{"gene":"MAPKBP1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2017,"finding":"MAPKBP1 is recruited to mitotic spindle poles (MSPs) during early phases of mitosis, where it colocalizes with its paralog WDR62; disease-causing mutations compromise this recruitment and/or its interaction with JNK2 or WDR62. Additionally, MAPKBP1 is absent from the primary cilium and fibroblasts from affected individuals show no ciliogenesis defects, indicating cilia-independent function. Knockdown of Mapkbp1 in murine cell lines increased DNA damage response signaling.","method":"Immunofluorescence, co-immunoprecipitation, patient fibroblast analysis, siRNA knockdown in murine cell lines","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IF, Co-IP, KD with defined phenotype) across patient and cell-line models, replicated across multiple families","pmids":["28089251"],"is_preprint":false},{"year":2013,"finding":"MAPKBP1 contains a C-terminal loop-helix dimerization domain (conserved with WDR62) that is necessary and sufficient for homodimerization; MAPKBP1 also heterodimerizes with WDR62. Endogenous WDR62 and MAPKBP1 co-localize to stress granules following arsenite treatment but not during mitosis.","method":"Sequence conservation analysis, co-immunoprecipitation, immunofluorescence, arsenite-stress assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and immunofluorescence in single lab with two orthogonal methods","pmids":["23341463"],"is_preprint":false},{"year":2020,"finding":"Truncation of MAPKBP1's C-terminal coiled-coil domains abolishes homodimerization and heterodimerization with WDR62, and results in loss of microtubule binding and severely reduced recruitment to centriolar structures in a cell-cycle-dependent manner. Wild-type MAPKBP1 shows centrosomal, basal body, and microtubule association. Mutant and wild-type proteins had no dominant negative effects on each other upon co-expression.","method":"Co-immunoprecipitation, fluorescence microscopy, exome sequencing with patient-derived deletion constructs, HeLa and IMCD cell overexpression","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, direct localization with functional consequence, multiple cell types, patient-derived constructs with mutagenesis equivalent (splice-site truncations)","pmids":["32505465"],"is_preprint":false},{"year":2018,"finding":"METTL8 interacts with Mapkbp1 mRNA and inhibits its translation, thereby suppressing JNK signaling and enhancing mouse ESC differentiation. This places MAPKBP1 protein levels as downstream of METTL8-mediated translational regulation in the JNK pathway.","method":"RNA immunoprecipitation (METTL8–mRNA interaction), translational reporter assay, JNK activity measurement, ESC differentiation assay","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP showing mRNA interaction and functional JNK readout, single lab with two orthogonal approaches","pmids":["29706498"],"is_preprint":false},{"year":2025,"finding":"Endogenous MAPKBP1 localizes to ciliary basal bodies, and this localization is lost in NPHP20 patient cells and MAPKBP1 knockdown cells, accompanied by shortened primary cilia. JNK activation leads to disassembly of cilia concomitantly with MAPKBP1 dissociation from the basal body. The activation status of JNK determines centriolar association or dissociation of MAPKBP1 via distinct protein domains. Pharmacological disruption of the JNK target actin restores ciliary length in NPHP20 patients, placing MAPKBP1 upstream of actin-mediated ciliary length regulation in JNK signaling.","method":"Overexpression of patient variants, patient fibroblast analysis, MAPKBP1 knockdown cells, immunofluorescence, pharmacological JNK/actin manipulation with ciliary length readout","journal":"Kidney international reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD, OE of patient variants, pharmacological rescue) in single study; not yet independently replicated","pmids":["40814602"],"is_preprint":false},{"year":2025,"finding":"Suppression of MAPKBP1 inhibited X-ray-induced cell apoptosis in HEK293T cells, indicating a role for MAPKBP1 in the DNA damage-induced apoptotic response downstream of translational upregulation via uORF bypass.","method":"Ribosome profiling, siRNA knockdown, cell apoptosis assay after X-ray irradiation","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown assay, no pathway placement beyond MAPK signaling enrichment","pmids":["39755339"],"is_preprint":false}],"current_model":"MAPKBP1 is a JNK pathway scaffold protein that localizes to mitotic spindle poles and centrosomal/basal body structures in a cell-cycle-dependent manner via its C-terminal coiled-coil dimerization domain; it homodimerizes and heterodimerizes with paralog WDR62, interacts with JNK2, and the activation status of JNK regulates its centriolar association—with JNK activation driving dissociation from the basal body and cilia disassembly—while loss of MAPKBP1 causes impaired JNK trafficking, shortened primary cilia, and increased DNA damage signaling, collectively contributing to cilia-independent nephronophthisis."