1) binds to and colocalizes with the novel testis-specific protein AMAP-1, which is post-meiotically expressed in the testis, implicating MYCBP in spermatogenesis through this interaction.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP and colocalization without detailed functional dissection\",\n      \"pmids\": [\"12151104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of MYCBP (AMY-1) in K562 cells induces erythrocyte differentiation (elevated ε-globin mRNA, hemoglobin accumulation) and accelerates AraC-induced differentiation, demonstrating a role in cell differentiation independent of or distinct from c-MYC.\",\n      \"method\": \"Stable overexpression, RT-PCR for differentiation markers, hemoglobin assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with defined molecular readout, single lab\",\n      \"pmids\": [\"10639579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The MYCBP promoter is synergistically activated by Sp1 (required in all cell types) and GATA-1 (required specifically in K562 cells), as shown by deletion reporter assays, mobility shift assay confirming protein binding, and co-immunoprecipitation of Sp1 and GATA-1 in K562 cells.\",\n      \"method\": \"Luciferase reporter assay, EMSA (mobility shift assay), co-immunoprecipitation\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods defining transcriptional regulation, single lab\",\n      \"pmids\": [\"12620400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MYCBP (AMY-1) localizes to the trans-Golgi network (TGN) and nucleus; its TGN localization is mediated specifically through interaction with BIG2 (but not BIG1), a guanine-nucleotide exchange factor for ARFs, as demonstrated by RNAi knockdown of BIG2 displacing AMY-1 from the TGN.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, immunofluorescence localization, in vitro binding\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP + RNAi rescue + localization with functional link, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16866877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MYCBP forms a complex with Gli and Sufu in the absence of Hedgehog signaling but remains inactive; upon Hh pathway activation, Sufu/p66β dissociate from Gli, enabling MYCBP to promote Gli protein activity and Hh target gene expression. MYCBP positively regulates Hh signaling downstream of Patched, Smoothened, and the primary cilium.\",\n      \"method\": \"Proteomic/co-IP identification of Sufu-interacting proteins, chromatin immunoprecipitation (ChIP), cell-based reporter assays, zebrafish genetic epistasis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (proteomics, ChIP, cell assays, in vivo zebrafish epistasis), moderate evidence\",\n      \"pmids\": [\"25403183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EYA4 suppresses MYCBP expression by dephosphorylating β-catenin at Ser552, reducing its nuclear translocation and thereby inhibiting β-catenin/LEF1-driven transcription of MYCBP; siRNA rescue and MYCBP overexpression in EYA4-KO cells confirmed MYCBP acts downstream of EYA4 to control HCC cell proliferation and G2/M arrest.\",\n      \"method\": \"Phosphatase activity assay, western blot, siRNA knockdown/overexpression rescue, co-immunoprecipitation, luciferase reporter\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via rescue experiment + biochemical phosphatase assay, single lab\",\n      \"pmids\": [\"31385398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The circular RNA circ_0002669 directly binds MYCBP protein (identified by biotin pulldown and mass spectrometry) and protects it from ubiquitin-mediated proteasomal degradation, thereby stabilizing MYCBP protein levels and promoting c-MYC target gene expression (CCND1, c-Jun, CDK4) in osteosarcoma cells.\",\n      \"method\": \"Biotin pulldown, mass spectrometry, luciferase reporter assay, RNA immunoprecipitation, ubiquitination assay\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein binding confirmed by pull-down/MS, ubiquitination assay, single lab\",\n      \"pmids\": [\"38570856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Drosophila MYCBP physically associates with itself, Sakura, and Otu forming binary and ternary complexes; germline-specific depletion of mycbp disrupts Dpp/BMP signaling, causes aberrant bam expression, and leads to GSC loss and sterility; mycbp is also required for female-specific splicing of sex-lethal.\",\n      \"method\": \"Co-immunoprecipitation, null mutant analysis, germline-specific RNAi, signaling reporter assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP defining complexes + null mutant with multiple defined molecular phenotypes in Drosophila ortholog\",\n      \"pmids\": [\"41325460\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYCBP (AMY-1) is an 11-kDa protein that binds the N-terminal transactivation domain of C-MYC and stimulates E-box-dependent transcription; it also acts as a modulator of PKA signaling by associating with AKAPs (AKAP84/95/149) and the RII regulatory subunit to suppress PKA catalytic activity, localizes to mitochondria (via S-AKAP84), the trans-Golgi network (via BIG2), and nucleus in a context-dependent manner, and positively regulates Hedgehog signaling in the nucleus by enabling Gli activity upon Sufu/p66β dissociation—collectively placing MYCBP at the intersection of transcriptional regulation, cAMP/PKA signaling, membrane trafficking, and Hh pathway control.