},"narrative":{"mechanistic_narrative":"MAPKBP1 is a JNK-pathway scaffold protein that links JNK signaling to centriolar/basal-body biology and to the regulation of primary cilia, and whose disruption causes a cilia-independent form of nephronophthisis (NPHP20) [PMID:28089251, PMID:40814602]. It dimerizes through a C-terminal loop-helix/coiled-coil domain that is necessary and sufficient for homodimerization and also mediates heterodimerization with its paralog WDR62 [PMID:23341463]; truncation of this C-terminal region abolishes both dimerization and microtubule binding and severely reduces cell-cycle-dependent recruitment to centriolar structures [PMID:32505465]. Wild-type MAPKBP1 associates with centrosomes, basal bodies, and microtubules and is recruited to mitotic spindle poles where it colocalizes with WDR62 [PMID:28089251, PMID:32505465], while endogenous MAPKBP1 also localizes to ciliary basal bodies in a manner controlled by JNK activation status: JNK activation drives MAPKBP1 dissociation from the basal body and concomitant cilia disassembly, placing MAPKBP1 upstream of JNK/actin-mediated control of ciliary length [PMID:40814602]. Disease-causing mutations compromise spindle-pole recruitment and JNK2/WDR62 interactions, and loss of MAPKBP1 produces shortened primary cilia and elevated DNA damage response signaling without overt ciliogenesis defects in patient fibroblasts [PMID:28089251, PMID:40814602]. MAPKBP1 protein abundance is itself a regulated node: METTL8 binds Mapkbp1 mRNA and represses its translation to suppress JNK signaling [PMID:29706498].","teleology":[{"year":2013,"claim":"Established the structural basis of MAPKBP1 self-association by identifying a C-terminal dimerization domain mediating homodimerization and WDR62 heterodimerization, defining MAPKBP1 as a WDR62-family scaffold.","evidence":"Sequence conservation analysis, reciprocal co-immunoprecipitation, and immunofluorescence including arsenite stress-granule assay","pmids":["23341463"],"confidence":"Medium","gaps":["No high-resolution structure of the dimerization interface","Functional role of stress-granule co-localization with WDR62 not defined","JNK-relevant consequences of dimerization not tested"]},{"year":2017,"claim":"Connected MAPKBP1 to human disease by showing it is recruited to mitotic spindle poles with WDR62 and that patient mutations disrupt this recruitment and JNK2/WDR62 interactions, while demonstrating the disease mechanism is cilia-independent.","evidence":"Immunofluorescence, co-immunoprecipitation, patient fibroblast analysis, and siRNA knockdown in murine cell lines","pmids":["28089251"],"confidence":"High","gaps":["Mechanism linking spindle-pole localization to nephronophthisis unclear","Cause of increased DNA damage signaling on knockdown not resolved","Did not reconcile cilia-independent claim with later basal-body findings"]},{"year":2018,"claim":"Placed MAPKBP1 protein levels under upstream control by showing METTL8 binds its mRNA and represses translation to dampen JNK signaling, identifying a regulatory input governing pathway output.","evidence":"RNA immunoprecipitation, translational reporter assay, JNK activity measurement, and ESC differentiation assay","pmids":["29706498"],"confidence":"Medium","gaps":["Mechanism of translational repression not defined at nucleotide level","Direct effect of MAPKBP1 protein on JNK activity not isolated","Relevance to centriolar/ciliary functions untested"]},{"year":2020,"claim":"Defined the C-terminal coiled-coil domains as required for microtubule binding and cell-cycle-dependent centriolar/basal-body recruitment, linking the dimerization module to subcellular targeting and disease.","evidence":"Reciprocal co-immunoprecipitation, fluorescence microscopy, and patient-derived deletion constructs in HeLa and IMCD cells","pmids":["32505465"],"confidence":"High","gaps":["Direct microtubule-binding region within the protein not mapped","How dimerization couples to centriolar recruitment mechanistically unknown","No dominant-negative interaction between mutant and wild-type"]},{"year":2025,"claim":"Integrated MAPKBP1 into JNK-dependent ciliary length control, showing JNK activation status governs basal-body association via distinct domains and that MAPKBP1 acts upstream of actin-mediated ciliary regulation.","evidence":"Patient-variant overexpression, knockdown, immunofluorescence, and pharmacological JNK/actin manipulation with ciliary length readout","pmids":["40814602"],"confidence":"Medium","gaps":["Single study, not independently replicated","Identity of the distinct domains mediating JNK-dependent association vs dissociation not fully resolved","Direct biochemical link between MAPKBP1 and actin regulation unestablished"]},{"year":2025,"claim":"Linked MAPKBP1 to the DNA-damage-induced apoptotic response, showing its suppression blunts X-ray-induced apoptosis downstream of uORF-bypass translational upregulation.","evidence":"Ribosome profiling, siRNA knockdown, and apoptosis assay after X-ray irradiation in HEK293T cells","pmids":["39755339"],"confidence":"Low","gaps":["Single-lab single knockdown assay without orthogonal validation","No pathway placement beyond MAPK signaling enrichment","Mechanistic connection to JNK scaffold function unclear"]},{"year":null,"claim":"How JNK activity, MAPKBP1 dimerization, microtubule/centriolar targeting, and DNA-damage signaling are mechanistically integrated into a single pathway driving nephronophthisis remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of MAPKBP1 in complex with JNK2 or WDR62","Direct kinase/substrate relationships in the scaffolded JNK module undefined","Causal chain from MAPKBP1 loss to elevated DNA damage signaling unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["WDR62","JNK2","METTL8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60336","full_name":"Mitogen-activated protein kinase-binding protein 1","aliases":["JNK-binding protein 1","JNKBP-1"],"length_aa":1514,"mass_kda":163.8,"function":"Negative regulator of NOD2 function. It down-regulates NOD2-induced processes such as activation of NF-kappa-B signaling, IL8 secretion and antibacterial response (PubMed:22700971). Involved in JNK signaling pathway (By similarity)","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/O60336/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAPKBP1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MAP4","stoichiometry":0.2},{"gene":"PMVK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAPKBP1","total_profiled":1310},"omim":[{"mim_id":"617271","title":"NEPHRONOPHTHISIS 20; NPHP20","url":"https://www.omim.org/entry/617271"},{"mim_id":"616786","title":"MITOGEN-ACTIVATED PROTEIN KINASE-BINDING PROTEIN 1; MAPKBP1","url":"https://www.omim.org/entry/616786"},{"mim_id":"256100","title":"NEPHRONOPHTHISIS 1; NPHP1","url":"https://www.omim.org/entry/256100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoli rim","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":69.6}],"url":"https://www.proteinatlas.org/search/MAPKBP1"},"hgnc":{"alias_symbol":["KIAA0596","NPHP20"],"prev_symbol":[]},"alphafold":{"accession":"O60336","domains":[{"cath_id":"2.130.10.10","chopping":"616-745","consensus_level":"medium","plddt":93.6112,"start":616,"end":745}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60336","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60336-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60336-F1-predicted_aligned_error_v6.png","plddt_mean":62.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAPKBP1","jax_strain_url":"https://www.jax.org/strain/search?query=MAPKBP1"},"sequence":{"accession":"O60336","fasta_url":"https://rest.uniprot.org/uniprotkb/O60336.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60336/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60336"}},"corpus_meta":[{"pmid":"28089251","id":"PMC_28089251","title":"Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis.","date":"2017","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28089251","citation_count":28,"is_preprint":false},{"pmid":"23341463","id":"PMC_23341463","title":"Identification and analysis of a novel dimerization domain shared by various members of c-Jun N-terminal kinase (JNK) scaffold proteins.