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MYCBP is a small adaptor protein that operates at the intersection of transcriptional regulation, cAMP/PKA signaling, membrane trafficking, and Hedgehog pathway control. It binds the N-terminal transactivation domain of C-MYC and stimulates E-box-dependent transcription without directly recognizing DNA, and its protein levels are stabilized by circ_0002669 through protection from ubiquitin-mediated degradation [PMID:9797456, PMID:38570856]. MYCBP associates with AKAPs (AKAP84, AKAP95, AKAP149) and the RII regulatory subunit of PKA, competitively excluding the PKA catalytic subunit to suppress PKA activity, and is directed to mitochondria via S-AKAP84 or to the trans-Golgi network via the ARF-GEF BIG2 [PMID:12414807, PMID:11483602, PMID:16866877]. In Hedgehog signaling, MYCBP resides in a nuclear complex with Gli and Sufu; upon pathway activation and Sufu/p66β dissociation, MYCBP promotes Gli-dependent target gene expression, and its Drosophila ortholog is required for germline stem cell maintenance and Dpp/BMP signaling [PMID:25403183, PMID:41325460].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying MYCBP as a direct C-MYC-binding partner established that an 11-kDa protein could stimulate MYC/Max-dependent transcription without itself recognizing DNA, raising the question of how it modulates transcription mechanistically.\",\n      \"evidence\": \"Co-immunoprecipitation, yeast two-hybrid mapping of binding domains, and E-box reporter assays in mammalian cells\",\n      \"pmids\": [\"9797456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural basis for how MYCBP enhances MYC transactivation\",\n        \"Whether MYCBP binds chromatin directly or solely through MYC is unresolved\",\n        \"Endogenous stoichiometry of the MYCBP-MYC complex unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating cell-cycle-dependent nuclear translocation of MYCBP during S phase linked its subcellular localization to C-MYC expression dynamics, suggesting regulated compartmentalization as a functional control mechanism.\",\n      \"evidence\": \"Immunofluorescence with cell-cycle synchronization in transfected cells\",\n      \"pmids\": [\"9797456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Nuclear import mechanism (NLS, carrier) not identified\",\n        \"Single overexpression system; endogenous protein not tracked\",\n        \"Functional consequence of nuclear translocation on specific MYC target genes not tested\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showing that MYCBP overexpression drives erythroid differentiation in K562 cells established a functional role beyond simple transcriptional coactivation, implicating it in lineage commitment.\",\n      \"evidence\": \"Stable overexpression with ε-globin RT-PCR and hemoglobin accumulation assays\",\n      \"pmids\": [\"10639579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the differentiation effect is MYC-dependent or independent was not resolved\",\n        \"Loss-of-function experiment not performed\",\n        \"Single cell line tested\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery that MYCBP binds the RII-binding region of AKAPs (AKAP149/S-AKAP84) and localizes to mitochondria through this interaction revealed a second, non-transcriptional function linked to cAMP/PKA scaffolding.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-IP, and immunofluorescence/subcellular fractionation in HeLa cells and sperm\",\n      \"pmids\": [\"11483602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of mitochondrial MYCBP on organelle biology not established\",\n        \"Whether MYCBP-AKAP and MYCBP-MYC interactions are mutually exclusive unknown\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that MYCBP competitively excludes the PKA catalytic subunit from AKAP/RII complexes defined a biochemical mechanism by which it suppresses PKA signaling, placing it as a negative modulator of cAMP-dependent phosphorylation.\",\n      \"evidence\": \"Co-IP, in vitro binding competition assays, and PKA enzymatic activity measurements\",\n      \"pmids\": [\"12414807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological targets of PKA suppression by MYCBP not identified\",\n        \"In vivo consequences of MYCBP-mediated PKA inhibition not tested in animal models\",\n        \"Structural basis for competitive exclusion not resolved\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of a quaternary complex (MYCBP/S-AKAP84/RII/AAT-1α) at mitochondria with PKA-dependent phosphorylation of AAT-1α provided the first candidate downstream event of MYCBP-scaffolded signaling in the testis.