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23341463","citation_count":18,"is_preprint":false},{"pmid":"35140360","id":"PMC_35140360","title":"Comprehensive genetic analysis using next-generation sequencing for the diagnosis of nephronophthisis-related ciliopathies in the Japanese population.","date":"2022","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35140360","citation_count":17,"is_preprint":false},{"pmid":"29706498","id":"PMC_29706498","title":"The STAT3 Target Mettl8 Regulates Mouse ESC Differentiation via Inhibiting the JNK Pathway.","date":"2018","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29706498","citation_count":15,"is_preprint":false},{"pmid":"32505465","id":"PMC_32505465","title":"Novel nephronophthisis-associated variants reveal functional importance of MAPKBP1 dimerization for centriolar recruitment.","date":"2020","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/32505465","citation_count":8,"is_preprint":false},{"pmid":"37644229","id":"PMC_37644229","title":"Ocular manifestations of renal ciliopathies.","date":"2023","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37644229","citation_count":6,"is_preprint":false},{"pmid":"22162401","id":"PMC_22162401","title":"Evaluation of conserved and ultra-conserved non-genic sequences in chromosome 15q15-linked periodic catatonia.","date":"2011","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22162401","citation_count":4,"is_preprint":false},{"pmid":"31312113","id":"PMC_31312113","title":"Hypertonic solution-induced preconditioning reduces inflammation and mortality rate.","date":"2019","source":"Journal of inflammation (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31312113","citation_count":1,"is_preprint":false},{"pmid":"40814602","id":"PMC_40814602","title":"Structure-Activity Analysis Reveals Perturbed Cilia-Jun N-Terminal Kinase Signaling in MAPKBP1-Associated Kidney Disease.","date":"2025","source":"Kidney international reports","url":"https://pubmed.ncbi.nlm.nih.gov/40814602","citation_count":0,"is_preprint":false},{"pmid":"39755339","id":"PMC_39755339","title":"Ribosome profiling reveals dynamic translational landscape following X-ray irradiation.","date":"2025","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39755339","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7411,"output_tokens":1710,"usd":0.023942,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8506,"output_tokens":2677,"usd":0.054727,"stage2_stop_reason":"end_turn"},"total_usd":0.078669,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"MAPKBP1 is recruited to mitotic spindle poles (MSPs) during early phases of mitosis, where it colocalizes with its paralog WDR62; disease-causing mutations compromise this recruitment and/or its interaction with JNK2 or WDR62. Additionally, MAPKBP1 is absent from the primary cilium and fibroblasts from affected individuals show no ciliogenesis defects, indicating cilia-independent function. Knockdown of Mapkbp1 in murine cell lines increased DNA damage response signaling.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, patient fibroblast analysis, siRNA knockdown in murine cell lines\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IF, Co-IP, KD with defined phenotype) across patient and cell-line models, replicated across multiple families\",\n      \"pmids\": [\"28089251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAPKBP1 contains a C-terminal loop-helix dimerization domain (conserved with WDR62) that is necessary and sufficient for homodimerization; MAPKBP1 also heterodimerizes with WDR62. Endogenous WDR62 and MAPKBP1 co-localize to stress granules following arsenite treatment but not during mitosis.\",\n      \"method\": \"Sequence conservation analysis, co-immunoprecipitation, immunofluorescence, arsenite-stress assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and immunofluorescence in single lab with two orthogonal methods\",\n      \"pmids\": [\"23341463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Truncation of MAPKBP1's C-terminal coiled-coil domains abolishes homodimerization and heterodimerization with WDR62, and results in loss of microtubule binding and severely reduced recruitment to centriolar structures in a cell-cycle-dependent manner. Wild-type MAPKBP1 shows centrosomal, basal body, and microtubule association. Mutant and wild-type proteins had no dominant negative effects on each other upon co-expression.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy, exome sequencing with patient-derived deletion constructs, HeLa and IMCD cell overexpression\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, direct localization with functional consequence, multiple cell types, patient-derived constructs with mutagenesis equivalent (splice-site truncations)\",\n      \"pmids\": [\"32505465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"METTL8 interacts with Mapkbp1 mRNA and inhibits its translation, thereby suppressing JNK signaling and enhancing mouse ESC differentiation. This places MAPKBP1 protein levels as downstream of METTL8-mediated translational regulation in the JNK pathway.\",\n      \"method\": \"RNA immunoprecipitation (METTL8–mRNA interaction), translational reporter assay, JNK activity measurement, ESC differentiation assay\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP showing mRNA interaction and functional JNK readout, single lab with two orthogonal approaches\",\n      \"pmids\": [\"29706498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endogenous MAPKBP1 localizes to ciliary basal bodies, and this localization is lost in NPHP20 patient cells and MAPKBP1 knockdown cells, accompanied by shortened primary cilia. JNK activation leads to disassembly of cilia concomitantly with MAPKBP1 dissociation from the basal body. The activation status of JNK determines centriolar association or dissociation of MAPKBP1 via distinct protein domains. Pharmacological disruption of the JNK target actin restores ciliary length in NPHP20 patients, placing MAPKBP1 upstream of actin-mediated ciliary length regulation in JNK signaling.\",\n      \"method\": \"Overexpression of patient variants, patient fibroblast analysis, MAPKBP1 knockdown cells, immunofluorescence, pharmacological JNK/actin manipulation with ciliary length readout\",\n      \"journal\": \"Kidney international reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD, OE of patient variants, pharmacological rescue) in single study; not yet independently replicated\",\n      \"pmids\": [\"40814602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Suppression of MAPKBP1 inhibited X-ray-induced cell apoptosis in HEK293T cells, indicating a role for MAPKBP1 in the DNA damage-induced apoptotic response downstream of translational upregulation via uORF bypass.\",\n      \"method\": \"Ribosome profiling, siRNA knockdown, cell apoptosis assay after X-ray irradiation\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown assay, no pathway placement beyond MAPK signaling enrichment\",\n      \"pmids\": [\"39755339\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAPKBP1 is a JNK pathway scaffold protein that localizes to mitotic spindle poles and centrosomal/basal body structures in a cell-cycle-dependent manner via its C-terminal coiled-coil dimerization domain; it homodimerizes and heterodimerizes with paralog WDR62, interacts with JNK2, and the activation status of JNK regulates its centriolar association—with JNK activation driving dissociation from the basal body and cilia disassembly—while loss of MAPKBP1 causes impaired JNK trafficking, shortened primary cilia, and increased DNA damage signaling, collectively contributing to cilia-independent nephronophthisis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAPKBP1 is a JNK-pathway scaffold protein that links JNK signaling to centriolar/basal-body biology and to the regulation of primary cilia, and whose disruption causes a cilia-independent form of nephronophthisis (NPHP20) [#0, #4]. It dimerizes through a C-terminal loop-helix/coiled-coil domain that is necessary and sufficient for homodimerization and also mediates heterodimerization with its paralog WDR62 [#1]; truncation of this C-terminal region abolishes both dimerization and microtubule binding and severely reduces cell-cycle-dependent recruitment to centriolar structures [#2]. Wild-type MAPKBP1 associates with centrosomes, basal bodies, and microtubules and is recruited to mitotic spindle poles where it colocalizes with WDR62 [#0, #2], while endogenous MAPKBP1 also localizes to ciliary basal bodies in a manner controlled by JNK activation status: JNK activation drives MAPKBP1 dissociation from the basal body and concomitant cilia disassembly, placing MAPKBP1 upstream of JNK/actin-mediated control of ciliary length [#4]. Disease-causing mutations compromise spindle-pole recruitment and JNK2/WDR62 interactions, and loss of MAPKBP1 produces shortened primary cilia and elevated DNA damage response signaling without overt ciliogenesis defects in patient fibroblasts [#0, #4]. MAPKBP1 protein abundance is itself a regulated node: METTL8 binds Mapkbp1 mRNA and represses its translation to suppress JNK signaling [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the structural basis of MAPKBP1 self-association by identifying a C-terminal dimerization domain mediating homodimerization and WDR62 heterodimerization, defining MAPKBP1 as a WDR62-family scaffold.