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, colocalization, in vivo and in vitro phosphorylation assays\",\n      \"pmids\": [\"12223483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional significance of AAT-1α phosphorylation unknown\",\n        \"Role of this complex in spermatogenesis not tested genetically\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that BIG2 (but not BIG1) recruits MYCBP to the trans-Golgi network expanded its compartment-specific functions to membrane trafficking, with BIG2 knockdown displacing MYCBP from the TGN.\",\n      \"evidence\": \"Co-IP, RNAi knockdown of BIG2, immunofluorescence localization, in vitro binding\",\n      \"pmids\": [\"16866877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"What MYCBP does at the TGN functionally (e.g., vesicle budding, ARF regulation) is not known\",\n        \"Whether TGN and mitochondrial pools of MYCBP are independently regulated is unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Proteomic identification of MYCBP in the Sufu/Gli complex and demonstration that Hh-induced Sufu/p66β dissociation licenses MYCBP to promote Gli activity established MYCBP as a positive nuclear effector of Hedgehog signaling downstream of Smoothened.\",\n      \"evidence\": \"Sufu interactome by co-IP/proteomics, ChIP, cell-based Hh reporter assays, zebrafish epistasis experiments\",\n      \"pmids\": [\"25403183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How MYCBP biochemically activates Gli (coactivator recruitment, chromatin remodeling) is unresolved\",\n        \"Whether MYCBP's MYC-coactivator and Hh-effector roles are coordinated or independent is unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placing MYCBP transcription under β-catenin/LEF1 control, suppressed by EYA4-mediated dephosphorylation of β-catenin, connected Wnt signaling to MYCBP expression and revealed its role in hepatocellular carcinoma proliferation.\",\n      \"evidence\": \"Phosphatase assay, siRNA knockdown/overexpression rescue, co-IP, luciferase reporter in HCC cells\",\n      \"pmids\": [\"31385398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Wnt-driven MYCBP upregulation acts through MYC, Hh, or PKA pathways in HCC was not dissected\",\n        \"Single cancer type; generalizability not established\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that circ_0002669 binds MYCBP protein and shields it from ubiquitin-mediated proteasomal degradation revealed a post-translational stabilization mechanism that amplifies MYC target gene expression in osteosarcoma.\",\n      \"evidence\": \"Biotin pulldown, mass spectrometry, RNA immunoprecipitation, ubiquitination assay in osteosarcoma cells\",\n      \"pmids\": [\"38570856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The E3 ubiquitin ligase targeting MYCBP is not identified\",\n        \"Whether circRNA-mediated stabilization operates in non-cancer contexts is unknown\",\n        \"Single study; independent confirmation needed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic analysis in Drosophila revealed that MYCBP forms complexes with Sakura and Otu and is essential for germline stem cell maintenance via Dpp/BMP signaling, bam regulation, and sex-lethal splicing, establishing conserved roles in stem cell biology and RNA processing.\",\n      \"evidence\": \"Co-IP defining binary/ternary complexes, null mutant and germline-specific RNAi in Drosophila, signaling reporter assays\",\n      \"pmids\": [\"41325460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the Sakura/Otu complex is conserved in mammals is unknown\",\n        \"Mechanism by which MYCBP influences sex-lethal splicing not defined\",\n        \"Whether BMP-pathway role in Drosophila GSCs reflects a mammalian Hedgehog or TGFβ function is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYCBP's distinct interaction modalities — MYC coactivation, AKAP/PKA scaffolding, BIG2-mediated TGN targeting, and Gli activation — are coordinated within a single cell, and which E3 ligase targets MYCBP for degradation, remain open mechanistic questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of MYCBP alone or in any complex\",\n        \"Conditional knockout phenotype in mammalian systems not reported\",\n        \"Integration of multiple signaling roles into a unified model lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 8, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 9, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 9, 11]}\n    ],\n    \"complexes\": [\n      \"AKAP/RII/MYCBP ternary complex\",\n      \"Sufu/Gli/MYCBP complex\",\n      \"Sakura/Otu/MYCBP complex\"\n    ],\n    \"partners\": [\n      \"MYC\",\n      \"AKAP1\",\n      \"AKAP2\",\n      \"PRKAR2A\",\n      \"ARFGEF2\",\n      \"SUFU\",\n      \"GLI1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}