\",\n      \"evidence\": \"Sequence conservation analysis, reciprocal co-immunoprecipitation, and immunofluorescence including arsenite stress-granule assay\",\n      \"pmids\": [\"23341463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the dimerization interface\", \"Functional role of stress-granule co-localization with WDR62 not defined\", \"JNK-relevant consequences of dimerization not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected MAPKBP1 to human disease by showing it is recruited to mitotic spindle poles with WDR62 and that patient mutations disrupt this recruitment and JNK2/WDR62 interactions, while demonstrating the disease mechanism is cilia-independent.\",\n      \"evidence\": \"Immunofluorescence, co-immunoprecipitation, patient fibroblast analysis, and siRNA knockdown in murine cell lines\",\n      \"pmids\": [\"28089251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking spindle-pole localization to nephronophthisis unclear\", \"Cause of increased DNA damage signaling on knockdown not resolved\", \"Did not reconcile cilia-independent claim with later basal-body findings\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed MAPKBP1 protein levels under upstream control by showing METTL8 binds its mRNA and represses translation to dampen JNK signaling, identifying a regulatory input governing pathway output.\",\n      \"evidence\": \"RNA immunoprecipitation, translational reporter assay, JNK activity measurement, and ESC differentiation assay\",\n      \"pmids\": [\"29706498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of translational repression not defined at nucleotide level\", \"Direct effect of MAPKBP1 protein on JNK activity not isolated\", \"Relevance to centriolar/ciliary functions untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the C-terminal coiled-coil domains as required for microtubule binding and cell-cycle-dependent centriolar/basal-body recruitment, linking the dimerization module to subcellular targeting and disease.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, fluorescence microscopy, and patient-derived deletion constructs in HeLa and IMCD cells\",\n      \"pmids\": [\"32505465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct microtubule-binding region within the protein not mapped\", \"How dimerization couples to centriolar recruitment mechanistically unknown\", \"No dominant-negative interaction between mutant and wild-type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated MAPKBP1 into JNK-dependent ciliary length control, showing JNK activation status governs basal-body association via distinct domains and that MAPKBP1 acts upstream of actin-mediated ciliary regulation.\",\n      \"evidence\": \"Patient-variant overexpression, knockdown, immunofluorescence, and pharmacological JNK/actin manipulation with ciliary length readout\",\n      \"pmids\": [\"40814602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, not independently replicated\", \"Identity of the distinct domains mediating JNK-dependent association vs dissociation not fully resolved\", \"Direct biochemical link between MAPKBP1 and actin regulation unestablished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked MAPKBP1 to the DNA-damage-induced apoptotic response, showing its suppression blunts X-ray-induced apoptosis downstream of uORF-bypass translational upregulation.\",\n      \"evidence\": \"Ribosome profiling, siRNA knockdown, and apoptosis assay after X-ray irradiation in HEK293T cells\",\n      \"pmids\": [\"39755339\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab single knockdown assay without orthogonal validation\", \"No pathway placement beyond MAPK signaling enrichment\", \"Mechanistic connection to JNK scaffold function unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How JNK activity, MAPKBP1 dimerization, microtubule/centriolar targeting, and DNA-damage signaling are mechanistically integrated into a single pathway driving nephronophthisis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of MAPKBP1 in complex with JNK2 or WDR62\", \"Direct kinase/substrate relationships in the scaffolded JNK module undefined\", \"Causal chain from MAPKBP1 loss to elevated DNA damage signaling unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WDR62\", \"JNK2\", \"METTL8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}